DEPARTMENT OF HEALTH AND HUMAN SERVICES

UNITED STATES FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE

Monday, June 6, 2005

8:00 a.m.

5600 Fishers Lane

Room 1066

Rockville, Maryland

P A R T I C I P A N T S

Erik R. Swenson, M.D., Chairman

Teresa Watkins, R.Ph., Executive Secretary

MEMBERS:

Mark L. Brantly, M.D.

Steven E. Gay, M.D., M.S.

I. Marc Moss, M.D.

Calman P. Prussin, M.D.

Theodore F. Reiss, M.D., Industry Representative

Karen Schell, RRT, Consumer Representative

David A. Schoenfeld, Ph.D.

SGE CONSULTANTS AND GUESTS (VOTING):

Jeffrey S. Barrett, Ph.D.

Lawrence Hunsicker, M.D.

Allan R. Sampson, Ph.D.

Jurgen Venitz, M.D., Ph.D.

Mary Lou Drittler, SGE Patient Representative

GOVERNMENT EMPLOYEES (VOTING):

James Burdick, M.D.

Roslyn B. Mannon, M.D.

Michael A. Proschan, Ph.D.

John Tisdale, M.D.

FDA STAFF:

Mark J. Goldberger, M.D., M.P.H.

Renata Albrecht, M.D.

Marc Cavaille-Coll, Ph.D.

Arturo Hernandez, M.D.

Jyoti Zalkikar, Ph.D.

C O N T E N T S

Call to Order and Opening Remarks,

Erik R. Swenson, M.D. 4

Conflict of Interest Statement,

Teresa A. Watkins, R.Ph. 7

FDA Introductory Remarks,

Renata Albrecht, M.D. 8

Sponsor Presentation:

Introduction, Michael Scaife, Ph.D. 14

Current State of Lung Transplantation,

Jeffrey Golden, M.D., University of

California, San Francisco 20

Clinical Evidence of Efficacy and Safety,

Sarah Noonberg, M.D., Ph.D. 28

Statistical Considerations,

Ronald W. Helms, Ph.D.,

Rho, Inc.; University of North Carolina 59

Safety and Benefit-Risk,

Stephen Dilly, M.D., Ph.D. 65

Questions from the Panel 70

FDA Presentation:

Overview of Clinical Trial Efficacy and

Safety Evaluation Discussion of Analysis,

Arturo Hernandez, M.D. 88

Safety Considerations and Conclusions,

Marc Cavaille-Coll, M.D., Ph.D. 105

Statistical Evaluation,

Jyoti Zalkikar, Ph.D. 111

Questions from the Panel (Continued) 121

C O N T E N T S (Continued)

Open Public Hearing:

Esther Suss, Ph.D. 151

John C. Sullivan 156

Bill Stein 158

Renee Moeller 162

Charge to the Committee, Renata Albrecht, M.D. 163

Committee Discussion and Vote 168

P R O C E E D I N G S

Call to Order

DR. SWENSON: Good morning, everyone. I

am Dr. Erik Swenson, from the University of

Washington, and I will be chairing this session.

This is the meeting of the Pulmonary and Allergy

Drugs Advisory Committee and today we are going to

be discussing inhaled cyclosporine, a product to be

presented by Chiron.

Let me begin with just a few items to keep

us on schedule and for organizational purposes.

One, I would request that everyone with cell

phones, please turn them off or at least down to

some vibrating or some innocuous mode. Then, we

will go around and introduce everyone here at the

table. I would ask that when you are questioning

anything during this meeting to please identify

yourself first. The transcriber will need to know

who is speaking. We have microphones here. All

you need to do is simply push down "talk" to go

ahead and be heard but, please, turn it off when

you have finished. If we get more than three

microphones on at one time things get confusing.

Without any further ado, I am going to

turn the meeting over to Dr. Teresa Watkins for

some introductory comments.

Introduction of the Committee

DR. WATKINS: Let's first go around the

table, starting with Dr. Reiss, if you will

introduce yourself and your affiliations, please?

DR. REISS: My name is Ted Reiss. I am

vice president of clinical research at Merck

Research Labs. I am the non-voting industry

representative.

DR. BRANTLY: My name is Mark Brantly. I

am from the University of Florida. I am a

professor of medicine.

DR. TISDALE: My name is John Tisdale and

I am in the intramural program of NIDDK.

DR. PRUSSIN: My name is Calman Prussin.

I am a clinical investigator with National

Institute of Allergy and Infectious Diseases.

DR. MANNON: I am Roslyn Mannon and I am a

transplant nephrologist and medical director of the

intramural solid organ transplant program at NIDDK.

DR. GAY: I am Steven Gay, assistant

professor at the University of Michigan, associate

director of the lung transplant program and

director of clinical support services.

DR. HUNSICKER: I am Larry Hunsicker, from

the University of Iowa. I am a transplant

nephrologist and professor of medicine, and I am a

member of the Chemical Immunosuppression Advisory

Committee but guesting on this one.

DR. VENITZ: I am Jurgen Venitz. I am a

clinical pharmacologist and associate professor at

Virginia Commonwealth University.

MS. DRITTLER: I am Mary Lou Drittler. I

am a lung transplant recipient and I am a patient

representative from here, in Silver Spring.

DR. BURDICK: I am Jim Burdick. I am

director of the Division of Transplantation and

Healthcare System, HRSA and a transplant surgeon.

DR. MOSS: I am Mark Moss. I am an

associate professor of medicine at Emory University

and section chief at Grady Memorial Hospital.

DR. BARRETT: I am Jeff Barrett. I am a

clinical pharmacologist from the University of

Pennsylvania and Children's Hospital of

Philadelphia.

DR. PROSCHAN: I am Mike Proschan and I am

a statistician from the National Heart, Lung and

Blood Institute.

DR. SCHOENFELD: I am David Schoenfeld. I

am a biostatistician and professor of medicine at

Harvard Medical School and Massachusetts General

Hospital.

DR. SAMPSON: I am Allan Sampson,

professor of statistics, Department of Statistics

at the University of Pittsburgh.

MS. SCHELL: I am Karen Schell. I am a

respiratory therapist from Emporia Kansas, and I am

the consumer representative.

DR. CAVAILLE-COLL: I am Marc

Cavaille-Coll, medical team leader, Division of

Special Pathogen and Immunologic Drug Products.

DR. ALBRECHT: I am Renata Albrecht,

director, Division of Special Pathogen and

Immunologic Drug Products.

DR. HERNANDEZ: I am Arturo Hernandez, a

medical reviewer for FDA, Division of Special

Pathogens and Immunologic Drug Products, and I am a

transplant surgeon.

Conflict of Interest Statement

DR. WATKINS: With that, thank you.

Welcome everyone. I am now going to now read the

conflict of interest statement.

The following announcement addresses the

issue of conflict of interest with regard to this

meeting and is made a part of the record to

preclude even the appearance of such at this

meeting.

Based on the submitted agenda for the

meeting and all financial interests reported by the

committee participants, it has been determined that

all interests in firms regulated by the Center for

Drug Evaluation and Research present no potential

for an appearance of a conflict of interest at this

meeting.

With respect to FDA's invited industry

representative, we would like to disclose that Dr.

Theodore Reiss is participating in this meeting as

a non-voting industry representative acting on

behalf of regulated industry. Dr. Reiss' role on

this committee is to represent industry interests

in general and not any one particular company. Dr.

Reiss is employed by Merck.

In the event that the discussions involve

any other products or firms not already on the

agenda for which an FDA participant has a financial

interest, the participants are aware of the need to

exclude themselves from such involvement and their

exclusion will be noted for the record.

With respect to all other participants, we

ask in the interest of fairness that they address

any current or previous financial involvement with

any firms whose products they may wish to comment

upon. Thank you. With that, we will have opening

remarks from Dr. Albrecht.

FDA Introductory Remarks

DR. ALBRECHT: Thank you, Dr. Watkins.

Good morning, everybody. On behalf of the Division

of Special Pathogen and Immunologic Drug Products

and the Office of Drug Evaluation IV, I would like

to welcome everyone to today's meeting.

We wish to thank the members of the

Pulmonary Advisory Committee, the Chair, Dr.

Swenson, and our consultants for taking the time

out of their schedules to come to Rockville and

join us here to discuss this application. I also

wish to express our appreciation to Chiron and the

investigators for the time and effort that they

have put into developing this drug product and to

the Chiron staff for their willingness and

preparation for this advisory committee meeting. I

would also like to recognize the dedication of the

Division staff and the long hours they have put in

for reviewing this application.

Let me speak briefly about this new drug

application for cyclosporine inhalational solution

and why we are bringing this application to the

advisory committee. Could I have someone run the

slides? I apologize, there are some slides that go

with this presentation so that you may follow

along.

Let me continue. There are currently no

FDA-approved products for the prevention of chronic

rejection in patients with lung allografts. There

are approximately 1100 transplants done in the U.S.

annually and the survival at five years is lower

than survival in other organ transplants such as

heart, kidney or liver transplants. Prevention of

rejection and increase in survival are critical

and, therefore, there is a clear need for safe and

effective therapy.

Next slide. Chiron has submitted the NDA

for Pulminiq and requested that the cyclosporine

inhalational solution be approved for the increase

in survival and prevention of chronic rejection in

lung transplant patients. The drug development

program and the NDA for this product are not

conventional. Unlike applications for

immunosuppressants in kidney, heart of liver

transplants for example, this NDA contained results

from one single Phase II study conducted at one

center. This trial enrolled 66 patients out of a

planned 136 patients. However, we learned that

there was a survival advantage, 88 percent survival

in patients who received aerosolized cyclosporine

plus a tacrolimus-based systemic immunosuppressive

regimen compared to 53 percent survival in patients

receiving aerosolized propylene glycol vehicle in

addition to a tacrolimus-based systemic

immunosuppressive regimen.

Therefore, the agency agreed to file and

review this NDA application. Based on the NDA

review of the information in the application, we

were unable to conclude that the observed

difference in survival and chronic rejection was

due to study drug. Therefore, we determined it was

important to bring this application to the advisory

committee for the following reasons:

This would represent the first drug for

immunosuppression in patients with lung

transplantation to garner FDA approval. This is a

new drug application. Although oral and systemic

cyclosporine are well characterized, cyclosporine

inhalational solution is a new formulation of

cyclosporine. It is seeking a new indication. It

is administered by a new route and it requests a

new dosage regimen. As I mentioned, we weren't

able to conclude that the differences in chronic

rejection and survival were due to the study drug.

For these reasons, we determined it was important

to have this application discussed in an open

public forum.

We have asked the help of the pulmonary

product advisory committee because it is a standing

committee with expertise in pulmonary disease. We

have invited experts in statistics and

transplantation to help with the deliberation, and

we are very much interested in the committee's

input regarding the adequacy of the clinical and

statistical evidence whether aerosolized

cyclosporine is safe and effective for the proposed

indication.

This morning Chiron will present most of

the background information, starting with Dr.

Michael Scaife's presentation on the drug

development program. Then Dr. Jeff Golden will

provide an overview of lung transplantation. Dr.

Sarah Noonberg will discuss the results of the

efficacy study, followed by Dr. Steven Dilly's

presentation and Dr. Ron Helms' views.

The FDA presentation will follow the

Chiron presentations and we will focus on those

areas that proved challenging during the course of

the review. Dr. Arturo Hernandez will discuss the

study design, various clinical issues and outcome

demographic characteristics and dosing. Dr. Marc

Cavaille-Coll will provide a summary of the safety

issues and Dr. Jyoti Zalkikar will give the

statistical presentation.

Then, in the afternoon, we would like you

to discuss, give advice and vote on a few

questions. So, as you listen to the presentations

this morning, please keep these questions in mind

for later discussion. The first question: Is

there sufficient information to make the

determination whether the observed survival

difference in study ACS001 is due to study

treatment or some other factors?

In your deliberations, we will ask you to

recall the statistical issues that were raised by

the application; differences in baseline donor and

recipient characteristics; whether the product

demonstrated an effect on various clinical outcomes

or things such as acute rejection, bronchiolitis

obliterans syndrome, obliterative bronchiolitis.

Depending on whether you conclude that the

answer is yes or no, we have a few additional

questions, namely, if the answer is yes we would

like you to talk about the generalizability or,

more specifically, the labeling issues that you

would recommend be put into a product label. If

the answer is no we would like you to consider what

additional studies you would recommend be

conducted. In these discussions we would also like

you to give us some suggestions regarding patient

population, drug dosing regimen, as well as

efficacy and endpoints that could be included in

such studies.

The next question would be whether the

safety of the product has been adequately

characterized for its intended use. Again, in this

particular question we would like you to also

consider the amount of preclinical and clinical

information that is available in this application;

infection about the cyclosporine and the vehicle,

as well as the number of patients who have been

exposed to the proposed dosage regimen.

If the answer to this question as well as

the preceding one is yes, then we would like you to

give us suggestions about what population the

product should be labeled for; what information we

should include in labeling on dosing regimen, dose

preparation and administration, dosing intervals

and duration of treatment. In addition, if you

could give us guidance on what should be included

in the labeling regarding the expected benefit on

acute rejection, BOS, OB and so forth. If your

answer to the latter question is no, then we would

like you to give us some advice about what

preclinical and clinical information would be

needed.

With that, thank you and I will turn it

back to Dr. Swenson.

DR. SWENSON: Thank you, Dr. Albrecht. We

will proceed now with the sponsor presentation and

I would like Dr. Michael Scaife to go ahead and

begin this, and I will let him introduce his

colleagues and their different presentations.

Sponsor Presentation

Introduction

DR. SCAIFE: First of all, good morning,

ladies and gentlemen. My name is Michael Scaife.

On behalf of Chiron, I would like to thank the FDA

as well as members of the advisory panel for this

opportunity today to present to you on the safety

and efficacy of an inhalable form of cyclosporine

that will be referred to throughout the talk as

either CyIS or the product's trade name, Pulminiq.

The first point I would like to make is

that currently in the United States there are no

drugs or combination of drug therapies approved for

the treatment of chronic rejection following lung

transplantation. The prognosis for these patients

is really poor. Despite aggressive care, only 45

percent of lung transplant recipients will be alive

five years following transplantation. This is much

worse than for other solid organ transplant

recipients. This is an orphan population in the

U.S. On average less than 1100 lung transplants

are performed each year.

We are here today to talk about certain

aspects of Pulminiq, a medication that is an

aerosolized form of cyclosporine dissolved in an

inert vehicle, propylene glycol. As you all know,

cyclosporine is not a new chemical entity.

Cyclosporine was approved by the FDA in 1983 and

currently has been approved in most countries of

the world. It is available in oral, IV and ocular

forms. In the U.S. it has been approved for the

prophylaxis of allogeneic heart, liver and kidney

graft rejection, and for the treatment of

refractory rheumatoid arthritis and plaque

psoriasis. In Europe cyclosporine is also approved

for use following bone marrow and pancreatic

transplantation, as well as for a variety of

immune-modulated pathologies such as nephrotic

syndrome, atopic dermatitis and Bessay syndrome.

Pulminiq is simply an inhalable form of

cyclosporine so, in essence, we are here today to

talk about a well-known drug given by a new route

of administration to enable delivery to the

required site of action. As I mentioned, Pulminiq

is a simple formulation consisting of cyclosporine

dissolved in propylene glycol, with no other

ingredients. Propylene glycol is also not new to

pharmaceutics. Since the initial inhalation tox

studies of propylene glycol in the '40s it has been

widely used as a compounding agent for intravenous

and oral pharmaceuticals, as well as foods. In

fact, it is currently listed by the FDA as an

approved inactive ingredient for use in inhalation

products.

Several preclinical inhalation studies

have been performed both with Pulminiq as well as

with the vehicle alone. Specifically, you will see

in the briefing book that we make mention of two

one-month studies in the rat and the dog and a

three-month study in the rat. I won't go into the

specific details but, as you will see, doses given

in those animals were in multiples 15, 17 times the

dose that we expected in man. The

histopathological findings again are detailed in

the book. You will find that aside from some small

punctate findings in the larynx in a few of the

animals, there were no long-lasting changes and, in

our view, the results are not significant.

How did Chiron first become aware of the

work on inhalable cyclosporine at the University of

Pittsburgh Medical Center, which we will refer to

from now on as UPMC? Well, in fact, from a sales

rep who was detailing our inhalable topromycine

product, TOBI, which is used for the treatment of

pseudomonas infections in cystic fibrosis patients.

The slide here details the development

activities at UPMC. The preclinical study started

in '88, followed in '91 by human studies in lung

transplant patients with chronic rejection. In '97

UPMC started a randomized, double-blind,

placebo-controlled study of cyclosporine that ended

in August, 2003. The results of this and other

studies will form the discussion of today's

meeting.

You may ask why did Chiron want to acquire

the rights to develop this product. Well, we

looked at the results of 15 years of work at one of

the largest lung transplant centers in the U.S. We

asked ourselves the same questions, frankly, and

had the same concerns as anyone would have had. It

is a single-center study. It was being conducted

by a single lead investigator. Has the study been

conducted appropriately? Are the data robust? Are

the striking effects seen on survival benefit real?

And, if so, are they due to cyclosporine or some

other factor or factors?

We did our initial due diligence of the

data and how it had been collected and we concluded

that the effect is real. Based upon our

conviction, we acquired the right to file an NDA

for the product. As you know, the FDA encourages

the filing of applications for products that

address a clear unmet medical need with a

demonstrated significant clinical benefit and an

acceptable safety profile. We went to UPMC and we

extensively audited the hospital records. We went

in and we collected all of these data on

standardized forms, and we analyzed the data in

every possible manner, as you will hear later.

In may, 2004 we met with the FDA. We

posed a very simple question, would the agency

consider the positive findings from one clinical

study, conducted by one principal investigator to

be registerable? The FDA response, and I think Dr.

Albrecht referred to it so she will forgive me for

paraphrasing I hope, was assuming that the data are

robust--and I happily stress the word "robust"--we

encourage you to file. It is rare for us at the

FDA to be provided with significant survival data

for such a product. Based upon this positive

meeting, Chiron filed an NDA for Pulminiq in

October, 2004.

I would like to acknowledge the

collaborative position taken by the FDA throughout

the NDA process. We have been encouraged to

maintain a dialogue with the reviewers and it is in

this spirit that we are here today.

The finding was accepted by the FDA and

priority review status was granted in December,

2004. Ladies and gentlemen, Chiron is here today

because we believe the data on survival benefit are

real and clinically relevant, as well as

statistically significant. We will present data

that confirm that CyIS is safe and efficacious for

the requested indication, which is to increase the

survival and prevent chronic rejection in patients

receiving allogeneic lung transplants in

combination with standard chronic immunosuppressive

therapy.

With that, I would like to introduce to

the panel and the audience the agenda for the

Chiron presentation as well as the speakers, their

background and affiliation. The first speaker is

Dr. Jeff Golden who is professor of clinical

medicine and surgery at the University of

California in San Francisco. Dr. Golden is also

the medical director of the lung transplant program

at UCSF.

We have asked Dr. Golden to speak to you

today for two main reasons, firstly, because he is

an eminent practicing physician and scientist who

actually treats and cares for lung transplant

patients, as well as being an active researcher

into the mechanisms of acute and chronic lung

rejection phenomena. Secondly, because he was not

involved in the study and we wanted his independent

views on the clinical findings. Dr. Golden will

address the current status of lung transplantation.

He will be followed by Dr. Sarah Noonberg

who is the clinical leader at Chiron for this

project. Dr. Noonberg will present to you the

clinical evidence for the efficacy and safety of

CyIS.

Dr. Noonberg will be followed by Dr. Ron

Helms, an emeritus professor of statistics at the

University of North Carolina. Why did we ask him

to be here today? As statisticians and physicians

have analyzed the data from every possible angle

and found the positive effect of Pulminiq on

survival to be clinically as well as statistically

robust, the FDA statisticians expressed some

concerns about our analyses and so we asked Prof.

Helms to look at our approaches, assumptions and

methodologies, as well as those of the FDA

reviewers, and to let us have his candid opinion.

He will share those views with you today.

The final presentation by Chiron will be

given by Dr. Stephen Dilly. He is the chief

medical officer for Chiron BioPharmaceuticals. He

will review the case for approval of Pulminiq

including a discussion of our proposed postapproval

study. We will then hand over the meeting to the

Q&A session that will be moderated by myself.

Finally, we have a list of additional

experts, both internal and external. I would like

to make the special point that we have the pleasure

of having Dr. Trulock here who is a world renowned

expert on lung transplantation and, again, as you

know, you are free to ask any of our experts for

additional information. With that, I would like to

hand over to Dr. Golden. Thank you very much.

Current State of Lung Transplantation

DR. GOLDEN: Thanks. I am extremely

delighted to be here as somebody who takes care of

patients after transplantation. I am here really

to give an overview of the current state of lung

transplant.

Just a brief statement about myself, about

15 years ago I helped start a lung transplant

program at the University of California in San

Francisco. In the past few years we have been

doing about 30 transplants a year, and this year we

are on a pace for 40 transplants. Just to give you

a perspective, this puts us in about the top 10

percent in terms of volume of annual transplants in

the world.

About two years ago I was asked to visit

Chiron and give a review of lung transplant. At

that time I was first shown some data from the

University of Pittsburgh on aerosolized

cyclosporine. Subsequently, as some of you may

know, I did attend the first FDA meeting in 2004

where I similarly presented an overview of lung

transplant. Well, I am back and actually nothing

has changed.

I would like to summarize on the next

slide the main points in terms of where we are in

lung transplant. First, the long-term survival of

lung transplant is 50 percent by five years. This

is a poor survival. Second, bronchiolitis

obliterans, or chronic rejection, is the primary

cause of this poor survival. Third, the future of

lung transplant really demands that we learn how to

prevent bronchiolitis obliterans.

By way of history, before cyclosporine

there had been approximately 40 lung transplants in

the world. Looking at their survival, the median

survival was somewhere around 10 days. One patient

lived 10 months. After the introduction of

cyclosporine there were one-year survivals, such

that eventually there was 75 percent one-year

survival in lung transplant. With this large

improvement compared to the pre-cyclosporine era,

the interest in lung transplant really took off.

As you can see from this slide, early on

in 1985 there were about a dozen transplants and as

of 2003 there are somewhere around 1700 transplants

in the world, about 1100 in the United States.

These are done for various recipient categories you

see listed here. Approximately half are for

emphysema or alpha-1 antitrypsin deficiency, cystic

fibrosis, and another large area is idiopathic

pulmonary fibrosis. Although in this registry

analysis it is 17 percent, at UCSF 60 percent of

our lung transplant patients have idiopathic

pulmonary fibrosis, a disease for which there is no

therapy and a disease that has a five-year

survival, somewhat similar to lung cancer.

However, despite this increased one-year

survival and this tremendous increase in the number

of transplants done around the world, we are,

unfortunately, still stuck at a low 50 percent

survival of around 4.5 to 5 years. Although one

might say emphysema has a slightly better outlook

at 4 and 5 years than idiopathic pulmonary

fibrosis, in general lung transplant survival is

about 50 percent at 4.5 to 5 years.

To give you some perspective, if you look

at kidney transplant at that interval of 4.5 years

after transplant there is 90 percent survival. And

if you look at heart and liver transplant it is

about 75 percent survival. Not only do we have

this 50 percent survival at 4 to 5 years, but this

has not changed in almost 20 years. We have

plateau'd in terms of poor survival in that period

of time.

As I say, the problem responsible for this

poor mortality clearly is bronchiolitis obliterans.

In this histology section, with an artery here, the

obliterative lesion that is established as a

fibroplastic plug diminishes the airway diameter

such that, instead of being this size, it is

reduced and constricted down to this tiny lumen

here secondary to this fibroproliferative process

of the lesion of bronchiolitis obliterans.

Bronchiolitis obliterans or chronic

rejection is diagnosed in two ways, histologically

through a transbronchial biopsy or clinically. The

problem with the histologic diagnosis of a

transbronchial biopsy is that it is a specific

finding but it is not very sensitive.

Transbronchial biopsy is simply not sensitive

sufficiently to diagnose this chronic airway

process. Therefore, over the years we have

developed a clinical diagnosis in the absence of a

histologic finding on the transbronchial biopsy

such that we look at specific decrease in air flow

when there is no alternative cause, and we label

this bronchiolitis obliterans syndrome.

It is important to stress that

obliterative bronchiolitis and bronchiolitis

obliterans syndrome, or BOS, are really histologic

and clinical manifestations of the same airway

process. Patients develop progressive shortness of

breath with this graft failure, progressive airflow

obstruction and recurrent pulmonary infections.

Regrettably, once this chronic rejection develops

the airway damage is progressive and irreversible

and patients die of graft failure and related

infections.

The registry for transplant would say that

somewhere around 5 years the percent of patients

dying from different etiologies would be

bronchiolitis obliterans about 30 percent, but

actually you cannot separate this from infections

which are always present in the setting of this

airway damage. Furthermore, in this registry

setting where they describe organ failure, that is

obviously bronchiolitis obliterans. So, when you

add up these categories of bronchiolitis obliterans

organ failure and related airway infections,

including pseudomonas, aspergillus, etc., let me

simply state that bronchiolitis obliterans

complications relate to the vast majority of deaths

at 4.5 to 5 years after lung transplantation.

No matter what we have done in the last 18

years, we have not prevented this development of

chronic rejection, this airway process, whether we

give tacrolimus, different combinations of

cyclosporine, micofenolate, azathioprine,

prednisone and, in fact, I could put rapomyacin up

there and various other lytic therapies and various

approaches to prednisone pulses for acute

rejection, etc. Despite all this systemic

immunosuppression, we really have not changed the

incidence of chronic airway rejection closely

related, unfortunately, to the poor survival at 4.5

to 5 years.

We now appreciate that there are

non-immune factors that relate to airway damage, be

these infection or reflux disease. These

non-alloimmune factors clearly relate to immune

activation. In fact, I believe we are now

understanding that when we see chronic airway

rejection and we increase systemic

immunosuppression we actually are helping to

promote such non-alloimmune factors, especially

infections which cause further airway immune

activation and actually make the process worse.

We have always known that there are

alloimmune factors such as acute rejection that

relate to damage of the organ. We are now

appreciating these non-alloimmune factors, again,

be it early airway damage with transplant, various

infections, reflux disease which is a very new

concept in terms of what injures the airway--that

these non-alloimmune stimuli, in consort with

alloimmune rejection, together damage the graft

leading to progressive, additive epithelial injury,

inflammation and fibroblastic repair culminating in

the picture I showed you of bronchiolitis

obliterans.

One newer concept in terms of immune

factors is called lymphocytic

bronchitis/bronchiolitis. One might call it airway

rejection. This histology reveals lymphocytic

bronchitis/bronchiolitis and airway disease wherein

you have submucosal lymphocytes working their way

into the mucosa. Let me point out that lymphocytic

bronchitis/bronchiolitis has been highly related to

the subsequent development of the more fibrotic

bronchiolitis obliterans. This concept of an

airway inflammation based on immune reaction in the

airway, lymphocytic bronchitis, was not on the

radar screen 15 years ago when the concept of

inhaled cyclosporine was conceived.

We have always known that acute rejection

is one of the factors that relates to the

subsequent development of bronchiolitis obliterans.

However, I want to separate out the airway process

from acute rejection which is a perivascular

process diagnosed by transbronchial biopsy. I

should emphasize that a transbronchial biopsy has

variable adequacy for obtaining small airway

samples to diagnose whether it is bronchiolitis

obliterans or the early airway inflammation of

lymphocytic bronchitis.

If I was designing a study today of any

inhaled immunosuppressant therapy I would try to

learn more about the biology of the airways. We,

at UCSF, and some other institutions have been

doing endobronchial biopsy. This is not standard

but we are learning a lot more about the airway

biology in terms of lung transplantation.

On my last slide I want to just emphasize

that although I might expect systemic

immunosuppression to clear up a perivascular

process, I am suggesting that bronchiolitis

obliterans, chronic rejection, is an airway process

and it makes eminent sense to employ inhaled

cyclosporine to treat the epithelium. It is clear

now that the epithelium is key to the development

of bronchiolitis obliterans. Bronchiolitis

obliterans is an airway disease.

Just to finish, my colleagues in the lung

transplant world are very excited about the

potential benefit of inhaled cyclosporine. As I

say, the epithelium is key and it makes eminent

sense to develop a system of local immune

suppression to the airway and the mucosa. Frankly,

given the poor survival of our transplant

recipients which, as I already mentioned, has not

changed in almost 20 years, I personally feel that

inhaled cyclosporine fulfills an unmet need.

I questioned whether I was going to say

the following but I think I will. On a personal

note, for people like myself who take care of these

patients, who see them terribly short of breath in

various diagnostic categories who go on to have a

lung transplant and then regain a normal life,

including family life, going back to work--to all

of a sudden see these patients once again slowly

develop progressive airway rejection, chronic

rejection and shortness of breath is extremely

disheartening to the patients, to say the least,

their family and, frankly, for their physicians.

Thank you for your attention.

Clinical Evidence of Efficacy and Safety

DR. NOONBERG: Good morning. My name is

Sarah Noonberg and I am the clinical leader for the

inhaled cyclosporine project. Over the next 45

minutes I will be reviewing the clinical data

supporting the use of inhaled cyclosporine in lung

transplant recipients.

I will begin with a brief discussion of

early preclinical and open-label clinical trials of

inhaled cyclosporine at UPMC. These trials

generated a lot of interest in inhaled cyclosporine

and really set the stage for the pivotal

randomized, double-blind, placebo-controlled trial

which we, at Chiron, refer to as ACS001.

I will then describe the study design and

baseline characteristics of patients in ACS001

before moving into a discussion of efficacy,

focusing primarily on the endpoints of survival and

chronic rejection. I will then switch gears and

summarize the safety data that has been generated

for inhaled cyclosporine from a safety database of

102 patients. Although the favorable safety

profile is clearly an important aspect of the drug,

I am going to be spending much less time reviewing

safety listings as this is an area of general

agreement with the FDA.

Finally, as with all studies, there are

limitations to ACS001 both with respect to study

design, as well as choice of the primary endpoint.

I am going to end this presentation with a

discussion of some of those limitations and how we

view them in light of the clear strengths of the

study.

As Dr. Golden has described, the

introduction of cyclosporine as an

immunosuppressant truly revolutionized lung

transplantation and allowed for the possibility of

long-term survival. Within a few years of FDA

approval investigators at UPMC began to develop an

aerosolized formulation, and within five years they

initiated preclinical trials.

In the first set of experiments

non-transplanted dogs were given a single dose of

inhaled cyclosporine. The dose was well tolerated

and revealed that pulmonary concentrations were

10- to 100-fold higher than concentrations in other

tissues. In addition, there was no change in lung

function and no histologic abnormalities.

In a canine lung transplant model dogs

were given single agent immunosuppression with

inhaled cyclosporine and investigators reported a

dose-dependent decrease in the frequency and

severity of allograft rejection.

In a rat transplant model rats were given

an identical dose of either inhaled cyclosporine or

intramuscular cyclosporine. Inhaled cyclosporine

was found to be at least as effective as

intramuscular cyclosporine in causing a

dose-dependent decrease in proinflammatory cytokine

production, as well as a decrease in allograft

rejection but with far lower systemic exposure to

cyclosporine.

These encouraging preclinical results led

to the development of a series of open-label

non-comparative trials with inhaled cyclosporine at

UPMC. These trials enrolled two different groups

of patients, both with established complications of

lung transplantation. In the first set of

protocols lung transplant recipients with

documented chronic rejection were given inhaled

cyclosporine in addition to their standard

immunosuppressive regimen. Investigators reported

improvement in rejection histology and

stabilization of pulmonary function relative to

pre-enrollment data. But, more importantly, these

patients had improved survival both compared to

contemporary UPMC unenrolled controls as well as

controls from a historical lung transplant

registry.

In the next set of protocols patients with

refractory acute rejection, defined as acute

rejection that failed to respond to

immunosuppressive intensification--this represents

a step earlier in the disease process as acute

rejection--as a risk factor for the subsequent

development of chronic rejection and was the

logical next population to study. When these

patients were given inhaled cyclosporine, again, in

addition to their standard immunosuppressive

regimen, investigators reported an improvement in

rejection histology, a reduction in proinflammatory

cytokine production, and a dose-dependent increase

in pulmonary function, all relative to

re-enrollment data. Once again, these patients had

improved survival compared to contemporary UPMC

unenrolled controls.

Despite the non-comparative nature of

these trials and their inherent limitations, they

made quite an impact in the transplant community,

and have led to unregulated compounding of inhaled

cyclosporine by a number of U.S. transplant

centers. In a survey of 2002, published in Chest,

of transplant practices 10 percent of U.S.

transplant centers already used inhaled

cyclosporine. They compound it in their pharmacies

and they give it to patients with progressive

chronic rejection.

These open-label trials were clearly

provocative but their interpretation is limited by

the lack of an adequate control group. However,

they laid the framework for the very first and one

of the only randomized, double-blind,

placebo-controlled trials in the lung transplant

population. Unlike the previous protocols that

enrolled patients with established complications of

lung transplantation, this trial was designed to

test the efficacy of inhaled cyclosporine in

preventing rejection and improving outcomes when

given prophylactically to patients shortly after

their single or double lung transplant procedure.

The trial had two phases. In a pilot

phase, the first phase, 10 patients were given

open-label inhaled cyclosporine and were followed

prospectively. They formed a cohort designed to

test the safety and tolerability of the drug in

this patient population. In the second phase, the

randomized phase, 58 patients were randomized and

56 were randomized and treated with either inhaled

cyclosporine or placebo, which in this case was

inhaled propylene glycol, the vehicle used to

create the inhalation solution. The primary

endpoint of the study was rate of acute rejection,

and secondary, prospectively defined endpoints of

survival, rate of chronic rejection and pulmonary

function.

The criteria for enrollment into ACS001

were fairly straightforward. To be included, you

had to be a recipient of a single or double lung

transplant and be 18 years of age or older.

Exclusion criteria included the presence of active

fungal or bacterial pneumonia or anastomotic

infections prior to the initiation of appropriate

antimicrobial therapy. Patients with bronchial

stenosis greater than 80 percent had to be treated

with standard techniques prior to enrollment.

Patients who failed to wean from mechanical

ventilation and women of childbearing potential

unwilling to use birth control were also excluded.

It is important to note that all patients met study

inclusion and exclusion criteria.

All patients in ACS001 were treated with

standard-of-care immunosuppressive therapy

following transplantation, and all were randomized

and enrolled within the first 7-42 days following

their transplant surgery. A total of 26 patients

were treated with inhaled cyclosporine and 30 were

treated with placebo. All patients underwent an

initial 10-day dose escalation period where they

were initiated on low dose inhaled cyclosporine at

100 mg, and that dose or equivalent volume of

placebo was gradually increased to a maximally

tolerated dose up to a protocol-specified maximum

of 300 mg. The dose or equivalent volume that they

reached on day 10 was the dose that they continued

3 times a week for a period of 2 years.

After completion of dosing patients

continued to be followed for study endpoints up to

the study end date of August 21, 2003. This

corresponded to 2 years after the last patient was

enrolled and, therefore, could complete their

2-year period of dosing. Therefore, the total

length of follow-up per patient depended on the

timing of enrollment and ranged from 24 months for

the last patient enrolled up through 56 months for

the first patient enrolled.

ACS001 was a randomized trial, and the

randomization scheme was developed by the

Department of Statistics at the University of

Pittsburgh. The randomization was stratified by

CMV mismatch, defined as donor positive/recipient

negative, versus all other combinations. This was

chosen because international registry data has

demonstrated that patients with CMV mismatch have a

32 percent increased relative risk of death in the

first year compared with other combinations, with a

p value of less than 0.0001. Therefore, the

assertion that the randomization was not stratified

by any variables known to affect outcome is

incorrect. The randomization was also stratified

by enrollment period and distinguishes patients who

generally had a less complicated postoperative

course, were stable and met exclusion criteria by

7-21 days versus those that had a relatively more

complicated postoperative course and met exclusion

criteria and were stable between 22 and 42 days

after the surgery. In line with ICH guidelines, it

is impractical and often counterproductive to

stratify by more than 2 factors in a study of this

size.

This slide illustrates the baseline

characteristics of patients enrolled in ACS001.

Overall, the two groups were well matched with

respect to the majority of relevant baseline

demographic characteristics. Donors were similarly

well matched for clinically relevant variables.

However, as can be expected from any randomized

study, there were a few important imbalances. The

two variables where clinically relevant imbalances

existed were with respect to primary diagnosis and

transplant type.

As Dr. Golden has demonstrated, the

primary diagnosis leading to transplantation can

have an important impact on survival. Patients

with COPD have traditionally been associated with

better outcomes, especially within the first year,

and this is statistically significant. Nearly

twice as many placebo patients had this more

favorable diagnosis. In addition, patients with

idiopathic pulmonary fibrosis or IPF have

historically had among the worst survival, both

short-term and long-term, and this is statistically

significant at one year and at five years, and

there were far more patients with IPF in the

inhaled cyclosporine group compared to placebo.

Both of these factors together could potentially

bias results for better outcomes in the placebo

group.

By contrast, double lung transplant

recipients have historically had marginally

improved survival compared to single lung

transplant recipients in the first several years,

and this difference becomes increasingly pronounced

with time but is not statistically significant at

one year or at five years, the time period of

interest for ACS001. However, there were more

double lung transplant recipients in the inhaled

cyclosporine group and this could potentially bias

results towards better outcomes in the inhaled

cyclosporine group. Therefore, although imbalances

exist, they are split between groups and would not

be expected to strongly influence results in one

direction or the other.

The protocol specified that patients were

to continue study drug for a period of two years.

However, due to the nature of the patient

population with its high mortality rate, frequent

complications and frequent hospitalizations, not

all patients could complete the two-year period of

dosing and this is not surprising. Roughly

two-thirds completed at least one year of therapy

and roughly half completed the full two years of

therapy. As the protocol specified that dosing

should be held temporarily in the presence of an

infection not responding to treatment, not all

patients had each and every one of their scheduled

doses. However, this just reflects the protocol

rather than any lack of compliance.

The median duration of dosing was

comparable among the two groups. Of the patients

that did prematurely discontinue dosing, the

primary reasons were adverse events in the placebo

group and withdrawal of consent in the inhaled

cyclosporine group. Of the six who withdrew

consent, two were due to early tolerability

problems; two were primarily due to unrelated

medical problems; and one was due primarily to an

unrelated social problem and for one the reason was

unknown.

Although no patients were lost to

follow-up, five patients, three in the inhaled

cyclosporine group and one in the placebo group,

were taken off the study, the randomized trial, and

crossed over into an open-label rescue protocol of

inhaled cyclosporine. Their data was censored at

the time of crossover and the treatment groups

remained blinded. In both groups there were

patients that were withdrawn due to protocol

deviations and violations that largely included

medical non-compliance and smoking.

This slide summarizes the important

efficacy and safety results from study ACS001.

Treatment with inhaled cyclosporine led to

significantly improved survival and chronic

rejection-free survival compared to placebo but did

not affect the rate of acute rejection. Treatment

with inhaled cyclosporine was not associated with

increased risk of nephrotoxicity, infections,

malignancies or any systemic toxicities known to

occur when cyclosporine is given orally or

intravenously. However, similar to other inhaled

drugs, inhaled cyclosporine was associated with

mild to moderate respiratory tract irritation and

bronchospasm.

I will first discuss the effect of inhaled

cyclosporine on survival. Using an unadjusted

analysis, inhaled cyclosporine was associated with

a significant survival advantage compared to

placebo, with a relative risk of death of 0.213 and

a p value of 0.007. This corresponds to a 79

percent decreased risk of death in patients treated

with inhaled cyclosporine compared to placebo.

This slide is the Kaplan-Meier plot of survival

duration from the time of transplantation to the

study end date, and is the primary reason that we

are all here today.

During the period of the study there were

3 deaths in the inhaled cyclosporine group compared

to 14 deaths in the placebo group. The results are

not only highly statistically significant but also

clinically very important. This is the first time

a cohort of lung transplant recipients has had

survival comparable to recipients of other solid

organ transplants and marks a major advance in

outcomes for this patient population.

The importance of an unadjusted analysis

rests on its robustness and how well it compares to

analyses that control for other baseline

characteristics that might affect outcome.

Therefore, we performed univariate analyses

adjusting for potential risk factors that might

affect survival, and found that the relative risk

of death and the p values were remarkably

consistent.

This graph illustrates the relative risk

of death and 95 confidence intervals when the

survival data is adjusted by a number of different

factors that have been documented in the literature

to potentially affect outcome. We also include two

factors suggested by the FDA, ICU time after

transplantation and the use of donors who at some

point during their hospitalization prior to

harvesting were treated with an inotrope. Neither

of these two factors is supported by the literature

or registry data as having an impact on survival.

For the case of donor inotrope use, it is not

considered in guidelines for optimal donors or

marginal donors. However, the key message is that

regardless of the baseline characteristic none of

these factors appreciably impacts the relative risk

of death and lends strong support to the validity

of the unadjusted analysis, and this is what is

meant by a robust endpoint.

In order to further test the robustness of

the survival endpoint, we performed multivariate

analyses which adjust for clinically relevant

baseline characteristics simultaneously. As not

all characteristics can ever be simultaneously

input into a single statistical model, the job of

the clinician is to decide which of these are the

most clinically relevant.

In order to determine the most clinically

relevant factors we searched through the literature

to determine those that had been documented to be

short-term or long-term prognostic factors. We

then reviewed registry data to determine the level

of significance and, finally, we discussed these

factors with transplant physicians who care for

these patients. The general agreement was that the

most clinically relevant factors were transplant

type, CMV mismatch, primary diagnosis, early acute

rejection--all shown in green. We also include in

our model the variable of enrollment period as this

was a randomization stratification variable and it

is in accordance with ICH guidelines.

This slide also illustrates the relative

distribution of 16 different baseline

characteristics that have been documented in the

literature to potentially affect short-term or

long-term outcome. As is evident, the majority are

balanced or, if anything, would favor better

outcomes in the placebo group.

This slide illustrates the results of the

multivariate analyses when these factors are

successively added into a Cox proportional hazards

model. The key point is the consistency of the

treatment effect. The addition of the five most

clinically relevant factors into this study does

not have any appreciable impact on the relative

risk of death or the p values, and provides even

further support for the robustness of the survival

endpoint.

Robustness was further evaluated by

performing a number of sensitivity analyses around

the survival endpoint. When we did so, we found

that the relative risk of death remained

consistent. The top row illustrates the unadjusted

analysis on the full data set. When we include

patients who were randomized and treated the

results are essentially unchanged. When we look at

survival relative to first dose of study drug

rather than time of transplantation, again the

results are essentially unchanged. When we exclude

three placebo patients who had early mortality and

died within the first three months--when we just

take them out of the analysis and we only analyze

the remaining 27, it remains statistically

significant. When we take out 14 patients who did

not receive at least 80 percent of the protocol

maximum dosing adjusted for death, we lose 25

percent of the sample size but still maintain

statistical significance and the relative risk of

death is barely altered.

The FDA has raised concern about the

effects of early pneumonia. So, if we remove from

analysis 15 patients who had an episode of

pneumonia within one month of initiation of study

drug we have lost greater than 25 percent of the

patient population and, therefore, expect that the

p value is going to increase but the key point is

that the relative risk of death, the treatment

effect, is barely changed.

Questions have also been raised about the

effects of ICU time after transplantation. If five

patients who were in the ICU greater than 14 days

were removed from analysis, the results are

statistically significant and in favor of the

inhaled cyclosporine group. Therefore, we have

looked at the survival data from a number of

different angles and found the survival data to be

robust.

To assess the duration of the survival

benefit we collected additional survival data 10

months after the study ended, and we found that the

survival benefit persisted. At that point there

were 5 deaths in the inhaled cyclosporine group

compared to 15 deaths in the placebo group, with a

p value of 0.017.

This post-study follow-up is important and

it is useful and supportive data. However, it has

its limitations. The first is that the study had

ended and it ended almost a year earlier. The data

was analyzed and patients were unblinded; treatment

groups were known. In addition, except for those

patients who had crossed over into an open-label

protocol, all patients were off study drug for a

substantial period of time, ranging anywhere from

10 months to a maximum of 3.5 years. When you

consider that the median time to diagnosis of

chronic rejection is 16-20 months, it is going to

confound the results. Also, there were placebo

patients that had crossed over and were now

receiving inhaled cyclosporine so the net effect,

as expected, is that it is going to trend toward

the null.

This is what the FDA refers to as the

five-year data and believes that it is the most

appropriate time point to analyze the survival

data, but for the reasons that I have just

described we disagree and we believe that the data

is best analyzed at the prospectively defined study

end date.

In order to verify that the placebo

population was representative of what would be

expected in a larger U.S. transplant population,

the placebo survival curve was compared with data

from the United Network for Organ Sharing, or UNOS,

that maintains a large transplant registry.

Placebo patients were matched with UNOS controls

who were transplanted during the same period of

enrollment as ACS001, and they were matched by the

variables on the slide. Matching also excluded

patients who died before they could have possibly

enrolled into ACS001.

This slide illustrates the results and

shows that both early mortality and late mortality

in the placebo group are extremely consistent with

what is expected in a larger multicenter patient

population. Roughly 50 percent survival at 4.5

years is exactly what has been documented in the

literature for years. Therefore, any analyses that

exclude early deaths or late deaths or deaths due

to particular causes have to be viewed with caution

as they would no longer lead to a placebo group

whose survival is representative. By comparison,

when the ACS001 inhaled cyclosporine group is

compared to the UNOS controls the relative risk of

death of 0.252 is very comparable to what was seen

in ACS001 where the relative risk of death was

0.213.

This is a busy slide but it makes a very

important point and brings us into our next topic,

namely, the primary reason for the improved

survival in patients treated with inhaled

cyclosporine is that inhaled cyclosporine prevented

chronic rejection. This slide illustrates the

timing and cause of death for both groups. As

expected, early deaths were predominantly due to

infectious causes. However, subsequently nearly

all deaths are associated with chronic rejection.

Of the five deaths that the agency calls attention

to in the mid portion of the graph as driving the

statistical significance, four out of the five had

chronic rejection. By contrast, in the inhaled

cyclosporine group the curve becomes flat and late

mortality is not occurring.

One question that has been raised is why

is the survival difference statistically different

at two years when all patients would have completed

their study drug. The reason, as evident from this

graph, is that chronic rejection is the predominant

cause of death in the first year so you wouldn't

expect to see early large separation of the two

curves. However, after a year it is the major

contributor, as Dr. Golden has demonstrated, to

mortality.

To review, chronic rejection is an

umbrella term for patients with histologic evidence

of bronchiolitis obliterans, or OB, documented by

transbronchial biopsy. It is also representative

of patients with clinical evidence of bronchiolitis

obliterans syndrome, or BOS, using a sustained and

unexplained decline in FEV1 as a surrogate marker.

It is not uncommon for patients to have

bronchiolitis obliterans but, due to the

progressive nature, they haven't met clinical

criteria for BOS. It is also not uncommon for

patients to have BOS but, due to the insensitive

nature of transbronchial biopsy in making the

diagnosis they don't have OB. So, these two

groups, patients with OB and patients with BOS, are

overlapping but they all represent patients with

chronic rejection. So, looking at each group

individually may be informative but it has to be

viewed as a subset analysis. Consistent with

direct delivery to the airway epithelium, the site

of chronic rejection, treatment with inhaled

cyclosporine led to a 72 percent decrease in the

risk of chronic rejection or death. As you will

see, when we performed the same univariate and

multivariate analyses, the results are even more

robust.

This slide illustrates the Kaplan-Meier

estimate of chronic rejection-free survival and

uses a composite endpoint of first diagnosis of OB,

first diagnosis of BOS or death. There are two

important points here. One is that there is

general agreement with the FDA that the rate of

biopsy and the rate of pulmonary function testing

is comparable between the two groups so that the

difference isn't driven by increased testing in one

group or the other.

The second is that the use of a composite

endpoint of chronic rejection and death implies

that patients who die and, therefore, can't go on

to be diagnosed with chronic rejection are counted

as events rather than censored in the statistical

analysis. To censor deaths in a statistical

analysis of chronic rejection would require the

assumption that there is no relationship between

chronic rejection and death, an assumption that we

know to be invalid.

The agency issued guidelines in April of

2005 endorsing a progression-free survival analysis

for similar oncology endpoints to avoid a type of

bias known as informative censoring. As with the

survival endpoint, we found a remarkable

consistency of the chronic rejection-free survival

endpoint when we performed a series of univariate

analyses. None of these baseline characteristics

had any appreciable impact on the treatment effect

or its significance, which speaks to the robustness

of this endpoint as well.

This slide illustrates the result of

multivariate analyses on the chronic rejection-free

survival endpoint. Once again, the addition of the

5 most clinically relevant factors in this

study--adding them into a Cox proportional hazards

model has essentially no real impact on the

treatment effect of the confidence intervals and

the p values remain highly statistically

significant.

Valid questions have been raised about

whether the survival benefit is so strong that any

composite endpoint that includes survival would be

statistically significant. Therefore, for

exploratory reasons we performed an analysis of

chronic rejection with death censored. This

clearly biases results against the inhaled

cyclosporine group due to the larger number of

deaths in the placebo group. As mentioned, this is

referred to as informative censoring. However that

said, when we performed the analysis the results

were still statistically significant and in favor

of the inhaled cyclosporine group. Chronic

rejection occurred in 50 percent of placebo

patients and 27 percent of inhaled cyclosporine

patients.

This slide illustrates the Kaplan-Meier

estimate of time to chronic rejection with deaths

censored and clearly illustrates a statistically

significant effect on chronic rejection independent

of death despite the large bias inherent in the

analysis. This analysis is important because it

leads to the conclusion that treatment with inhaled

cyclosporine prevents chronic rejection, the

leading cause of late mortality in lung transplant

patients.

However, the primary endpoint of the study

was not survival or chronic rejection but rate of

acute rejection and this endpoint was not met.

Approximately 70 percent of patients in both groups

had at least 1 episode of documented grade 2 or

higher acute rejection prior to study termination.

After the start of dosing rates were comparable

between the 2 groups, with a p value of 0.73.

Dr. Golden has explained the paradigm

shift that has occurred in the transplant community

in terms of how acute and chronic rejection are now

understood. Acute rejection is primarily a

vascular process so an immunosuppressant with low

vascular exposure would not be expected to have a

significant effect, and that is what we are seeing

in ACS001. By contrast, chronic rejection is an

airway process. It is mediated in the airway

epithelium so an immunosuppressant delivered

directly to the airway epithelium would be expected

to have an effect, and that too is what we are

seeing in ACS001.

Now I am going to switch gears and briefly

discuss safety. This slide illustrates the

relative systemic exposure to cyclosporine when

given by an inhalation route compared to an oral

route. A 300 mg dose of inhaled cyclosporine has

been demonstrated to lead to a mean peak blood

concentration of 206 ng/mL, roughly 11-14 percent

of what you would expect in an oral dose. the

levels at 24 hours are barely detectable by

standard assays, and these numbers are reflected in

the mean AUC, or area under the curve, which

suggests a roughly 8-fold lower systemic exposure

to cyclosporine when it is given by an inhaled

route compared to an oral route. This low systemic

exposure explains why no additional systemic

toxicities were seen in the inhaled cyclosporine

group compared to placebo.

Data to support the safety of inhaled

cyclosporine and propylene glycol come from

multiple sources, and this is outlined in much

further detail in the briefing book. The first are

preclinical toxicology studies in dogs and rats,

performed both by Chiron as well as referenced in

the literature. These studies show that no

unexpected toxicities were seen when animals were

treated at many-fold higher doses than what would

be used clinically.

The next source is the randomized,

placebo-controlled ACS001 trial where safety data

from 30 placebo patients were compared with safety

data from 36 inhaled cyclosporine patients, the 26

randomized and the 10 placebo.

The next source is ACS002, which was a

retrospective safety analysis of 70 patients

enrolled in 1/7 different open-label protocols of

inhaled cyclosporine in patients with refractory

acute and chronic rejection. The ISS, or

integrated safety summary, is a combination of all

patients treated with inhaled cyclosporine in

either ACS001 or ACS002 and represents 102 unique

patients in our safety database.

To summarize our clinical safety data,

review of the adverse event listings in ACS001

revealed that inhaled cyclosporine was safe. There

was no increased risk of nephrotoxicity,

neurotoxicity, infections, malignancies or any

other toxicities that occur with oral or

intravenous cyclosporine. In addition, there were

no new or unexpected systemic toxicities.

So, the key point is that treatment with

inhaled cyclosporine led to a 79 percent decreased

risk of death compared to placebo, with no systemic

toxicity. However, inhaled cyclosporine was

associated with respiratory tract irritation and

bronchospasm and this will be discussed in the next

slide. Review of adverse event data in ACS002 and

the ISS confirmed the safety findings of ACS001,

and no new safety signals were seen after review of

the serious adverse event data.

After review of the ACS001 adverse event

listings and case report forms, it became clear

that there were two distinct but interrelated

safety signals that appeared to be a direct result

of inhaled cyclosporine. The first was

bronchospasm manifested primarily by cough,

exacerbated dyspnea and wheezing. The second was

respiratory tract irritation manifested primarily

by pharyngitis but also laryngitis and non-cardiac

chest pain. In general, these events were mild to

moderate. They occurred early in the patient's

treatment course and diminished with time, and once

they resolved it was rare for them to recur. But,

most importantly, there was no progression to more

serious respiratory complications such as acute

respiratory failure or ARDS. The adverse event of

lung consolidation was noted in higher frequency in

the inhaled cyclosporine group but the clinical

relevance of this finding is unclear as underlying

causes such as pneumonia, lung mass, atelectases or

other underlying causes were comparable between the

2 groups.

Having reviewed the most important

clinical results for inhaled cyclosporine, it is

appropriate to take a step back and take a look at

some of the outstanding issues surrounding the

data. Study ACS001 was conducted at a single

center, and this was discussed with the FDA well

before Chiron decided to move ahead and file the

NDA. However, it is important to note that no

other transplant studies or registry analyses have

ever shown a survival benefit comparable to what

was seen in the inhaled cyclosporine group of

ACS001.

We also looked at the placebo group and

found that survival was comparable to a multicenter

matched database. Single-center trials are not

ideal. However, they do have one important

advantage. Because confounding due to differences

in patient care is minimized, single-center trials

are actually better at determining a treatment

effect than multicenter trials of the same size.

Finally, Chiron has committed to a multicenter

postapproval trial to further study the efficacy

and safety of inhaled cyclosporine.

The sample size of N equals 56 for

efficacy and N equals 102 for safety is small.

However, the lung transplant population is

exceedingly small, with 1100 lung transplants

performed in the United States each year. Despite

the small sample size, the survival and chronic

rejection data are highly statistically significant

so the sample size was sufficient to test the

hypothesis that inhaled cyclosporine improves

survival and chronic rejection-free survival.

Cyclosporine and propylene glycol are

well-known and well-characterized, and the safety

profile of inhales cyclosporine is extremely

favorable, especially in light of the survival

benefit. Again, Chiron has committed to creating a

larger efficacy and safety database through a

postapproval trial.

The randomization code was susceptible to

unblinding and CRF assembly was retrospective. The

randomization code used a patient subject number

followed by an A, B, C or D designation, with A and

D referring to placebo patients, B and C referring

to inhaled cyclosporine patients, and it is

possible that the study could have become unblinded

due to the simple nature of this designation.

However, there are several factors that make this

very unlikely. First is that the principal

investigator was never exposed to the subject

numbers. Second, the investigator removed 3

inhaled cyclosporine patients from the inhaled

cyclosporine arm only to cross over into an inhaled

cyclosporine open-label rescue protocol. In

addition, the pathologist reading the

transbronchial biopsies and making the

determination of bronchiolitis obliterans was never

exposed to study numbers.

The issue with retrospective CRF assembly

is whether somehow in the retrospective nature of

filling out these forms an assessment of an outcome

is altered. However, when the outcome is death, or

the presence or absence of bronchiolitis obliterans

on an original histopathology report, or whether

FEV1 has declined by 20 percent or more from a

post-transplant maximum, these are hard endpoints

and would not be expected to be altered by

retrospective CRF assembly.

Treatment groups were not balanced on each

and every baseline characteristic. The purpose of

randomization is not to eliminate all imbalances

but, rather, to randomly distribute them between

groups. The two treatment groups are comparable,

and of the clinically relevant baseline

characteristics we examined the majority are

balanced or, if anything, would favor better

outcomes in the placebo group.

Finally, when imbalances do occur in

clinically relevant variables statistical models

can be used to adjust for these both in univariate

or multivariate analyses, and we have presented

such analyses that show that the data is robust.

So, we feel extremely confident in saying that

baseline imbalances did not explain the efficacy of

inhaled cyclosporine.

The study did not meet its primary

endpoint of decreased rate of acute rejection.

However, scientific understanding has evolved since

the design of ACS001 and the lack of an effect on

acute rejection is consistent with low systemic

exposure. The design of the study doesn't impact

the assessment of survival or chronic rejection or

alter how the data is obtained. It is also

important to note that survival and chronic

rejection were prospectively defined secondary

endpoints. These analyses are not post hoc nor do

they constitute data mining.

Finally, the survival and chronic

rejection data are clinically important,

statistically significant and scientifically sound.

Inhaled cyclosporine is delivered directly to the

airways, the site of chronic rejection. Inhaled

cyclosporine prevented chronic rejection and, in

doing so, markedly improved survival. The

importance of this data is illustrated by the fact

that physicians from 30 different transplant

centers in the United States, which represents

almost half of all active lung transplant centers,

have requested early access to inhaled cyclosporine

as part of our early access program.

We have been advised to make it clear to

the advisory committee where there are differences

of opinion between Chiron and the FDA, and that is

really why we are here today. So, this slide

illustrates five of the most important areas where

we disagree.

First, we believe that covariates in a

statistical model should be chosen based on an

association with the clinical outcome rather than

because of an imbalance. In the case of ICU time,

the use of ICU time greater than ten days, there is

an imbalance toward the placebo group. However,

this is not documented to be associated with

survival. If an ICU time greater than seven days

is chosen that imbalance is minimized, and if an

ICU time greater than four days is chosen the

imbalance is reversed. We believe that it is

important to differentiate patients who had an

earlier, easier postoperative course from those who

had a harder postoperative course, but believe that

this is best accomplished by the randomization

stratification variable enrollment period, early

versus late.

In the case of donor inotropic support, we

have yet to find a single reference that even

considers this variable, much less finds it

clinically relevant and the FDA has called this one

of the most clinically relevant factors in the

study.

We do have variables and we do have data

on donor quality through other variables that have

been documented in the literature to be clinically

important, such as donor age, donor bacterial

colonization, donor graft, ischemic time, and these

are balanced between the two groups. The important

point is that the use of a covariate that is

imbalanced but not clinically relevant will always

cause results to trend toward the null and that is

what we have seen with the FDA analyses.

Second, in analyses of survival we

disagree that patients whose use of donor inotrope

or the donor inotrope data is missing--we disagree

that these patients should be excluded from

analyses. In the FDA analysis, by excluding

long-term survivors in the inhaled cyclosporine

group, the treatment effect and p values are going

to be altered inappropriately.

Three, we believe that survival is best

analyzed at the prospectively defined study end

date rather than one year after--or nearly a year

after the study was over. I have already discussed

our reasons for this.

Four, we believe that patients with

bronchiolitis obliterans, or OB, should be included

in an analysis of chronic rejection. The diagnosis

of OB has a specificity of over 95 percent.

Patients with BOS and OB represent overlapping

subsets and, therefore, to look at either one

alone, we believe, is a subset analysis.

Finally, five, analyses of BOS should not

censor deaths. This is clearly informative

censoring, and when deaths are not censored and

BOS-free survival is analyzed the results are

statistically significant and remain so when

controlled for by CMV mismatch, primary diagnosis

and early acute rejection. Analyses that censor

death can be informative but we have shown in our

chronic rejection that although they can be

informative they shouldn't be used as the primary

analysis.

So, I would like to end with a summary of

the clinical data that I presented. In the lung

transplant population with no appropriate approved

drugs, very few randomized clinical trials and a

dismal prognosis that hasn't changed in almost 20

years, treatment with inhaled cyclosporine was

associated with a 79 percent decrease in the risk

of death. Treatment with inhaled cyclosporine was

associated with a 72 percent decrease in the risk

of chronic rejection or death. We have

demonstrated that our efficacy results are robust

through a number of different analyses. We have

also demonstrated that the ACS001 placebo

population is representative of a larger U.S.

transplant population. We have demonstrated that

treatment with inhaled cyclosporine was not

associated with any systemic toxicities. Finally,

inhaled cyclosporine was associated with local

respiratory tract irritation and bronchospasm, a

relatively small price to pay in light of the

profound survival benefit.

Thank you. I would like to end and turn

this presentation over to Dr. Ronald Helms,

Professor Emeritus of Biostatistics of the

University of North Carolina, who is going to spend

a few minutes discussing the statistical

considerations of the study.

Statistical Considerations

DR. HELMS: Thank you, and thank you for

the opportunity to come and address this group here

this morning. My time is short so I am going to

dive right in, if I may.

Why are we here? Well, this survival

curve tells why we are here, the profound

difference in survival in these two treatment arms,

as has been discussed at length already.

A second reason I am here is that this is

a very interesting project, a very interesting

project. Let me first establish a disclaimer and

my conflict of interest issue. The views that are

expressed in this presentation are mine alone and

do not represent either the FDA or Chiron or Rho,

my current employer, or the University of North

Carolina, my former employer. It is possible that

these views may represent the best interests of

future lung transplant patients. In terms of

financial conflict of interest, neither Rho nor I

have any financial stake in the outcome of this

submission. Less than half a percent of Rho's

total income this year will come from Chiron.

Chiron pays Rho an hourly consulting fee for my

time plus travel expenses and, in fact, my board of

directors told me they would prefer that I work on

other projects that are more financially rewarding

to the company.

[Laughter]

So, I am here despite that. Also, neither

Rho nor Chiron has edited my presentation and I

have reviewed the briefing documents that you have

seen from both the FDA and Chiron, plus some other

more comprehensive documentation. So, I feel

unconflicted here.

So, why am I here? Well, coming back to

the results of this study and the fact that it is a

very interesting project--it is a very interesting

project and we have a problem. By "we" I mean the

professionals sitting here around the table, the

FDA professionals, the Chiron staff--we have a

problem.

This Kaplan-Meier graph tells that this

product has the potential to save the lives of a

statistical number of lung transplant patients.

The NDA does not meet the usual regulatory

requirements for approval. Should it be approved?

Well, there are advantages and

disadvantages to approval in this case. The

results indicate that if approved, widespread use

of this product would probably save the lives of

around 300 to 350 lung transplant patients a year.

Now, I should just comment that my comments here

are really aimed at the non-statisticians on this

panel. The statisticians know how to interpret

relative risk and those kinds of things. I thought

it would be useful to translate this into lives

saved after a period of time when the product was

in widespread use. It appears to improve the

survival probability by about 30 or 35 percentage

points. You see the numbers there, somewhere

around 50-90 percent, and there are about 1000 or

1100 transplant patients so if you do the

arithmetic it comes out to around 300 to 350 lung

transplant lives saved a year.

Another advantage is--and this is a

practical advantage--if this product were approved

FDA could require Chiron to conduct the

sufficiently large follow-up study that Chiron has

proposed. If the study were negative the approval

could be withdrawn and, as a practical matter,

without approval the follow-up study will never be

done. Off-label use of the product would

ultimately become a standard of care and failure to

use it would be considered unethical and subject to

lawsuits and those sorts of things. And it is an

interesting aside that we have a very closely

related case. Cyclosporine, which is used

universally in the treatment of lung transplants,

is not approved for that indication; it is all

off-label use. The studies have never been done.

There are some obvious obstacles to

approval. We have the results of only one small

unconfirmed study. This is a serious problem. It

is a serious problem. This one study has a number

of flaws that have been noted by both Chiron and

FDA. Here are some opinions, one of these is very

important; some are potentially important; and some

really are inconsequential in my opinion.

The very important flaw in this clinical

trial from a statistical perspective is that the

stated primary outcome was acute rejection, not

mortality or survival. The statistical methods

that we routinely use for Phase III confirmatory

studies aren't very helpful with this problem, the

problem of switching the primary endpoint from what

was stated in the protocol to a secondary endpoint.

But good, old-fashioned common sense can be

helpful. When you see that big an effect on

survival you very likely made an important

discovery.

Now, we could use, as statisticians, a

branch of statistics called decision theory for

formal risk-benefit analyses here but the fact is

that if we did that the analyses would be based on

a number of assumptions and if you are strongly

opposed to approval here you challenge the

assumptions, and rightly so. The result is so big,

the difference in survival is so big here that we

can tell what the outcome would be anyway, that it

would lead to a decision in favor of the product.

Some potentially important flaws--let me

address those. My time is brief and I won't go

into statistical details but there is an important

side note here. At least as of a few weeks ago,

the FDA and Chiron biostatisticians had confirmed

each other's statistical calculations. The point

is that there is no issue about correctness of

populations. Now, you are going to hear different

perspectives obviously from Chiron and FDA. In my

opinion, the issues here are about how to use and

interpret the statistics, not the actual results,

and I think that is good to know.

There are some potentially important flaws

that have already been mentioned and you will hear

some more about that in the FDA presentation. The

randomization, if done improperly, could be an

important flaw; the lack of balance with respect to

important baseline characteristics; unmasking or

unblinding--we used to call it unblinding but then

I worked with some ophthalmologists and they taught

me to use the word "unmasking." The study was

conducted in such a manner that the investigators

could have been unmasked essentially, and the study

was conducted at a single clinical center, not

multiple centers.

I want to cut to the chase because my time

is limited. The bottom line is I reviewed each of

the potentially important flaws and my conclusions

for each one were that each was either not a flaw

at all or was relatively unimportant. For example,

the randomization failed to balance with respect to

all the baseline factors. It rarely does in

clinical trials, even large clinical trials. It

has been my experience over the last 15 years since

I began looking at this that only one out of

hundreds of clinical trials was balanced with

respect to all important baseline factors. So, it

is not a case of failure. On request, on somebody

else's time, I will be happy to talk about some of

these issues.

There are some unimportant flaws in the

clinical trial, and they are listed there. We

don't have to spend time on that.

Let me raise an important ethical point

for the members of the panel. Suppose the data

from this study were the results of an interim

analysis half way through the study, and suppose

the members of this advisory panel were instead

sitting as the study's data and safety monitoring

board, would we be ethically bound to terminate the

study to protect future patients who might be

assigned to placebo? I suspect that many of you

have sat as members of data and safety monitoring

boards and faced precisely this question in the

middle of a study. I have. And I believe that

everyone on the DSMBs in which I participated would

have stopped this study to protect placebo

patients, the results of the study are that

compelling.

I think there is another important ethical

point. I think the people in this room--again, the

FDA staff, the advisory panel, the Chiron

staff--are ethically bound to find a way to make

this product available on-label to U.S. lung

transplant patients. It will be used off-label.

It already is being used off-label but without

approval for some years this product will only be

available to people who can afford to pay for it

from their own funds because it won't be covered by

insurance. So, we have a product that would be

made available to wealthy people and not others.

We also, I think, are ethically bound to

find a way to make it necessary for Chiron to

conduct the proposed postapproval follow-up study.

If we don't, it won't be done. Realistically, it

can only be done as a postapproval study for

financial reasons that Chiron can talk to you

about.

What an interesting project! Thank you

for the opportunity to talk to you.

Safety and Benefit-Risk

DR. DILLY: Thank you, Prof. Helms and

thank you, everyone, for your patience in following

through our presentation. I am going to conclude

with about five minutes of remarks to end the

Chiron presentation.

What I would like to do is consider some

of the issues relevant to the potential approval of

Pulminiq. Clearly, we believe the best way to help

lung transplant patients now is to make CyIS

available. Lung transplant, as you heard, is in

many ways the poster child of the orphan drug

indication. Despite the incentive provided by the

orphan drug designation, no drugs have been

developed for lung transplantation, probably

because the economics simply don't work for a

conventional development program. So, if we are

looking for new drugs, it is going to come from

sources like this.

Now, we are not suggesting for a moment

that the burden of evidence is any different for an

orphan indication. Rather, what we are suggesting

is that we must consider the evidence that exists

on its merit and, in fact, the case for approval of

this drug is very strong.

The scientific premise for inhaled

cyclosporine is extremely straightforward. We are

giving an effective drug, with systemic toxicity,

by inhalation to achieve higher lung levels. This

has been done, of course, successfully in asthma,

in COPD, in cystic fibrosis. It is a well

precedented approach. In fact, as you heard, the

idea is so straightforward that many lung

transplant centers were already using inhaled

cyclosporine empirically before the clinical data

of ACS001 were known.

Of course, these are the essential

clinical data. Patients who received inhaled

cyclosporine in the pivotal trial lived

significantly longer than those who did not. You

have heard compelling arguments that the difference

in survival was due to inhaled cyclosporine and

that the benefit is highly likely to be

generalizable to other patients in other treatment

centers. Publication of these data will rightly

have a major impact on the treatment of lung

transplantation with or without approval of

Pulminiq. The case for benefit is very strong.

Also as you have heard, there is very little risk

of harm. This is a known drug. Local toxicity in

the lung is minor and systemic exposure is not

clinically important. Finally, this is a very

small population with an entirely clear-cut

diagnosis, lung transplantation. So, the chances

of a major public health problem from broad usage

is very, very small. In other words, the

demonstrated benefit far outweighs the potential

for harm. The bottom line is patients will live

longer if inhaled cyclosporine is made available to

them.

Of course, some questions remain open

because of the nature of the clinical program

conducted to date. So, the right thing to do for

patients is to approve inhaled cyclosporine now and

conduct the appropriate postapproval study to

address those outstanding questions. So, I would

like to finish the Chiron comments by considering

what that postapproval study should look like.

The central question really is how to give

inhaled cyclosporine. We have seen benefits from

therapy lasting for up to two years. All logic

dictates that for a chronic rejection endpoint

chronic therapy should be better. We need to study

that. We need to study dosing beyond two years.

We need to work on making the first few doses as

tolerable as possible so we can get as many

patients as possible onto an effective dosing

regimen.

We would also love to know more about the

interplay of the key clinical endpoints, survival,

rejection, lung function. You can only interpret

so far based on a single, relatively small study

with such a bright line survival effect. We

believe that 300 mg of inhaled cyclosporine by

nebulizer three times a week is a perfectly

appropriate inhaled regimen and the right thing to

put in the label, but there are some questions we

need a bigger study to answer.

How do patients do if they actually

tolerate a dose below 300 mg--100 mg or 200 mg? Is

the need for systemic dose intensification reduced

with effective long-term inhaled therapy? What is

the best way to deal with treatment interruptions,

for instance during concomitant illnesses? Of

course, it will be informative to have a much

bigger safety experience.

So, here is our proposal, essentially this

is a very large single-arm study with external

controls. We believe that we could draw the

control arm now from the UNOS database. From the

comments you heard from Dr. Golden and others, we

know what happens to lung transplant patients

treated with current standard of care. So, 250

patients will be treated with a labeled regimen of

inhaled cyclosporine for 5 years. A placebo group

is not appropriate and not necessary given the

robust survival advantage already demonstrated with

inhaled cyclosporine. There will be 2 external

controls, firstly, about a thousand matched

patients with long-term follow-on data drawn from

the UNOS database. Secondly, a group of

contemporaneous controls who will not receive

inhaled cyclosporine. The exact size of this

group, of course, will be somewhat dependent on the

rapidity of uptake of inhaled cyclosporine therapy.

So, we would expect that the availability of those

patients would go down over time.

What I am attempting to describe to you

here is a study that is entirely doable in the

postapproval context. The primary endpoint will be

chronic rejection-free survival, with all-cause

mortality and lung function as secondary endpoints.

We see three safety endpoints as particularly

interesting: Firstly, infections requiring

hospitalization because we believe that that signal

in favor of the lower incidence of pneumonia on the

inhaled cyclosporine group in ACS001 is probably

real and due to decreased lung damage from chronic

rejection, making the lungs less susceptible to

infection. Secondly, we want to look at renal

dysfunction and malignancy as readouts of systemic

immunosuppressive status, as well as diligent

follow-up for the other safety events. In fact,

this will be the largest study ever done and the

longest study ever done in the lung transplant

setting.

In conclusion, based on what we know now

lung transplant patients will clearly live longer

with inhaled cyclosporine. The outstanding

questions can be addressed in a postapproval study

and so we believe that inhaled cyclosporine should

be approved now.

Now I would like to invite Dr. Scaife to

the podium as well and we can take your questions.

DR. SCAIFE: Thank you very much, Dr.

Dilly. We can open to the FDA and the panel for

questions.

Questions from the Panel

DR. SWENSON: Go ahead.

DR. SCHOENFELD: I just had a few

questions on acute rejection since that endpoint

wasn't exactly described. How is that diagnosed?

DR. SCAIFE: Dr. Sarah Noonberg?

DR. NOONBERG: It is diagnosed by

transbronchial biopsy and it is graded 0-4. So, it

is the same transbronchial biopsy that can be used

to make the diagnosis of bronchiolitis obliterans.

DR. SCHOENFELD: So, was there sort of a

program of periodic transbronchial biopsies in

these patients during the study?

DR. NOONBERG: Yes, approximately the

first month and then three to four months afterward

for a period of two years and then as clinically

relevant. It should be noted that the mean greatly

exceeded that. All patients had the minimum and

the mean was far higher.

DR. SCHOENFELD: Another question about

acute rejection, once a patient has bronchiolitis

obliterans can they have acute rejection also?

DR. NOONBERG: Yes.

DR. SCHOENFELD: I see. So, it can happen

after the chronic rejection has begun.

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: I would like to ask Dr.

Golden if he would be willing to comment on this.

Let me give perhaps a little bit of a setting for

my concerns here. We have a study in which the

primary outcome was not met and the secondary

outcome is met that at the time the study was

conceived didn't correspond to biology that was

understood. The understanding of biology has

changed but--I would like to say I am not a

pulmonary person but I am a transplanter--is still

not very well understood. So, I think I need to

have somebody who really understands the pulmonary

rejection business to tell me a little bit about

the preclinical information on the impact of local

immunosuppression for chronic rejection in the

lungs. Right now the general assumption is that

most of the effects of immunosuppression are

central. I grant you that there is some very real

interest in the possibility of local immunocytes

being locally immunosuppressed but this is not what

I would call a robustly well understood part of

science. So, since we can't look at this really in

most of the forms of transplantation, it may be

that we have some better understanding of this from

the pulmonary point of view and I would like to get

the best understanding I can have of what is

currently understood about the impact of local

immunosuppression for pulmonary rejection.

DR. GOLDEN: First of all, nobody knows

with precision exactly where you are treating

locally along the airway. I would infer, given

that there is a difference in chronic rejection,

that that is generally a more peripheral airway

portion.

DR. HUNSICKER: Let me clarify that. I

wasn't talking where along the airway, I was

talking about central immunological events as

opposed to peripheral immunological events. Most

of us have assumed that the primary effects of

immunosuppression are central rather than in the

peripheral organs, particularly of the calcineurin

inhibitors. So, what I want to know is, is it

known what the effects of local immunosuppression

in lung rejection are in experimental models for

instance?

DR. GOLDEN: Let me make sure I understand

the question. You want to know when you give

systemic immunosuppression centrally how that might

affect the airway.

DR. HUNSICKER: Actually, it is the other

way around. Let's assume that when cyclosporine

gets into the body where it really is doing its

thing is in the lymph nodes and the spleen, and

stuff like that where the cells are being

developed. Then it doesn't make a whole lot of

sense that local application should be effective.

If, in fact, there is local effect on the lymphatic

cells that are in the bronchi, then it might make

sense. Right now this is something that is not

understood in other forms of rejection because we

can't get at the local tissues quite so well. What

is known about this?

DR. GOLDEN: I think this is a new area.

To answer it the best I can, one would have to

infer that systemic therapy does not reach a level

of mucosal benefit, that applying the medicine

locally, as you say, must have some local immune

benefit. The slide I showed of the mucosa with

lymphocytes moving into the submucosa--I can only

infer that systemic therapy or having a central

effect on lymph nodes, etc., as you say, is not

reaching a level of immunosuppression along the

airway that is benefitted by a direct local

application to the epithelium of an

immunosuppressant.

I must say that there are ongoing studies

now with other agents, like inhaled rapomyacin, to

also try and treat this. That is an animal study,

very preliminary. So, the best answer is I really

don't know. I infer that there is a benefit

locally to applying, as you can uniquely do in the

lung as you said, to a mucosal process.

DR. PRUSSIN: Calman Prussin, NIAID. Just

to follow-up, in all immunologic and allergic lung

diseases I know T-cells are being activated in the

lung locally and expressing cytokines locally. So,

if you are applying that drug locally you would

expect that it would have an effect there as

opposed to cells that are in the spleen which are

mostly resting and not producing cytokines. So, it

does make sense immunologically.

DR. SWENSON: Dr. Gay?

DR. GAY: Steve Gay, University of

Michigan. I had a question concerning the early

stoppage of the trial. Pittsburgh is a fairly

aggressive transplant institution and it seems as

if the study was initially powered for 120

patients. The study was stopped at 56 patients. I

was wondering what factors led to the early

stoppage with the fact that the primary endpoint

was clearly not achieved at that point.

DR. DILLY: The original sample size

estimate was based on the availability of patients

during the predefined study duration, and the study

ended on the day that the study was intended to

end. That was not influenced by the primary

endpoint. It was simply that there were

approximately 120-odd patients during that period

who were transplanted at Pittsburgh and around half

of those patients went on to the study. So, in

100

fact, this was a pretty good enrollment of eligible

patients at the site.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: I also have a question

about that because you say it was not influenced by

the results. Does that mean the results were not

known at that time?

DR. DILLY: The study was done blinded at

that time so the results were not known and the

blind was well preserved. We really became aware

of those results after the unblinding.

Another thing that we have looked at in

some detail--and perhaps Dr. Noonberg or Dr. Capra

would like to talk about this--is whether there was

something special about the patients that went into

the study. Was there something about the placebo

group and whether these were a selected group of

patients? All the evidence says is that these were

the same kind of patients as were not enrolled in

the study.

DR. NOONBERG: When we compared the

placebo and ACS001 to UPMC unenrolled controls we

101

found that the survival curves were comparable,

with a p value of 0.99, so these didn't represent a

select group of patients. One of the reasons for

the poor enrollment is that there just simply

weren't enough transplants performed during that

period of time. During those three years there was

a far lower time for--I am just going to stop and

show this slide quickly that demonstrate the

survival of screen failures, so patients who were

not enrolled in ACS001 and those that were enrolled

into the placebo group.

But to go back to my previous thought, I

mean, they couldn't have enrolled 136 patients.

There were 105 transplants performed during the

enrollment period. The enrollment period didn't

stop early; the enrollment period had a three-year

duration and it stopped at that three-year

duration. It just didn't enroll the requisite

number of patients that it anticipated.

DR. SWENSON: I believe Dr. Proschan has

another question, but for the members of the panel

here, if you will just simply hit your "talk"

102

button we will be able to see the light on and you

needn't raise your hand. That will probably be

easier for us. Dr. Proschan?

DR. PROSCHAN: I guess I was just

following up on that because, you know, usually

even if it is the primary endpoint to stop early

there are boundaries that you use and, you know,

the commonly used boundary is called the

O'Brien-Flemming type of boundary, and this trial

would not have met that level of evidence. But

that is a concern, mainly motivated by my thinking

that the results were known at the time you stopped

and, therefore, the possibility on a random high.

DR. SWENSON: Dr. Moss?

DR. MOSS: I have a question I guess for

Dr. Noonberg but you, guys, might answer it too.

It has to do with the generalizability of your

results and I think you showed it on that slide.

Normally when you have figures on a study you say

we screened this many people; these many were

excluded and we were left with 10 percent of the

population. That wasn't included in any documents

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but I think you brought it out a little bit there

so could you just go over that and say, you know,

these many people were screened and these many were

excluded and you were left with what percentage of

the patients that were actually enrolled in the

study, so we can get an idea about the

generalizability of your data?

DR. SCAIFE: Dr. Noonberg?

DR. NOONBERG: You want to go back to that

last slide?

DR. MOSS: I think the data was there but

you never mentioned it before. You don't need the

slide, just how many people were screened and how

many were excluded and you were left with this many

people so we can see how generalizable your data

are.

DR. NOONBERG: Right. There were 105

transplants performed during the roughly 3-year

enrollment period and there were 68

patients--actually, 58 patients enrolled during

that 3-year period; 10 were enrolled the year

previous. So, approximately half and, as I say,

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the survival in the enrolled and the placebo

survival in the unenrolled group is comparable,

with a p value of 0.99.

DR. SWENSON: Dr. Venitz?

DR. VENITZ: I want to follow-up on Dr.

Hunsicker's question in a different way. He was

questioning the biology supporting localized

administration versus systemic administration. You

obviously looked at exposure to cyclosporine after

inhalation relative to oral or systemic

administration. Did you look at exposure to the

lung in either clinical or preclinical models and

compare systemic administration to inhalation?

DR. DILLY: We actually have access to

data on a scintigraphy study looking at labeled

inhaled cyclosporine, conducted by Dr. Corcoran at

the University of Pittsburgh, and I think it would

be extremely relevant to show you those data. I

will give you the editorial comment while Sarah

retrieves the slide.

But with the 300 mg dose put into a

nebulizer, what we have seen is that about 25 mg is

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the applied dose to the lung. That is achieving

dose levels in the lung that would require

approximately doubling of the systemic

immunosuppressive dose, and that is our central

premise, which is that that is not something that

you could routinely do in clinical practice because

of the toxicities.

DR. NOONBERG: Again, just going back to

the first animal experiments in 1988 where they

just gave single doses of inhaled cyclosporine,

they found that pulmonary concentrations were

10- to 100-fold higher than concentrations in other

tissues. In the rat model that I described

pulmonary concentrations were at least 3-fold

higher than systemic concentrations. So, that is

the data that we have for preclinical.

DR. VENITZ: Again just to follow-up, how

does that compare if you give cyclosporine

systemically? You are talking about what happens

after inhalation. Right? The levels in the lung

are higher than in other tissues, higher than in

plasma?

106

DR. NOONBERG: Right.

DR. VENITZ: And I am wondering how would

that compare if a dose of cyclosporine was given

intravenously to those animals. What lung

concentrations would you be able to achieve?

DR. DILLY: What we showed was a 25 mg

dose applied to the lung through inhalation. You

have to remember that when you put 300 mg into a

nebulizer an awful lot goes into the atmosphere and

an awful lot doesn't get into the lung. That 25 mg

applied dose, in terms of mg/g lung weight, equates

to approximately an 8-fold higher systemic dose.

If you assume 100 percent bioavailability of the

systemic dose you have given parenterally, that

would mean that you are looking at something like a

200 mg dose given orally to get to the same lung

levels. That is based on AUC calculations. If you

are thinking about peak levels, then the difference

is far greater because, of course, you get the

early distribution phenomenon into the lung.

DR. VENITZ: And that is in humans? Any

preclinical data to back that up?

107

DR. DILLY: Actually, that is in the

briefing book. The best data we got is in humans.

It is actually in the briefing book.

DR. SWENSON: Dr. Burdick?

DR. BARRETT: In Dr. Golden's presentation

he showed some data looking at BOS as a disease

progression marker. However, in the documentation

provided both BOS and FEV1 were not determined to

be significantly different between the two groups.

So, assuming chronic rejection as the indication

here for this product, can you give some reasons

why you think that occurred?

DR. SCAIFE: Dr. Bill Capra is the lead

statistician for Chiron.

DR. CAPRA: Actually, CyIS did show an

effect on BOS, specifically BOS-free survival. The

reason why our results are different than the FDA's

is that the FDA censors BOS in their analysis and

this is informative censoring. Because the reasons

for death are disease related, it is invalid to

censor deaths in a disease progression endpoint.

The FDA has recently issued a guidance on

108

this type of endpoint for oncology studies where

they recommend using a progression-free survival

endpoint in such an analysis rather than time to

progression analysis. If you do such an analysis

with this BOS what you see is an effect of

cyclosporine on improving BOS-free survival with a

p value of 0.99.

DR. BARRETT: Could you comment on the

FEV1 though?

DR. CAPRA: Sure. We looked at FEV1 in a

number of ways. We looked at change from baseline

to the final value; change from post-transplant to

the final value. We looked at time adjusted area

under the curves and we looked at slopes. In none

of these analyses did we see a statistical

significance. However, in each and every analysis

the point estimate favored the active group. As an

example, up here I have the results of the change

from baseline to the final value and we see that

the placebo group increased by 0.15 L and the

active group increased by 0.40 L. So, there seemed

to be a trend, however it was not statistically

109

significant.

We think there are some limitations to the

FEV1 analysis and we think one of the major

limitations is the informed censoring. Because

there is such a large number of deaths and because

the FEV1 values cannot be obtained from subjects

after they die it goes against censoring. Also,

FEV1 itself is highly variable. Any single subject

might have short-term fluctuations and what BOS

does is it basically ignores those short-term

fluctuations and looks for a sustained 20 percent

decrease. So, when you look at BOS, removing some

of that variability, and when you address the

informed censoring by use of progression-free

survival endpoint rather than time to progression

endpoint, we see an effect of cyclosporine on lung

function, namely, BOS-free survival with a p value

of 0.019.

DR. DILLY: Can I just add one

supplementary comment? This is exactly the kind of

question that we need to nail down in the next

study because what we want to do is take a large

110

group of patients, enroll them, nail down what

their lung function is and follow them over time

because, remember, the objective of this treatment

is to preserve the lungs in a good condition. So,

actually a no-effect on FEV1 in that context in a

large group of patients would be a great outcome,

and that is what we want to show next.

DR. SWENSON: Dr. Gay?

DR. GAY: My question is to follow Dr.

Moss' question from a while ago. I am still not

clear on the number of patients, why the number is

so small, the number of patients that were included

in the study. It is essentially a single-site

study in which every therapy is an off-label one

for the treatment of rejection in transplantation.

I am trying to get a grasp of why there were so

many screening failures, essentially 50 percent

screening failures in the study over the course of

the three years. Why weren't more patients

included or made available to be included in the

study, and what were the reasons for that?

DR. DILLY: In fact, what we would

111

consider the 50 percent enrollment of eligible

patients as quite good in a clinical study. Our

experience has been typically when we are trying to

enroll clinical trials, which is what we do for a

living, that we see something like 25-40 percent

enrollment into the study. So, when we went into

Pittsburgh and we looked at this whole body of data

we were quite reassured that the patients had gone

to the study in an elegant way; that about half of

them got into the study; and there was nothing

particularly strange about the patients that did

and the patients that didn't. So, we did not see

that as an issue and we came back to the fact that

we saw the data as robust.

DR. SWENSON: Dr. Prussin?

DR. PRUSSIN: I was impressed by the

heterogeneity in terms of the cyclosporine group in

terms of the dose that they received. You know,

some of the subjects received all the doses for the

full length of the study, and various documents

suggest that something like 9/36 received 1 month

or less. So, my question is did you ever stratify

112

the analysis for survival based on how much drug

they received? It is pretty impressive that 9 of

these patients received only a month of drug and

yet presumably had a fairly good survival.

DR. SCAIFE: Dr. Noonberg?

DR. NOONBERG: There are several responses

to that question. The first is that ACS001 wasn't

a dose-response study and we don't have formal

dose-response data. However, in one of our

sensitivity analyses we did exclude patients, 14,

who didn't receive at least 80 percent of the

protocol maximum dosing and they are excluded from

analysis. As would be expected, the p value is

going to go up due to loss of power, however, the

treatment effect is essentially unchanged.

DR. PRUSSIN: But on the flip side, why

did the patients who essentially didn't receive

drug respond to a drug they didn't get? That is

what I am more concerned about, not the ones that

did receive the drug. Yes, they responded even if

the p value is going to be higher, but the ones

that essentially were on the active side of the

113

protocol but who effectively did not receive drug

still had an effect in their survival. Correct?

DR. NOONBERG: I mean, we used an

intent-to-treat analysis so we include those

patients, but there are placebo patients that have

long-term survival too. This isn't a uniformly

fatal diagnosis so you would expect to see

variability in survival. But we include the

intent-to-treat analysis in accordance with

guidelines.

DR. SWENSON: Dr. Noonberg, I have a

question that somewhat follows up on that very same

one but is occasioned by one of your graphs here,

and that is you continue to see and, in fact, you

even highlighted that more patients seemed to be

prevented in their chronic rejection appearance

following the cessation of their two-year therapy,

if I read this graph correctly. Can you explain

why this drug may, in fact, have benefits beyond

its cessation?

DR. NOONBERG: The CR that is in green on

this graph doesn't represent new diagnoses of

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chronic rejection but, rather, deaths associated

with chronic rejection. So, they are not

necessarily new rejection episodes. So, this just

highlights the strong association of chronic

rejection with death and the fact that you don't

see that in the inhaled cyclosporine group. But

the chronic rejection episodes are actually

occurring throughout the process.

DR. SWENSON: Okay. Dr. Hunsicker?

DR. HUNSICKER: On that same graph, it was

not clear to me when you put that up--you don't

have to put it back up again, I think we have all

seen it--how you made the diagnosis of chronic

rejection in those cases. Was that either well

defined BOS or a biopsy, or was that a clinical

definition of chronic rejection based on the fact

the patient had died with lung disease?

DR. NOONBERG: It is either by

transbronchial biopsy with histologic proof of the

lesion of bronchiolitis obliterans or clinical

BOS--

DR. HUNSICKER: So, all of those patients

115

that had the CR in green there either had one or

the other?

DR. NOONBERG: Correct.

DR. HUNSICKER: I have a couple of other

questions just to be sure I am correct on this, you

referred to the analysis plan. First of all, there

was a prospective analysis plan that specified that

the total survival at the end of the study was to

be used as the primary outcome rather than the data

at the end of two years of treatment? I wasn't

quite sure. There were three or more different

types of analysis that were discussed in the

briefing books. What did the original prospective

analysis plan say was to be used as the primary

evaluation? Was it total survival at March 31, or

whatever it was, or was it supposed to be at the

end of the two years of treatment?

DR. NOONBERG: It should have been at the

end of the study. Dr. Aldo Iacona, the principal

investigator is nodding his head so, yes.

DR. PROSCHAN: But it was not survival; it

was acute rejection.

116

DR. HUNSICKER: Well, I understand--

DR. NOONBERG: Right, but the survival is

the secondary endpoint--

DR. PROSCHAN: We have so many secondary

endpoints to look at, we have to figure out which

endpoint we are looking at.

DR. HUNSICKER: And the second question I

have is that I thought I found in the briefing book

that of the ten patients who were put into the

so-called pilot thing, five of them had eventually

died. Is this correct?

DR. NOONBERG: That is correct.

DR. HUNSICKER: So, five out or ten

patients, and they received treatment for the full

two years or at least as much of the two full years

as one would have expected them to get?

DR. NOONBERG: Correct. When those

patients are included in the statistical analysis,

and that was one of the sensitivity analyses that

we performed, the results were still statistically

significant. They died but the timing of death is

very important, as well as the fact that they

117

died--

DR. HUNSICKER: Sure.

DR. NOONBERG: Here is a Kaplan-Meier of

survival from time of transplantation to study end

date including the randomized and the pilot, with a

p value of 0.018.

DR. SWENSON: At this time we should

break. I know there are more questions and they

can be taken up in our other discussion sessions

later today. We will reconvene at 10:15.

[Brief recess.]

DR. SWENSON: We should make a start on

the next session, and Dr. Hernandez, of the FDA,

will lead the discussion.

FDA Presentation

Overview of Clinical Trial Efficacy

and Safety Evaluation

Discussion of Analysis

DR. HERNANDEZ: Thank you. Good morning.

During this presentation I will describe the

Division's perspective on the application for

cyclosporine inhalation solution. I will start by

118

saying that this is not a regular NDA application.

The study, submitted to support the proposed

indication, is a small Phase II study that failed

to meet its primary endpoint for the prevention of

acute rejection. However, the potential for the

prevention of chronic rejection and improved

survival are very important aspects for the lung

transplant population for which long-term survival

is mostly limited by chronic rejection.

The agency considered that the potential

survival benefit in this specific transplant

population was reason enough to accept this new

drug application for review. The proposed

indication for cyclosporine inhalation solution

requested by Chiron is for increase in survival and

prevention of chronic rejection in patients who

receive allogeneic lung transplantation, in

combination with standard immunosuppression.

In my presentation I will give an overview

of the data submitted in this NDA. Then I will

summarize study ACS001 objectives, outcomes and

limitations. I will describe the FDA review which

119

will address the following subjects: Acute

rejection, obliterative bronchiolitis,

bronchiolitis obliterans syndrome and FEV1 data,

and survival. Then I will discuss the recipient

and baseline characteristics, donor baseline

characteristics, the primary causes of death,

available autopsy results, dosing information and

related outcomes and, finally, Dr. Cavaille-Coll

will give you a summary of the safety

considerations and our summary conclusions.

The data submitted to support this

application was derived from two reports generated

by Chiron Corp. That report was referred to as

ACS001 and ACS002. The study ACS001 is actually

the name given by Chiron to the study report that

summarizes the findings from the University of

Pittsburgh Medical Center, protocol 003. In this

protocol a total of 68 patients were studied in two

phases. First, 10 patients were enrolled in an

open phase and treated with cyclosporine inhalation

solution. Then the total of 58 patients were

randomized to cyclosporine inhalation solution

120

which contains propylene glycol as a vehicle or

propylene glycol vehicle alone.

From here I will refer to these groups as

cyclosporine inhalation solution as CyIS or

propylene glycol group as PG. Twenty-six patients

received CyIS and 30 patients received propylene

glycol vehicle. This was administered by

inhalation with a nebulizer. It should be noted

that all patients received concurrent

tacrolimus-based systemic immunosuppressive

therapy.

Study ACS002 was the name that Chiron

Corp. gave to the study report that summarizes the

findings on adverse events in 70 patients selected

from seven open-label studies conducted at UPMC. I

will refer to these study reports later. Also, I

will refer to the ACS001 study and study ACS002 to

avoid confusion.

The rest of my discussion will focus on

study ACS001, and the primary objective of this

study was to determine if cyclosporine delivered to

the lung allograft by inhalation prevents the

121

development of acute cellular rejection.

As you can see from this slide, the study

failed to show superiority of cyclosporine

inhalation solution over PG vehicle. The mean

number of acute rejections of grade 2 or higher per

patient was 1.3 in the cyclosporine arm and 1.2 in

the PG arm. The median number of acute rejections

grade 2 or higher was 1 in both arms. Therefore,

the study failed the primary endpoint.

However, we noted that the sponsor

reported a difference in mortality and obliterative

bronchiolitis between the two arms. In the study

report and database OB was reported as 1 for its

presence or 0 for its absence. No additional

histopathology information was provided. The

specimens for diagnosis of OB were obtained by

transbronchial biopsies.

The reporting mortality was 12 percent in

the CyIS arm and 40 percent in the PG arm. The

applicant noted that this represents a 79 percent

decrease in risk for mortality in this specific

population. The reported rate of bronchiolitis

122

obliterans or death was 19 percent in the CyIS arm

and 60 percent in the PG arm, with a reported p

value of 0.003. It should be noted that this

difference is mostly driven by the difference in

mortality.

In study ACS001 all patients were followed

up for three years after enrollment, and thereafter

were followed up to document mortality. At the

time of the study end when the last patient

completed two years of aerosolized treatment in

August, 2003, the mortality was 12 percent in the

cyclosporine arm and 40 percent in the PG arm.

Follow-up data obtained through July, 2004 was

submitted in the NDA and it showed mortality of 19

percent in the cyclosporine arm and 50 percent in

the PG arm. Additional information submitted in

the safety update in May, 2005 showed a mortality

rate of 31 percent in the CyIS arm and 50 percent

in the PG arm.

At the time the NDA was submitted to the

agency, the limitations of the study were known to

us. These included the following: This was a

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single-center Phase II study. There was a small

sample size. The study intended to enroll 136

patients. The case report forms were created

retrospectively. Therefore, some important

recipient and donor implementation was not

captured. Some data were not systematically

collected, for example, prospective routine

transbronchial biopsies. Some data were not

available, for example, some donor characteristics

or information on management on acute rejection

episodes grade 2 or higher that appeared prior to

enrollment.

FDA concerns included the lack of effect

on the primary endpoint. We also shared the

sponsor's concerns that the study may have become

unblinded. For example, patients at UPMC with

identification numbers ending in letters B or C

received cyclosporine inhalation solution, while

those patients with numbers ending in A or D

received PG. This may have allowed the

investigators to identify if a given patient was

receiving propylene glycol or cyclosporine

124

inhalation solution.

Protocol documentation was limited.

Chronic rejection or survival were not designed as

the primary endpoints. Furthermore, the protocol

for this study did not specify how secondary

endpoints would be analyzed, and there was no

pre-specified statistical analysis plan.

There were nine protocol amendments. The

study was stopped before completing enrollment.

There were various protocol violations and there

was no stratification by risk factors important for

chronic rejection or mortality. We can give an

example such as double lung versus single lung.

Despite randomization, there were imbalances in

baseline characteristics.

Now I would like to describe our approach

to the analysis of chronic rejection and mortality

in study ACS001. Acute rejection is considered a

major risk factor for the development of chronic

rejection or obliterative bronchiolitis, and a

number of acute rejection episodes experienced

early after transplantation are considered to have

125

a significant impact on the subsequent development

of OB.

Even though acute and chronic rejection

represent different histopathology and

pathophysiology, there is general consensus that

the frequency, intensity and duration of acute

rejection episodes are correlated with subsequent

development of obliterative bronchiolitis.

Strong evidence suggests that acute

rejection is the principal cause of chronic

allograft dysfunction. However, the role of other

immunologic and non-immunological factors have to

be considered. Therefore, we examined the

following data on acute rejection, obliterative

bronchiolitis histological findings, FEV1 and BOS

clinical manifestations of the disease, and

mortality as a clinical outcome.

Obliterative bronchiolitis is an important

cause of mortality after the first year from

transplantation, accounting approximately for 30

percent of deaths. FEV1 is the best surrogate

marker available for OB, and has been proven

126

successful in describing--very important--the

pattern of lung function decline, described as

acute or chronic BOS onset; the identification of

the main risk factors for BOS; and the extent and

the rate of progression of OB.

The International Society of Heart and

Lung Transplantation subcommittee has recommended

that the slope of serial FEV1 measurements over

time, before and after a therapeutic intervention,

should be used to compare treatment responses.

Therefore, if chronic rejection is

effectively prevented, we should expect to observe

an evident therapeutic effect on FEV1 and BOS.

Obliterative bronchiolitis, as defined in the study

report, was documented by transbronchial biopsies

and was found in 12 percent of the CyIS patients

and 30 percent of the propylene glycol patients.

Now there are three points that I would

like to make regarding FEV1. First, as you can

see, FEV1 values pre-enrollment, that is, after the

transplantation but before randomization to the

cyclosporine or PG arms, were not available in 40

127

percent if the patients. This data is shown in the

first row. Second, by 3 months there is FEV1 data

on essentially all patients, all 26 patients in the

CyIS arm and 26/30 in the PG patients. Third, you

will notice that there is a difference in mean FEV1

values between the 2 groups. At all point times

the mean FEV1 values are higher for the CyIS group

as compared to the PG group. Even before treatment

assignment higher mean FEV1 values were observed in

the cyclosporine inhalation group. This difference

may be attributable to the greater number of double

lung transplants that were performed in this group,

which we will discuss later in greater detail.

Here is a graphical presentation of the

data shown in the previous slide. You can see that

even though the FEV1 values in the cyclosporine

inhalation group are higher than the PG group, the

yellow line below, the two curves are essentially

parallel. Therefore, it does not appear that

cyclosporine inhalation solution has an effect on

FEV1.

Complete FEV1 values were not available so

128

BOS, bronchiolitis obliterans syndrome, as defined

by the International Society of Heart and Lung

Transplantation could not be calculated using these

criteria. Therefore, an alternative definition of

BOS, defined by the sponsor and qualified by an

independent investigator was used.

As seen in this graph, the time to BOS

between the 2 arms is similar, and the log-rank b

value is 0.214. This also indicates that the

cyclosporine inhalation solution has no effect on

BOS. Patients who died without double-blind of

BOS, as defined by the applicant, were censored at

the time of the last follow-up for BOS.

We observed a difference in OB and

mortality at the end of the study in August, 2003.

OB was present in 12 percent in the cyclosporine

inhalation solution versus 30 percent in the PG

group. Mortality was 12 percent in the CyIS arm

versus 47 percent in the PG group. No difference

was observed in acute rejection, FEV1 or BOS. As a

clinician, FEV1 values are really, really

important. Questions like "how are you breathing"

129

are really important questions.

The association between acute rejection

and chronic rejection and the effect on patients

and graft survival is well documented in registry

and published literature. Acute rejection is a

major risk factor for the development of chronic

rejection or obliterative bronchiolitis. In light

of the strong association between acute rejection

and chronic rejection, the difference observed in

OB was not expected in the absence of differences

in acute rejection, FEV1 or BOS, and this warrants

further exploration.

Therefore, we asked the question is the

mortality difference between cyclosporine

inhalation solution and PG in the absence of

differences in acute rejection, FEV1 or BOS due to

treatment effect or could other factors account for

this difference? For example, difference in

baseline characteristics of donors and recipients

between the study arms, or other factors such as

study conduct.

I want to remind you that there was no

130

difference in acute rejection grade 2 or higher at

randomization to the drug or to the placebo arm.

In contrast, there is a clinical and meaningful

difference in acute rejection grade 2 or higher

before treatment assignment. Thirty-one percent in

the CyIS arm and 42 percent in the PG patients had

grade 2 or higher acute rejection prior to

enrollment. Although data were incomplete,

approximately 40 percent of the CyIS allografts and

50 percent of the PG allografts were colonized with

bacteria or fungi. So, this data is incomplete but

I still think it is worth mentioning it. So, if we

assume that patients who had acute rejection grade

2 or higher prior to enrollment received some type

of steroid treatment or any other treatment

augmentation, they could be predisposed to

infectious complications such as pneumonia or

sepsis.

Now I will discuss other imbalances in

patient characteristics. There is well documented

association between the type of lung transplant and

survival. In this study there is an imbalance in

131

the number of single lung and double lung

transplants between the two arms. Single lung

transplants were done in 58 percent in the CyIS arm

and 80 percent of the PG patients. Conversely,

double lung transplants were done in 42 percent of

the CyIS patients and 20 percent of the PG

patients. This difference is statistically

significant at a level of 10 percent. FEV1

pre-enrollment was lower in the PG arm and may be a

reflection of more single lung transplants in this

group.

The imbalance between single and double

lung transplant is important. The literature and

registry data show an advantage for long-term

survival and freedom from BOS in double versus

single lung transplants. Single lung

transplantation is associated with lower exercise

tolerance, poorer pulmonary mechanics, and higher

infectious complications such as pneumonia.

The International Society of Heart and

Lung Transplant registry data show that the there

is a difference in survival between single and

132

double lung transplant patients. The half-life of

double lung transplant patients is 5.3 years, as

shown in the top line, while the half-life for

single lung transplants is 3.9 years. The average

survival is shown in green in this graph.

As noted before, the information on donor

characteristics was incomplete. Therefore, we

examined the data available that was informative

about the state of the donor lung, and we noted a

difference in donor inotropic support. Fifty

percent of the donor lung transplantations to the

CyIS patients and 83 percent of the donor lung

transplantations to the PG arm came from donors

that received inotropic support.

PaO2/FiO2 ratio is an indicator of the

severity of acute lung injury and it is useful to

indirectly assess the degree of ischemic

re-perfusion injury sustained by an allograft.

PaO2/FiO2 ratio of greater than 200 percent

indicates limited alveolar damage and gas exchange.

Another difference between the two arms

was the time in the ICU. While most of the

133

patients stayed in the ICU for less than 10 days, 4

percent in the cyclosporine arm patients and 20

percent in the PG patients were in the ICU for more

than 10 days, and this is kind of important in a

single center where the criteria for keeping the

patients in the ICU pretty much remained the same

The other important thing is that it will reflect

how the patients are in terms of degree of severity

of the disease. Patients are not allowed to go out

of the ICU if there is something that still needs

to be taken care of. So, it is a good reflection

of the degree of sickness that these patients have.

PaO1/FiO2 ratio is an indicator of the

ability of the lung to perform adequate gas

exchange, and it is useful to indirectly assess the

severity of acute allograft injury. The baseline

PaO2/FiO2 ratio on ICU admission was worse in the

PG group, suggesting a major degree of ischemic

re-perfusion injury in these allografts. Also,

perioperative renal dysfunction was in 4 percent in

the cyclosporine inhalation solution and 13 percent

in the PG patients. Prolonged ICU stay, inadequate

134

gas exchange and perioperative renal dysfunction

are factors that reflect a more severe condition

after surgery.

We also looked at the time to the first

pneumonia. As noted, there were more cases of

pneumonia in the PG arm and this was within the

first one to two months of the study. The outcome

in patients with these pneumonias is summarized in

the next slide.

A large number of patients in the PG arm

had early pneumonias and there was a strong

relationship between pneumonia and death. The

relationship is not surprising given what we know

about the causes of death after lung

transplantation. The occurrence of these early

pneumonias is not likely to be related to any

treatment effect but may be related to baseline

donor and recipient characteristics or other events

which occurred prior to enrollment. These events

include but are not limited to episodes of acute

rejection requiring additional immunosuppressive

therapy or microbial colonization of the graft.

135

I would like to underline that early

pneumonia may lead to histopathological findings

compatible with obliterative bronchiolitis. This

has been documented to be a risk factor for the

development of obliterative bronchiolitis. There

were five patients in cyclosporine inhalation

solution arm and two patients in the PG arm who

developed pneumonia in the first month. By two

months there were an additional three PG patients

with pneumonia. Of these patients that developed

pneumonia, 2/5 died in the cyclosporine arm and

7/13 in the PG arm; 1/5 developed OB in the

cyclosporine inhalation solution and 7/13 in the PG

group; and BOS was observed in 3/5 in the CyIS arm

and 3/13 in the PG arm.

I want to make two observations. There is

a strong association between early pneumonia and

risk of death. Second, early pulmonary infections

and early acute rejection episodes are well

recognized risk factors for the subsequent

development of chronic rejection.

This table show the primary causes of

136

death by July, 2004. Three patients in the

cyclosporine inhalation solution arm and seven

patients in the PG group died of infections,

pneumonia or sepsis. In the CyIS arm one patient

died of graft failure and in one patient the cause

was unknown. In the PG group two patients died of

OB; one patient died of pulmonary embolism and

another from congestive heart failure, and one from

lung cancer. There were three patients in which

the cause of death was unknown. The distribution

of causes of death is consistent with registry data

where infections remain the major cause of death

during the first year after transplantation while

chronic rejection begins to become an important

cause of death after one year, as seen in table 3,

reference 1 in your background package.

Autopsy results--from the available data

in the application CRFs, narratives and data sets

we learned that some patients who died had autopsy

performed. In the cyclosporine inhalation solution

arm one patient had autopsy and OB was not

reported. In the propylene glycol arm 15 patients

137

died and there were six autopsies. In two of these

OB was reported and four of them died of infection,

and there was no OB reported out of the six

reports.

The protocol specified that patients

should receive treatment for two years. The dose

should be titrated from 100 mg to 300 mg for the

first three days of treatment, then daily dosing up

to three consecutive days with the maximum

tolerated dose, and thereafter three times weekly

dosing for two years. There was a lot of

variability in individual patient dosing in this

trial.

This table shows the number of doses

received by patients. The protocol dosing schedule

was not followed in many patients. In fact, six

CyIS and five PG patients received less than 25

doses, as you can see circled in this slide. The

large variation in the number of doses received

makes it difficult to establish a relationship

between the specific treatment regimen and the

improvement in survival.

138

Six cyclosporine inhalation solution

patients who received less than 25 doses are shown

on this table. Two patients received a single

dose; others received 3, 12, 13 and 24 doses

respectively. The doses show that not all patients

succeeded in titrating up to 300 mg. Five out of

these six patients experienced adverse events

directly related to the administration of the

cyclosporine inhalation solution, and three

patients discontinued due to adverse events, and

three additional patients withdrew consent. We

noted, however, that all six patients survived and

all are included in the mortality calculations as

cyclosporine inhalation solution successes.

There were five patients in the PG arm who

received less than 25 doses and, as can be seen,

four/five died. Could these be attributable to the

lack of cyclosporine inhalation solution? All

these deaths are included in the mortality

calculation as PG failures.

In addition to the 3 cyclosporine

inhalation solution who withdrew consent after

139

receiving 1, 3 and 13 doses, 3 additional patients

withdrew consent--these are the last 3 rows in this

slide--1 at 4 months and 2 others at 20 months.

The right-hand column shows that 2 of these 3

additional patients survived.

At this point I would like to turn the

podium over to Dr. Cavaille-Coll to discuss our

safety considerations and give our conclusions.

Safety Considerations and Conclusions

DR. CAVAILLE-COLL: Good morning. We are

in general agreement with the applicant that the

systemic safety profile of cyclosporine after oral

or intravenous administration is well characterized

and that the amount of systemic exposure to

cyclosporine, meaning what was deposited in the

lung and entered in the bloodstream before being

eliminated, was not associated with detectable

increases in systemic toxicity. There is more

limited information on the safety of cyclosporine

when administered by inhalation in a propylene

glycol solution.

As you have heard, propylene glycol is

140

classified as an additive that is generally

recognized as safe for use in food, mainly through

studies using oral and dermal exposure. It is used

to absorb extra water and maintain moisture in

certain medicines, cosmetics or food products. It

is a solvent for food colors and flavors. However,

information on the inhalation toxicity of propylene

glycol is more limited. There is no approved

product for inhalation containing nearly 100

percent propylene glycol such as this product.

The applicant has submitted some

preclinical safety data, including a 28-day study

in dogs and a 28-day inhalation study in rats. The

28-day inhalation study in dogs demonstrated lung

irritation, alveolar and interstitial inflammation

in all cyclosporine dose groups and the vehicle

control. Laryngeal inflammation with ulceration

was seen in the mid-dose group males. Inflammatory

cell infiltrates, lymphocytes, plasma cells,

monocytes were seen in the control and treated

group as well. The dog studies did not contain a

sham control. Thus, this confounded the separation

141

of the extent of pulmonary toxicity due to

cyclosporine versus that of the propylene glycol

vehicle. No additional cyclosporine inhalation

toxicity was observed in the animals. Dose levels

in the dogs were limited, however, by the maximum

feasible dose. However, serum cyclosporine levels

in the high dose group exceeded the human exposure

by 2.5-fold.

Again, there were also studies that were

done in rats which showed similar findings, except

that the doses in rats did exceed about 80-fold the

human exposure and there was evidence of increasing

toxicity with increasing doses of cyclosporine.

The rat studies did include an air control and did

show that even in the propylene glycol group there

were findings that were not present in the sham

control animals.

I would like to address now the clinical

safety. In the usual safety review we would look

at the rates of adverse events, the grade of

severity, the duration of the events and their

reversibility, as well as the temporal relationship

142

to dosing with the study drug. Collection of such

information is facilitated by the use of

prospectively designed case report forms. The

latter often provide another very useful source of

safety information in the form of handwritten

comments by the investigators on the margins of the

pages of the case report forms. Such forms and

comments were not available and it is in the

context of these limitations that we must evaluate

the safety of this product. Evaluation of safety

in this fragile population receiving systemic

immunosuppression and numerous medications is

admittedly complicated.

There are no prospectively designed case

report forms to guide the systematic collection of

safety data throughout the conduct of the study

including but not limited to the use of concomitant

medications used to prevent or treat the

complications associated with the administration of

study drug. Clinical safety data was collected

retrospectively from source materials from one

double-blind, controlled study and a number of

143

small open-label, uncontrolled studies at the

University of Pittsburgh Medical Center.

Comparative safety data is available on only 26

randomized subjects in study ACS001, or 36 subjects

that include the first 10 non-randomized subjects

from the study. Additional non-comparative safety

data was obtained in report ACS002 by pooling data

from seven open-label, uncontrolled studies that

enrolled 70 lung transplant recipients who were

receiving similar tacrolimus-based systemic

immunosuppression.

Subjects in study ACS001 were titrated in

a double-blind fashion to a maximum tolerated dose

not to exceed 300 mg or the propylene glycol

control equivalent. That dose was then to be

administered three times a week for up to two

years. As mentioned earlier, there was a great

variation in dose, 100 mg to 300 mg per day, the

number of doses administered and, consequently,

duration of exposure. I think we have seen those

slides before. Subjects also received per protocol

premedication with aerosolized lidocaine and

144

bronchodilators to improve tolerance.

This slide comes from the integrated

summary of safety and lists basically the adverse

events that occurred with a statistical

significance of greater than 10 percent. I think

we are in general agreement with the applicant's

description of the safety data they were able to

collect. We do note that there seemed to have been

more respiratory, and thoracic adverse events in

the cyclosporine group compared to the propylene

glycol group. In all these categories, of course,

as I mentioned before, the significance was greater

than 10 percent. As in the 28-day preclinical

animal studies, there was a sham treatment group to

help discern the potential contribution of inhaled

propylene glycol to the respiratory tolerability in

both treatment groups. Here we do see that more

events occurred in the cyclosporine group. These

findings in general are consistent with the

respiratory safety findings that were found in the

28-day preclinical animal studies.

Another thing we look at when we are

145

evaluating safety is the discontinuations and

withdrawal of consent. Although a greater

proportion of subjects in the propylene glycol

group, 33 percent, were reported to discontinue

study drug due to an adverse event, other than

death, than in the cyclosporine group, 15 percent,

this comparison must be interpreted with caution.

Six patients in the cyclosporine group, or

23 percent, were reported to have discontinued due

to withdrawal consent compared to none in the

propylene glycol group. Further examination of the

individual case report forms revealed a number of

respiratory adverse events associated with the

study drug administration which could have

influenced their continued willingness to

participate in the study. Taken together, a

similar proportion of subjects discontinued study

drug due to adverse events or tolerability in the

propylene glycol group and the cyclosporine group.

We also have some non-comparative data

that was presented in report ACS002 from a pool of

70 lung transplant recipients. Again, these

146

represent a variety of lung transplant types,

mostly patients with refractory acute rejection

and/or OB who were treated with cyclosporine

inhalation solution in seven open-label,

uncontrolled studies at UPMC. They were also

receiving systemic tacrolimus-based

immunosuppression. These, again, represent an

experience of a wide range of dosing and duration

of treatment, which is really very difficult to

interpret. Patients were generally administered

the maximum tolerated dose which was individualized

and depended on the characteristics of the patients

and their response to medication.

In summary, the overall safety database is

smaller than usually expected in a commercial

application. Respiratory adverse events were

common despite premedication and limited the

maximum doses used and the durations of the

treatment. Data available in the study report and

case report forms did not allow us to fully

evaluate a temporal relationship between study drug

administration and particular adverse events.

147

Ultimately the acceptability of the safety

information in this NDA must be weighed against the

degree of certainty of the potential clinical

benefit.

These are briefly our conclusions: We

have a single small study. There is no effect on

the primary endpoint of acute rejection or on

measurements of pulmonary function of FEV1 or

bronchiolitis obliterans syndrome. There are

differences observed in mortality and bronchiolitis

obliterans. There also important imbalances in the

donor/recipient baseline characteristics. There

are also variable causes of death, most with no

evidence of bronchiolitis obliterans syndrome.

There is variable dosing in both groups, and we

have limited safety information.

At this point, I would like to turn the

podium over to Dr. Jyoti Zalkikar who will present

the statistical perspective of this review. Thank

you.

Statistical Evaluation

DR. ZALKIKAR: Hello. My name is Jyoti

148

Zalkikar. I am the statistical reviewer for the

application for Pulminiq, which is the trade name

for cyclosporine inhalation solution.

I will be focusing on the efficacy of the

product during this presentation. As you know, the

efficacy of this product is based on just one small

Phase II, single-center study conducted at the

University of Pittsburgh Medical Center. This was

not designed as a confirmatory study. The planned

sample size was 136 patients as per the applicant's

study report. The investigators did not use case

report forms during the conduct of the study.

These were generated retrospectively by the

applicant. Also, there was no prospective

statistical data analysis plan and no formal

stopping rules.

The study began in 1997. The first 10

patients were who were enrolled received

cyclosporine as part of the open-label pilot phase.

The next 58 patients were randomized to either

cyclosporine with propylene glycol as vehicle or

propylene glycol alone. Two of these patients did

149

not receive any dose of the study medication and

were excluded from all analyses. The applicant

says that the enrollment was stopped in August,

2001 at 68 patients. The study was vehicle

controlled. As you know, all subjects received

systemic immunosuppression.

Now I will briefly go over some aspects of

the study design. As per the initial design, the

patients were to be enrolled from 7-21 days after

the transplant. But later a 22-42 days window was

added to speed up the enrollment. Three patients

out of the total of 56 were enrolled past 42 days

after their transplant. Randomization was

stratified by the enrollment window and CMV

mismatch. Donor positive/recipient negative was

defined as a mismatch and all other combinations of

donor and recipient CMV status were called a match.

Two out of 56 patients were incorrectly stratified.

Patients were to be on treatment daily for the

first 10 days and 3 times a week thereafter for a

total of 2 years. Thirty out of the 56 patients

discontinued treatment early. All 56 patients were

150

followed for at least 33 months in the data

submitted with the NDA. That is the database I

will be using in this presentation.

Evaluation of survival and chronic

rejection were not the primary objectives in the

study. The prespecified primary objective was

superiority over propylene glycol in terms of the

rate of acute rejection. The study failed to

achieve that objective. In fact, the mean number

of acute rejections was slightly higher in the

cyclosporine group.

Here is the graph for survival

distributions in the two arms. This graph is based

on all the data submitted with the NDA and,

therefore, is slightly different from the one based

on the study end date that was previously

presented. The 24-month line indicates the end of

protocol specified treatment period. When we saw

this dramatic survival difference at the pre-NDA

meeting we were excited and encouraged the

applicant to submit the application.

When the NDA was submitted, given that the

151

trial had failed on the primary endpoint, the

challenge for the review team was to determine if

the observed survival difference was due to

cyclosporine inhalation solution.

One of the first things we found was the

baseline imbalance between the two treatment

groups. Although randomized, due to a small sample

size, the study failed to benefit from

randomization. Several baseline factors that

clinicians consider to influence patient survival

are not balanced between the two groups. This

means that the two groups are not comparable for

evaluating survival or chronic rejection.

Here are the factors that show imbalance.

All of these are statistically significant at the

10 percent level, with the exception of grade

2-plus acute rejection prior to dosing. Dr.

Hernandez has discussed the clinical importance of

the influence of these factors on patient survival.

All patients in the study had at least one of these

risk factors.

Here is the nature of the imbalance. The

152

yellow bars represent patients in the propylene

glycol group and the red bars represent patients in

the cyclosporine group. As you can see, the

majority of the cyclosporine patients are on the

left, with two or less risk factors, whereas the

majority of the propylene glycol patients are on

the right side, with three or more risk factors.

This can occur in randomized trials, and more so in

the trials with small sample sizes such as this

one. That is why it is important to prespecify the

primary endpoint so that appropriate stratification

may variables can be used at randomization to

control for at least some factors known to

influence that primary endpoint. The study could

not accomplish that since the primary endpoint was

not survival or chronic rejection.

In this situation statistical methods can

be used to adjust for these imbalances, but using

these methods to adjust for factors individually

one at a time is not appropriate as the groups are

still not comparable due to imbalances with respect

to the other factors. For simultaneous adjustment

153

for all the factors the sample size is too small in

the study.

We also considered methods that in some

situations allow us to handle a large number of

factors such as propensity scores, but these have

limitations and there are underlying assumptions

that need to be validated.

So, given that the trial failed to show a

difference in terms of the primary endpoint of

acute rejection, given the absence of prospectively

defined analysis plan including statistical details

such as multiplicity adjustments and stopping

rules, and given the baseline imbalances with

respect to many factors, the validity of any

further inferential statistical analyses on the

data from this trial is questionable and lends to

caution.

Now I would like to draw your attention to

another problem the review team faced. The study

was designed as a double-blind study but, as you

have heard, a code A, B, C, D was added to the

patient number to aid pharmacy in preparing study

154

medication. Patients with A and D in their patient

number received propylene glycol and patients with

B and C received cyclosporine. The applicant

stated in their study report that this may have

revealed a treatment assignment to the

investigators. This fact, together with the

retrospective nature of the study, makes it

vulnerable to the introduction of bias, as

inadvertent as it may be. For example, if the

investigators knew that patients were getting

propylene glycol they may have adjusted systemic

immunosuppression to compensate for the lack of

cyclosporine, inadvertently predisposing the

patients to infections like pneumonia and sepsis

which were among the leading causes of death in the

study, as discussed by Dr. Hernandez. Detection of

the presence and magnitude of bias is difficult,

but its possibility certainly lends to caution when

interpreting the study results.

Now I would like to illustrate how small

perturbations in the assignment of the subjects in

a small study such as this one can change the

155

picture dramatically. Here is a graph of survival

distributions again. Please notice that there were

three early deaths in the control arm due to

pneumonia and sepsis. These patients received very

few doses of the study medication. The review team

felt that these deaths were not expected to be

influenced by the treatment assignment. There are

eight different possible ways to assign these three

patients to the two groups. The current assignment

is the only assignment that results in statistical

significance in terms of the p value. For

assignments in which one of these patients gets

assigned to the cyclosporine arm the p value is

over five percent. For assignments in which two of

these patients get assigned to the cyclosporine

arm, the p value is over 12 percent. And one

possible assignment in which all 3 patients get

assigned to the cyclosporine arm uses this picture.

This is completely different and no longer shows a

survival difference. This illustration shows that

due to small sample size the results of the study

are extremely sensitive to very small perturbations

156

in the assignment of the patients.

Now let's look at the discontinuations.

More than 50 percent of the patients in the study

discontinued for various reasons. Please note that

there were six patients who withdrew consent. They

all were in the cyclosporine arm. One of them was

crossed over to the open-label cyclosporine study.

All of these patients were followed for survival

even after the withdrawal of consent.

This table shows the number of doses

received by the patients in the study. As you can

see, there is large variation in the amount of

treatment received. Please note that there are 11

subjects who received less than 25 doses, which is

less than 10 percent of their protocol specified

treatment. Four of these 11 subjects received only

one or two doses. As discussed by Dr. Hernandez,

the review team felt that this short duration of

treatment would not be expected to result in

significant benefit to the patients.

Therefore, we conducted sensitivity

analyses to assess the impact of the data from

157

these patients. In the first analysis we would

exclude all 11 patients. Here are the results.

The survival difference is no longer statistically

significant.

In the second analysis we will treat the

six cyclosporine patients as a control patients.

So, we will have 20 patients in the cyclosporine

arm and 36 patients in the control arm. And here

are the results. Once again the survival

difference is no longer statistically significant.

In the third sensitivity analysis we

define treatment failure as death or

discontinuation within 25 doses due to either

adverse events or withdrawal of consent, and we

analyzed time to treatment failure. Here are the

results. These results do not show a difference

between the two arms in terms of time to treatment

failure.

I recognize that all these sensitivity

analyses are subject to criticism, but the point is

that the data from subjects who discontinued very

early and received very little treatment has a big

158

impact on the study results, as shown by these

sensitivity analyses. This certainly lends to

caution when interpreting the study results.

Now moving away from survival, I will

briefly go over some results related to lung

function. Here is the descriptive data on FEV1

previously discussed by Dr. Hernandez. Please

recall that data on pre-enrollment is missing for

43 percent of the patients in the study. But the

available data shows lower FEV1 values on average

for the propylene glycol arm at pre-enrollment

compared to the cyclosporine arm. This may very

well be the effect of observed baseline imbalance

with respect to the type of lung transplant among

other factors.

Here is the graph of these numbers. The

lines for the cyclosporine and the control arm are

parallel over the length of the study, showing that

treatment with cyclosporine had no effect on lung

function in terms of FEV1. This, together with the

observed survival difference, raises an interesting

question. Is it plausible that the patients in the

159

PG arm were predisposed at pre-enrollment due to

compromised lung function to a higher probability

of getting serious infections such as pneumonia and

sepsis and then dying from them? If so, how can

one adjust for this phenomenon to get an unbiased

estimate of the treatment effect in terms of

survival in this small data set, where nearly 43

percent of the pre-enrollment FEV1 values were

missing?

Here is a graph of time to BOS as defined

by the applicant when patients who died without

diagnosis of BOS were censored at the time of last

follow-up for BOS. This analysis is subject to

criticism of informative censoring but it helps to

assess the effect of cyclosporine on BOS in the

absence of a survival difference. Again,

consistent with the analysis of FEV1, the

difference between the two arms is not significant.

Please recall that there were 10 patients

who received cyclosporine as part of the open-label

phase of the study. There was very limited

information on these patients but here is some that

160

was available. Please note that these 10 patients

showed remarkable similarity with the propylene

glycol group in terms of 2 important factors, the

type of lung transplant and emphysema as the

underlying condition requiring lung transplant.

So, we overlaid the survival curves from

these 10 patients. Please keep in mind that the

patients were not randomized to this group so

direct statistical comparison is not possible. But

given that, this group does not seem to support the

survival difference between the randomized

cyclosporine group and the propylene glycol group.

In summary, the study failed to

demonstrate effect in terms of the prespecified

primary endpoint of acute rejection. Several

baseline factors considered to affect patient

survival were not balanced between the two arms.

There were concerns that blinding may not have been

adequately preserved in the conduct of the study.

The study is also highly sensitive to small

perturbations in the assignment of patients.

Patients who discontinued early and received very

161

little treatment had a big impact on the study

results. The study failed to demonstrate a

treatment effect in terms of FEV1 and BOS, and

additional data were not supportive.

So, the question still remains is the

observed survival difference between the two arms

in the randomized portion of the trial due to

cyclosporine inhalation solution or due to other

factors? This concludes the FDA presentations.

Questions from the Panel (Continued)

DR. SWENSON: We are ahead of time here

and there were a number of questions that were left

from the previous session. I believe we could

probably open it up to both the applicant and the

FDA. So, let me begin with Dr. Sampson.

DR. SAMPSON: I had a number of questions,

this one to both the applicant and the FDA. It is

still not clear to me about the actual data that

was collected in the original UPMC study and the

data that was collected retrospectively. I

understand the safety data was primarily

retrospective but, for example, was the designation

162

of BOS at a specific time point designated in the

charts as occurring at that time point, or was that

made by reviewing the charts and saying yes/no

there was BOS at that time point? I think I have

asked that question appropriately.

The other thing is when the charts were

reviewed, were these reviewed blinded to treatment

or did the reviewer know the treatment the patient

was on? I have several other questions in addition

but just give me some information on that, please.

DR. CAPRA: You are correct that the

safety data was collected retrospectively. The

efficacy data consisted of survival, the results of

the histology, the FEV1 data which was used to

calculate BOS. The survival data was obtained on

CRFs but retrospectively but it was confirmed

through the source data with the autopsy reports.

The results of the transbronchial biopsies were

sent electronically from the University of

Pittsburgh to Chiron. So, we didn't collect that

information on case report forms. They basically

maintained the database throughout the study and

163

they sent that database electronically to Chiron.

Similarly, the FEV1 data and their lab data as well

were collected on a central database at the

University of Pittsburgh Medical Center. Those

data were sent electronically to Chiron as well.

So, none of the efficacy data, with the exception

of the actual survival days, were collected on

retrospective case report forms.

DR. SAMPSON: There is something there

that says 20 percent reduction in FEV1 in the

presence of no other clinical symptoms. How would

that be determined just purely from FEV1? Is it

just such an automatic algorithm that you don't

look at other clinical symptoms, or was there a

judgment made on that?

DR. NOONBERG: Well, it is a definition

that was determined by a consensus group from the

International Society of Heart and Lung

Transplantation and the definition of BOS grade 1

or higher--and there is successive grading--is 20

percent decline in FEV1 from a post-transplant

maximum. Now, post-transplant maximum generally

164

doesn't occur for three to six months due to

postoperative factors. So, the missing early

FEV1's are not expected to influence at all the

designation of BOS because all patients, unless

they die early, increase their FEV1 up to a period

of time, generally an average of about three to

four or five months. Then that post-transplant

maximum, a rolling average, is used as their

baseline from which you determine a 20 percent

decline. So, that is how the definition is and

that is not set by us; that was a definition

proposed by the International Society for Heart,

Lung Transplantation. The 20 percent was just

programmatically defined and then we reviewed the

cases to determine that there were no other

clinical causes which were defined as acute

rejection, concurrent pneumonias or other clinical

causes that would impair lung function.

DR. SAMPSON: Again, were all the

retrospective chart reviews done by people--was it

possible to blind them to the treatment assignment,

or did they know the treatment assignment when they

165

did the chart reviews?

DR. NOONBERG: Treatment assignment was

known at the time of chart review.

DR. SAMPSON: I would like to switch gears

and ask a different question that I have been

puzzling a little bit over, and that is the study

design stratified by two variables, the CMV

match/mismatch and the start date. I don't recall

seeing survival data--there is possibly something

for the CMV mismatch, but does the sponsor have

survival data done by strata? In particular, one

of the standard questions when you have a

stratification factor in any clinical trial is the

question of whether or not there is strata by

treatment interaction; whether or not the survival

is comparable across strata; is it something that

is poolable? And I have not seen any demonstration

of that, I don't think, for this data either for

CMV match/mismatch or the start post day 21. I was

hoping you might have slides on that some place as

backup.

DR. CAPRA: Can we see slide CE-18,

166

please? Unfortunately, I don't have the analysis

here just limited to two stratification factors but

the results are consistent. But here, in the last

row of this slide, we show the survival analysis

where the 2 stratification factors, as well as the

other known risk factors that were imbalanced and

were agreed to by both Chiron and the FDA, were

included, namely, single versus double lung

transplant, prior acute rejection, and primary

diagnosis. The results show a significant value of

0.032 with a consistent p value. The results aren't

shown here but the results are very similar when

you just limit it to CMV mismatch and the primary

diagnosis.

DR. SAMPSON: I did some sketching of my

own. I don't have it with me for the CMV

match/mismatch. I think you have some of that

data, don't you, in the document? It is page 17 in

the document.

DR. CAPRA: Can we put slide BD-5 up,

please? You are correct, in the briefing document

there is a table showing the number of deaths by

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the CMV match and mismatch. For those who had a

CMV match, 51 percent of those--I am sorry, this is

on chronic rejection-free survival. Can we have

BD-3? For survival data, 39 percent of the placebo

subjects who had a CMV match died versus 14 percent

of the cyclosporine. Among the mismatches, 71

percent of placebo, 0 percent for cyclosporine.

The numbers are small but what we are not seeing is

we are not seeing the survival effect limited to

just one of the two subgroups.

DR. SAMPSON: Again, I agree that the

sample sizes are small, but it looks like there is

quite a bit of difference in the effect of CyIS

depending on whether you are a match or mismatch.

I realize that is the log-rank but I am trying to

figure out if it is comparable across both arms.

Would you have just a log-rank statistic on the

matched group alone for the folks that had the CMV

match? Is there really a significant difference in

survival based on 9 and 23 and 3 and 21?

DR. CAPRA: I don't have that log-rank

limited to that subgroup.

168

DR. SAMPSON: And then you don't have

anything on the other stratification variable?

DR. CAPRA: We looked at that similarly

where you see that in the case of the breakdown is

limited to 1 into 2 subgroups. But, you know, the

numbers are small and what we did was we did a

stratified log-rank rather than do a log-rank by

subgroups because the numbers are limited.

DR. SAMPSON: There wouldn't be an

interaction here though. I mean, that is clear at

least for the CMV mismatch, but you don't have that

data for the other--

DR. CAPRA: We looked at the interactions

between the major risk factors and we didn't see

any significant interactions, nor interactions with

those major risk factors with the treatment effect.

DR. SCHOENFELD: I am curious about one

other thing. You know, I looked at the AR data.

There is a real difficulty even analyzing that

data. For instance, the three patients who died

early, they may have been the bad actors and they

may have been the ones that would have had a lot of

169

acute rejections. So, I don't know if either you

or the FDA made any attempt at trying to

analyze--you know, it is a strange situations when

the primary endpoint is essentially an endpoint

which is un-analyzable. It comes from the fact

that I assume you assumed there would be no

survival difference so you chose an endpoint that

is very hard to analyze in the face of a survival

difference. So, was any attempt made to model

that? I don't see the study as negative in terms

of the AR difference.

DR. CAPRA: We looked at AR-free survival

but what happens is the ARs are occurring very

quickly and I didn't feel that that was necessarily

as meaningful on average because the effect seems

to be limited quite early in the first couple of

months.

DR. SWENSON: Dr. Mannon?

DR. MANNON: I had a couple of questions

and a continuation so let me just pose one to both

the applicant and FDA. There was a comment made

about drug levels between the two groups. That

170

information isn't always clinically obtained. Do

you have a sense of mean levels over time between

the two groups both for tacrolimus and/or

cyclosporine between the two groups?

DR. NOONBERG: We looked at mean blood

levels of tacrolimus. It is really dosed by levels

rather than by actual doses, and at the three-month

time points the results were always comparable

between the two groups. We also looked at

prednisone doses between the two groups and they

were comparable as well. We looked at

immunosuppressive intensifications between the two

groups and that was also comparable.

DR. MANNON: But these are three-month

levels that you were measuring. So, then looking

at the comparability later of intensification, that

is based on dose again or based on level?

DR. NOONBERG: I am sorry, can you repeat

that?

DR. MANNON: So, the levels that you had

at three months where you saw no difference between

the two groups--

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DR. NOONBERG: Three months, six months,

nine months, all the way up through final.

DR. MANNON: My second question deals with

nephrology insofar as there appeared to be a

significant increase in perioperative renal failure

between the propylene glycol versus the CyIS. What

was the sense of serum creatinine or calculated

creatinine clearances between the two groups, say,

at six months and 12 months? Also as a second part

of that question, was there a difference in the

possibility of dialysis or intervention of dialysis

between the two groups?

DR. NOONBERG: We looked at creatinine

levels because we had all the laboratory values

transferred electronically to Chiron, and we didn't

see any difference in creatinine levels at the same

specified time periods. moxifloxacin

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: Yes, I would like to

address a question both to Drs. Zalkikar and also,

if he is still willing to talk about things, Dr.

Helms. I am interested in what I might call study

172

ascertainment bias. This is a small study. Let me

again start out by saying that the reason that we

are here is that there was a striking p value for

the difference in survival. So, that p value is

reasonable if it is a true p value that is not a

selected p value. The company has described how

they became involved in this as having been told by

a rep. that there was a study that was remarkably

positive. So, we have here now a selected study.

This is a classic issue in selection bias of

studies, or what is called publication bias, and I

would like to have both Dr. Zalkikar and also Dr.

Helms discuss how seriously we should take this

primary p value given that it was a study that was

selected on the basis that the p value was highly

significant, without knowing how many studies it

might have been selected from. What I am basically

doing is challenging whether the primary p value is

a real p value. Did you understand my question,

Dr. Zalkikar?

DR. ZALKIKAR: The primary p value was

actually the p value associated with acute

173

rejection because that was the primary endpoint.

DR. HUNSICKER: No, I am sorry, I am not

talking about the designed study's primary p value.

I am saying that we are looking at this study

because it has a p value of 0.007, as I recall. Is

that something that we can rely on, that this is

truly an unexpected result based on chance given

that the study was selected based on the fact that

there was a very highly significant primary p

value?

DR. ZALKIKAR: From the only analysis that

I have seen in the data, I would be very concerned

that the study was selected in terms of the p

value.

DR. HELMS: You remind me of a couple of

students in my linear models class who always ask

the tough questions. I think the short answer is

that the p value that is reported with the

Kaplan-Meier curve is not a real p value. I have

warned you in one of my slides that the opinions I

express are not those of Chiron or FDA, or anybody

else perhaps. There is some obvious selection

174

going on here.

But if you will let me be informal for a

moment, the difference is so big it passes the

intraocular trauma test--it hits you between the

eyes. So, if there were a good statistical

procedure--I also made the point in my slides that

this is the primary problem here. This is the real

problem that we are facing because we don't have a

real p value. As I said, we could do the decision

theory analysis. But, again, if you didn't want to

approve it you could question the assumptions, and

so on. But the difference is so huge that we

cannot ignore it. So, the short answer to your

question is no, the p value--I mean, you could put

in as many decimal places as you wanted; it is

computed, but it is not a real p value in that

sense.

Let me make a point that might help, and

my statistical colleagues can correct me.

Basically, this is high stakes gambling, and the

best people at gambling in the world are the

casinos and there are certain bets in a casino

175

where you get partial data and then you can place

an additional bet. Black Jack is one of those. I

am not an expert at that. We are in that kind of a

situation. We now have the results. How striking

are these values? And it is very difficult for

statisticians to come up with real answers to that

question. We have to bounce back to common sense.

DR. HUNSICKER: If I might, I do have one

other question. There seems to be a difference

between the survival curves that we have been shown

by the company and by the FDA based on time to

either BOS or death, depending upon exactly how the

BOS has been defined. I am not sure I understand

whose graph is the one that I should be looking at.

As I understand it--and I am putting this question

to both groups--as I am understanding it, the

company has shown us that if you look at time to

BOS, when you include death when it is presumed to

be due to BOS there is a significant difference. I

think you showed 0.01, or something like that.

When the FDA showed this based on censoring all of

the patients whose death was not proved to be due

176

to BOS, when that BOS was defined according to a

specific thing, it was no longer significant. I do

not understand what the discrepancy is here. Can

this be clarified for me by the company and by the

FDA?

DR. CAVAILLE-COLL: Well, I think that all

the BOS-free survival is largely driven by the

difference that is observed in mortality, and we

tried to look at it differently. Is there a

possible way of seeing an effect on BOS? Looking

at the FEV1 plots, we don't believe that there

really is a treatment effect on BOS. Certainly, we

were not able to use the definition of the

International Society of Heart, Lung

Transplantation because the baseline would require

the average of two maximum values more than three

weeks apart. We didn't have that type of database.

So, we were able to look at it basically based on

the applicant's definition, but we are really very

concerned about the completeness of the collection

of that data.

I also want to go back to another issue

177

having to do with the background immunosuppression.

That information was not available in the original

application. We had to request some of that

information from the company, and they even said

there was a lot of difficulty in collecting that.

Therefore, we asked them to provide us at least

with some summary statistics of what would be the

mean exposure at certain time points to at least

give ourselves a qualitative impression of whether

there was similar treatment between the two groups.

But this is certainly a very unconventional

application and we did not have the level of detail

that we normally get in an application.

DR. HUNSICKER: Could I get the company to

clarify for me then? If you use your definition of

BOS, which we understand cannot be ISHLT's

definition because you don't have the baselines--if

you use yours and do time to BOS, whether it was

ascertained at death or otherwise, do you or do you

not find a significant difference?

DR. CAPRA: We find a significant

difference and there are two differences between

178

our analysis and FDA's. Number one reason is the

informative censoring because we are including

deaths as an endpoint, as occurs by FDA's own

guidelines for oncology studies. I also want to

make the point that we did get all the FEV1 values

electronically from the Pittsburgh database. There

were no values that were missing from our data.

The second difference is that we are

including in a definition of chronic rejection both

BOS, as determined by a sustained decrease in FEV1,

and OB, defined by presence of OB or change on

bronchial biopsy.

If we could show slide CE-30, please.

Combined in that chronic rejection analysis we are

including as chronic rejection either OB or BOS.

When we censor those patients and, granted,

informative censoring is going to bias against the

treatment groups, we still get a significant value

of 0.015 in favor of the treatment group.

This is an analysis of chronic

rejection-free survival with deaths censored, and

it demonstrates that inhaled cyclosporine prevented

179

chronic rejection. So, the effect of cyclosporine

on chronic rejection was not determined solely by

mortality.

DR. HUNSICKER: If I could be clear on

this because I think it is a fairly important

thing, Dr. Cavaille-Coll, do you agree that this is

an accurate survival curve, assuming that you are

now looking at time to chronic rejection as

evidenced either by BOS in accordance with the

applicant's definition or biopsy documented OB? Is

that fair?

DR, CAVAILLE-COLL: This is one of the

retrospective analyses. This was not from

prospectively designed data analysis plan, and it

is combining two things, OB as diagnosed by

transbronchial biopsy, for which we know the

sensitivity is fairly poor--the specificity is

great but the sensitivity is very poor, and also

bronchiolitis obliterans syndrome, which is the

clinical description of that. As we have seen

before in the FEV1 plots, there really is no

treatment effect. If you want to look at it this

180

way I am not sure how we would interpret that p

value when you are combining two different types of

things.

DR. HUNSICKER: But I am taking a

clinician's judgment here that if there is anything

that you can say, it is that when you have a biopsy

documented OB, that is OB, for God's sake. So, if

you add biopsy documented OB into your analysis, do

you then get this graph?

DR. CAVAILLE-COLL: We didn't do this

particular analysis and we didn't mix OB with BOS

because BOS tells you something about the rate and

the extent of progression. The transbronchial

biopsy doesn't tell you anything about the extent

or the rate of progression so we didn't mix the

two.

DR. SWENSON: Dr. Hernandez, do you have a

quick question here relevant to this?

DR. HERNANDEZ: Yes. I just want to make

a comment from a clinical perspective. When you

are analyzing chronic rejection and you combine OB

and BOS there are several things that you have to

181

take into consideration. The first is the natural

history of the disease of chronic rejection. It is

something that can be rapidly progressing; it could

be slowly progressing. So, the diagnosis of OB by

transbronchial biopsy in a patient that has a very

slow progression is not of the same significance as

the patient that has, you know, OB biopsy diagnosed

that is rapidly progressive. That is why the best

surrogate marker is FEV1.

So, when we are trying to analyze by

putting together two of these definitions for

chronic rejection we come to that problem. So, the

problem of this natural history of the disease that

we still do not understand is not only due to

immunological causes. There are other non-immunological

causes that contribute to how this

disease behaves. So, basing our diagnosis and

taking that as an endpoint as OB by biopsy becomes

clinically not really meaningful because the bottom

line is how well the patient is breathing, and FEV1

as a diagnosis of BOS is really relevant.

DR. NOONBERG: I just want to make the

182

point that Dr. Golden made initially, which is that

OB and BOS are not two different entities. They

are clinical and histologic manifestations of the

same process. The problem with BOS is that you

have to use an unexplained decline in FEV1 and we

already know that BOS is intricately related with

pneumonias so patients will often have pneumonia

and, by definition, you have to say, "okay, not yet

BOS," wait for the pneumonia to be treated and see

whether the decline in FEV1 is still there and the

patient gets another episode of pneumonia.

So, the diagnosis of BOS, exactly when you

get BOS, is very hard to make, unlike

transbronchial biopsy where you have that

diagnosis. Really it is a spectrum of disease and,

therefore, we feel that both have their strengths

and limitations in the diagnosis and the

specificity and sensitivity, but they are the same

clinical process.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: Yes, I think that was a

really good question Dr. Hunsicker asked and I just

183

wanted to clarify. In your analysis--you may want

to pull up a chair--

[Laughter]

--in the analysis that you did, are you

saying you effectively used the composite endpoint,

death or BOS, or did you only count deaths for

which you could confirm there was BOS?

DR. CAPRA: It was death or BOS. In the

analysis of chronic rejection-free survival we

include all-cause mortality. So, it is death or

chronic rejection or both.

DR. HUNSICKER: But is it not the case

that the non-prospective--all of that

stuff--analysis that showed time to either death

with documented BOS or OB with death is not due to

those documented, censored?

DR. CAPRA: Yes, 0.015. So, we looked at

a sensitivity analysis where we censored deaths.

So, we included just time to first case of chronic

rejection, either OB or BOS, and we basically

ignored death and that was significant.

DR. BRANTLY: I still have one concern.

184

The definition that the sponsor is using for BOS is

20 percent drop. Is that correct?

DR. CAPRA: It is the 20 percent drop from

the previous peak FEV1 that is unexplained by other

clinical manifestations.

DR. BRANTLY: My concern in using that is

basically the difference between a double lung

transplant and a single lung transplant because,

obviously, if you use that 20 percent it is going

to take a lot longer to drop to 20 percent on

double lung than it is on single lung.

DR. CAPRA: Not necessarily. Dr.

Zalkikar, in fact, showed that the double lungs had

higher FEV1s and we agree with that. But we are

looking at a change, a decrease in 20 percent. So,

a double lung transplant subject who is starting

with an FEV1 higher has more room to drop.

Basically, what happens is you are controlling for

that in the analysis because you are looking for a

change from the previous values.

DR. SAMPSON: Excuse me, we have seen OB

or BOS censored by death. We have seen BOS

185

censored by death. Does somebody have OB censored

by death?

DR. CAPRA: We have that.

DR. SAMPSON: Did you show it to us? Did

I miss that?

DR. CAPRA: No, we haven't presented any

of that. It is one of our backups. Can we look at

SA-35? Again, this is censoring deaths. It

includes informative censoring so it is going to be

biased against the treatment group. But when we

look at this analysis we get a p value of 0.06 on

time to first case of OB.

DR. SAMPSON: And this is the deaths that

resulted from OB that are included as an OB event?

Correct?

DR. CAPRA: No, but they would have had OB

before. It is only cases of OB documented through

the histology. We are ignoring deaths in the

analysis. We are censoring those subjects. So,

those subjects who died for other causes are

basically censored in the analysis. Subjects who

had an OB and later died are included on the

186

Kaplan-Meier curves at the time of first case of

OB, first diagnosis of OB.

DR. SAMPSON: I am not asking the right

question but I am going to try, were there subjects

that did not show OB before death but on autopsy

were diagnosed as dead primarily from OB?

DR. NOONBERG: In our autopsy reports all

patients that were said to have had OB were called

OB, and none of the patients that we didn't say had

OB have OB on autopsy.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: I would like to think about

the biology of what happens in the lung a little

bit. We have this huge difference between the two

groups and you would have thought that if the huge

difference is due to the only thing we think

cyclosporine can be doing you would have a huge

effect on what you think cyclosporine is supposed

to be doing. We have just had a long argument

about OB and, leaving that aside, I am also

concerned about the absence of effect on acute

rejection. If the tests we are looking at for both

187

OB or chronic rejection and acute rejection are

meaningful, it is of some concern.

In particular, we have talked about

systemic versus local effects and the biology of

that, and I think that is a bit speculative at this

point, as people have said, but one thing that is

very clear is that cyclosporine is chemically very

lipophilic and it ought to move rather quickly

through the small distances between the bronchioles

and the small vasculature. I am concerned about

the interpretation that somehow this is only

affecting what is going on in the respiratory space

and not in the vasculature nearby where it ought to

have a big effect on acute rejection if it is an

immunological effect that the cyclosporine is

having. So, I just wonder if there is anything

more to be said about that.

DR. DILLY: Because of the very phenomenon

you describe, the lipophilicity, we know that when

cyclosporine is given directly into the lung the

plasma half-life is actually 40 hours as opposed to

when it is given systemically where the plasma

188

half-life is six hours. So, it is clearly sticking

around in that compartment for a long time.

Now, one admittedly simplistic way of

looking at this whole picture is that everyone was

getting full dose of systemic immunosuppression.

If you accept that acute rejection is largely

driven from the vascular compartment you would

expect it to be treated similarly in both groups

because we believe, for the reasons you say about

the short diffusion distances, there is really

little difference between getting immunosuppression

into the vascular compartment and diffusing out on

both sides in terms of the vascular compartment.

In fact, we think the very lack of an

effect on acute rejection makes the chronic

rejection difference more meaningful because we

don't have the confounding variable. Imagine if

were trying to interpret this study and there was a

huge signal that cyclosporine had suppressed acute

rejection, then we would all be standing here,

saying, well, you can't then surmise it did

anything to chronic rejection. So, our hypothesis,

189

put really simply, is acute rejection was treated

systemically; we are treating chronic rejection.

The fact that there was no difference in acute

rejection actually makes the effect on chronic

rejection and survival more interpretable rather

than less interpretable. We are deliberately

keeping it simple right now because that is the

extent of our biological knowledge if we are really

truthful about it.

DR. SWENSON: Dr. Tisdale?

DR. TISDALE: I am having trouble here.

There are two pieces of data--I didn't mention when

I introduced myself that I am a hematologist so I

don't know anything about the way that you grade

BOS in this clinical context, but there are two

pieces of objective data that I find very striking.

One is the survival curves that you presented and

the other is the analysis of FEV1, which are

parallel. So, to me these seem almost

irreconcilable. On the one hand, we have mortality

decrease presumably due to decrease in chronic

rejection, which should be shown by change in the

190

slope of the FEV1, much like you would see for

creatinine in chronic allograft nephropathy.

So, I am wondering, number one, did you do

the analysis for the FEV1 with all patients, or was

that censored in some way? If so, maybe somebody

could comment to me on what is the proposed

mechanism of action of inhaled cyclosporine if it

doesn't prevent a decline in FEV1?

DR. CAPRA: We did look at FEV1 in a

number of ways. We looked at changes from

baseline. Could we have slide SA-27 up, please?

We saw a trend in favor of the active group. This

is a representative example, a 0.15 increase in the

placebo group versus a 0.40 increase in the

cyclosporine group. It was not significant, as

were all the analyses, but all the analyses did

trend towards a favor of the active group.

Could we have the next slide, please? We

think the reason why is because of two reasons.

Number one is informative censoring. We are not

able to get FEV1s on subjects after they are

deceased. Secondly, FEV1 is highly variable and it

191

is subject to short-term variations. The BOS

analysis basically ignores short-term variations

and looks at a sustained 20 percent decrease in

FEV1. By sustained, it has to be for a period of

at least 3 weeks.

So, ignoring the short-term variations and

addressing the informative censoring what you have

is an analysis of BOS-free survival and that was

significant, with a p value of 0.019. We are not

claiming a direct effect on FEV1 because we did not

hit that statistically in the analysis, but we do

think that these data support that there seems to

be some improvement in lung function, namely,

through BOS-free survival.

DR. HUNSICKER: Could I address that

specific issue very quickly? You said that you

can't get the data after the people have died, and

that is true, but you can do a mixed model and

still get an accurate and relatively unbiased

assessment of whether there is a difference in

slope and I am surprised that that wasn't presented

by either of you.

192

DR. CAPRA: We did look at slopes through

a mixed model in the NDA and, again, that was not

significant but the point estimate favored the

active group.

DR. HUNSICKER: That should eliminate some

of the problems of missing data.

DR. NOONBERG: One of the pieces that we

looked at, since it is the heart of your question,

is biological plausibility and, to simplify it,

chronic rejection is mediated in the airway

epithelium. Dr. Golden has described that the

epithelium is key to this process and we are

delivering an immunosuppressant directly to the

airway epithelium. Chronic rejection is a

progressive problem and so it is decline in FEV1

but it is also recurrent pneumonias and all sorts

of other complications. Graft failure as you see

in the chronic rejection process is really a setup

for all sorts of mortality and, therefore, the key

point that we want to make, and what is so

important about the analysis where we censored the

deaths with our chronic rejection, is that

193

treatment with inhaled cyclosporine prevented

chronic rejection, and by preventing chronic

rejection we improve mortality. I mean, it is

clearly more complicated than that but that is the

simplified story and to me, as a clinician, it

makes good sense.

DR. SWENSON: Dr. Barrett?

DR. BARRETT: I was really struck by Dr.

Zalkikar's simulations or the analyses looking at

the assignment, in particular one looking at

partitioning out subjects who got little drug. I

know there was no a priori statistical analysis

planned, but I guess I was curious from the

standpoint of the sponsor, would you declare

evaluable subjects based on the limited number of

doses received with inhaled cyclosporine based on

this data? And what is your take on that?

DR. DILLY: Our take on that is that when

we go from 26 patients treated with active and

long-term follow-on to 10 times that number we will

be able to draw a much more accurate confidence

interval around the trajectory of the patient. We

194

think that is really the bottom line of what needs

to be done now because I think Prof. Helms'

statement about is the p value real--who can say?

We want to put a real p value on what happens to

respiratory function; what happens to survival;

what happens to chronic rejection. At the moment,

we need to include in the prospective study that we

want to do an intent-to-treat analysis because we

want to describe what happens when patients are

prescribed 300 mg three times a week of inhaled

cyclosporine. So, yes, we would evaluate those

patients. Does that answer your question?

DR. BARRETT: No, I guess I was looking at

if you were going to define criteria on evaluable

subjects based--I mean, in this situation you had

difficulties. Again, it was a study that was done

already at the University of Pittsburgh, but very

heterogeneous dosing exposures.

DR. DILLY: So, one of the things that we

have clearly not done, we have clearly not got a

formal dose-response study sitting in front of us.

Right? One of the analyses that we want to do is

195

an achieved dose duration analysis versus benefit.

Absolutely, that is one of the critical parameters

in the study.

DR. ZALKIKAR: Can I just put in a couple

of words regarding FEV1? We looked at the FEV1

data as much as we could. The pre-enrollment data

was missing on a large number of patients, as I

mentioned. We tried to impute the pre-enrollment

data by the type of lung transplant that the

patients received and see the difference between

the final FEV1 and the pre-enrollment FEV1, and

none of those analyses has shown any difference

between the two arms.

We also looked at the three-month data and

treated that as some sort of baseline because it

was available, and saw a difference from that to

the final FEV1 that was indicated in the database

and, again, there was no difference between the two

arms in terms of that.

DR. PROSCHAN: Yes, I thought it was very

interesting to see the sensitivity analyses, and it

seems like both parties did something

196

reasonable--you know, not that you haven't been

doing other reasonable things. You basically threw

out those early deaths and did a sensitivity

analysis and showed that the results were still

significant. On the other hand, you switched the

treatment labels and showed that things become not

significant once you do that.

You know, I want to go back to their

analysis. You would think that if you threw out

those three placebo patients with the early deaths,

you are throwing out sick patients and, therefore,

the remaining placebo patients should be healthier

than the patients left in the CyIS arm. So, it

seems like that is somewhat reassuring, that even

when you throw those out it retains the

significance. I guess it is not really a question

but a comment.

DR. SWENSON: At this stage we are close

to the end of the morning session--oh, Dr. Reiss?

DR. REISS: I just have one question. It

might have been discussed and I might have missed

it, but the bronchial biopsies for the diagnosis,

197

were they done in a routine, standard manner or

were they done for cause?

DR. NOONBERG: The short answer is both.

There was a protocol specified minimum and then

also for clinical cause.

DR. WATKINS: At this point, I just have a

brief statement before we adjourn for lunch. I

would like to remind the committee that, in the

spirit of the Federal Advisory Committee Act and

the Sunshine Amendment, discussion about today's

topic should take place in the form of this meeting

only and not occur during lunch or in private

discussions. We ask that the press honor the

obligations of the committee members as well.

Additionally, any open public hearing

speakers who have not yet checked in, please do so

at the registration desk. And, if everyone could

return just prior to one o'clock we will reconvene.

[Whereupon, at 12:00 p.m., the proceedings

adjourned for lunch, to reconvene at 1:00 p.m. this

same day.]

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A F T E R N O O N P R O C E E D I N G S

DR. SWENSON: Welcome back to the

afternoon session. This session will have

initially an open public hearing to hear from

interested parties outside the company and the FDA.

Then we will move back to general discussions of

concerns and problems and issues, and then

ultimately we will vote on the particular questions

that are posed to us by the FDA.

Before starting the open public hearing, I

would like to read this particular message: Both

the Food and Drug Administration and the public

believe in a transparent process for information

gathering and decision-making. To ensure such

transparency at the open public hearing session of

the advisory committee meeting, FDA believes that

it is important to understand the context of an

individual's presentation.

For this reason, the FDA encourages you,

the open public hearing speaker, at the beginning

of your written or oral statement to advise the

committee of any financial relationship that you

199

may have with the sponsor, its products and, if

known, its direct competitors. For example, this

financial information may include a sponsor's

payment for your travel, lodging or other expenses

in connection with your attendance at this meeting.

Likewise, FDA encourages you, at the beginning of

your statement, to advise the committee if you do

not have any such financial relationships. If you

choose not to address this issue of financial

relationships at the beginning of your statement,

it will not preclude you from speaking.

So, with that said, I would like to

introduce Miss Esther Suss. She will be our first

presenter. Miss Suss, are you here? You can use

that microphone over there.

Open Public Hearing

MS. SUSS: Before I start my statement I

would like to point out to the board members that I

was one of five persons on Team Pittsburgh who

agreed to be filmed and interviewed by Chiron

during the 2004 Transplant Games as part of an

internal campaign by Chiron to...[microphone

200

off]...

As a follow-up to that interview that I

gave at the games, Chiron asked me to demonstrate

the use of inhaled cyclosporine as part of a

demonstration DVD to be given to new users of this

therapy. Thus, in March of 2005 Chiron paid my

travel and other expenses to Orange County,

California for the taping of my portion of the DVD.

Now, ladies and gentlemen, I appreciate

the opportunity to tell my story in this public

forum because I feel that the FDA approval of

inhaled cyclosporine is extremely important to

persons like me. For over 30 years I worked for

the International Monetary Fund and traveled

extensively to Latin America, Europe, the Soviet

Union and Africa. In fact, in 1992 I opened the

IMF's rep. office in Latvia and was essentially the

ambassador there and I lived there for two years.

After working in Latvia, I then was based in

headquarters but traveled to Uzbekistan where I

worked for two and a half years, and then to

Armenia where I worked for two years, and then I

201

returned to work in Latin America.

During this time I often had trouble with

some bronchitis, some asthma but I was away from

Washington for over half of the year. In January,

2000, after a vacation to Florida and a visit to

Pittsburgh to see my family over the holidays I

came down with what I thought was the flu and had

trouble breathing and my inhalers weren't working.

At that point, I finally went to the doctor. I

went to the hospital and I was admitted to the

hospital where my doctor told me we think it is

just an exacerbation of your asthma by the flu;

your x-rays look fine. But the next day I had a

classic asthma attack in the hospital and went into

total respiratory failure. After not improving for

the next two weeks, they brought in a

pulmanologist. The pulmanologist told me "you're

in end-stage emphysema and you will never go off

oxygen again." And I was devastated. I was 52

years old. I couldn't believe that this could

happen so quickly and I asked him, "how could this

happen?" And he said, "first of all, your x-rays

202

were terrible. Secondly, some people push

themselves so that they use up every margin that

they have and when they fall, they fall completely

off the cliff." And, that was the situation that I

was in.

At 52 I faced the possibility of never

being able to travel again, quite honestly. I

spent about a month in the hospital and was able to

improve significantly more than they had

anticipated. In the end, by the time I was out in

a month, I was on oxygen only when I was doing any

real physical activity. But I returned to work

full-time and during the day I didn't really need

to use my oxygen. But if I needed to walk--today,

for example, to walk from this building across the

street to the cafeteria would have just about

killed me even using my oxygen.

In June I asked my doctor to check, to do

PFTs again to see if anything had really improved

and the answer was no, it hadn't. That was as good

as I was going to be. I was told then the only

other thing to do was to have a transplant. So, I

203

asked my doctor to write the necessary letters of

introduction and I was evaluated both at the

University of Pittsburgh and at NOVA Fairfax. I am

originally from Pittsburgh. I have my Ph.D. from

the University of Pittsburgh. My younger brother

is a physician from the University of Pittsburgh

Medical School. So, I was pretty familiar with the

programs in the hospital there and I felt quite

comfortable with the people there.

Well, 22 months and five calls later I got

my transplant in August, 2002. It was just

incredible. On August 13, 2002 I had a new

beginning. I had a new lung. I no longer had blue

lips, and for one week my progress was impressive.

Then I had a major acute rejection, was in the

intensive care unit on a ventilator for several

weeks, and I just kept taking one rejection after

another. I had an agreement with the doctors and

Dr. Iacona was wonderful--"if you don't give up on

me I'll keep fighting" and that model has worked

very well. They haven't given up on me. I kept

fighting and here I am today.

204

I returned to Washington in November of

2002 to have Thanksgiving with friends but then had

to be rushed back to Pittsburgh again at the

beginning of December with a major infection which

resulted in another rejection episode, and came

back to work full-time in March, 2003 and I started

traveling again. I went to South Africa to visit a

very dear friend in October but, unfortunately, in

December, 2003 I came down with a viral infection

which got my immune system roughed up again and

gave me another acute rejection. At that point the

doctors decided, once they got the acute rejection

under control, to put me on the inhaled

cyclosporine therapy.

Since then I have spent the whole year of

2004 out of the hospital and, with the exception of

an intestinal flu on New Year's Day of 2005, I have

been out of the hospital and I have not had a

rejection episode for over a year. I have been

able to resume my life that I had before I got

sick. In October, 2003, as I said, I went to South

Africa to visit a dear friend and in June, 2004 I

205

took my nephew to Paris and Madrid for his 13th

birthday. I participated in the 2004 Transplant

Games where I ran an 800 meter, women's 800 meter

and got a silver medal, and I did a 5K in about one

hour. Pre-transplant I would never have been able

to do that even with oxygen in two weeks, the 5K.

The inhaled cyclosporine is the first, and

at this time the only drug which is aimed at

preventing or at least postponing the onset of

chronic rejection. I am a classic profile for

someone who will get chronic rejection because of

my multiple acute rejections. For those of us who

have been given a second chance for having a good

life it is so important to have this treatment

available. I am eternally grateful to my donor for

the gift that I received and I feel that wherever I

go I am taking my donor with me, and I hope that he

enjoys traveling because he is doing a lot of it.

I am aiming at setting the record of being

the longest survivor as a lung transplant

recipient, not withstanding the survival statistics

that you all know quite well. As we know,

206

statistics are for large numbers of people and for

any individual they don't necessarily apply, and I

intend to be on the plus side of those statistics.

And, I believe that by using the inhaled

cyclosporine I am doing everything possible that I

can to preserve and protect this wonderful gift

that has been given to me and that it will help me

accomplish my goals.

I have had no adverse reactions or

problems using the inhaled cyclosporine, and my

hope is that your approval of this drug for the

general population will allow many other people to

have the same long-term goals for themselves.

Thank you.

DR. SWENSON: Thank you Miss Suss. Our

next speaker is Mr. John Sullivan.

MR. SULLIVAN: My name is John Sullivan.

I appreciate the opportunity to address you today.

I have not had any financial rewards from UPMC or

Chiron to come here and speak.

I would like to tell you a little bit

about myself. I had alpha-1 anti-trypsin

207

deficiency when I was 35 years old. That was in

1981. In 1991 I had a single right lung

transplant. I did fairly well for about six months

when I came down with pancreatitis which they for

some reason thought immune suppression caused. So,

they had to reduce my immune suppression and I am

still alive but after three weeks my lung capacity

had greatly been reduced and I was rejecting. I

had a couple of bouts of acute rejection then I had

chronic rejection.

In 1994 I came down with aspergillus and I

ended up there at the UPMC for three months on a

ventilator. Then I went home for three years on a

ventilator and I was put back on the list again. I

was lucky enough in February, 1997 to receive a

double lung transplant. I had to have a double

because of the aspergillus. I was in a coma for

two weeks after that and I also lost my kidney

during that operation. As soon as I came out of

the coma, Dr. Iacona and also Dr. Griffith put me

on inhaled cyclosporine because I already had shown

that I was a chronic rejector. I have been on

208

inhaled cyclosporine to the current time. I have

been reduced to once a week.

The only time I have had any chronic

rejection or any type of rejection was in June of

1997. I had fallen and broke my left hip. So

then, when they put the pins in I came home and I

was doing fine for about 10 days. All of a sudden

I had a grand mal seizure and I drove my femur

straight through my pelvis on my right side but and

on the other side bent the ball right over. But

because of the grand mal seizure they put me on

dilantin which reduces or dilutes your immune

suppression. So I went into acute rejection. I

was actually in Michigan and then Pittsburgh had me

switched over to Norantin. That is the only

rejection I have had since 1997.

In January of this year I had the flu and

my immune system kicked in. My temperature went up

to 102, which isn't very good. And, I was on it

once a week. They jumped it up to twice a week,

hoping to stop any kind of rejection. I have had

my PFTs done as well as biopsies and I show no

209

signs of rejection at all.

I feel that the main reason I have done so

well is because of the inhaled cyclosporine. I

think that has helped me. I don't show any

rejection and there hasn't been any adverse effect

on me at all. Thank you very much.

DR. SWENSON: Thank you, Mr. Sullivan.

Our next presenter is Mr. Bill Stein.

MR. STEIN: I want to address the

committee today and tell them that I appreciate you

allowing me to take the time to tell a little bit

about my past disease history and what the

transplant has done for me to date.

I am a 32 years old and I had a double

lung transplant in August of 2002, after suffering

devastating effects of cystic fibrosis. I was

diagnosed at the age of eight and I lived a fairly

healthy childhood in adolescent years until I was

approximately 20 years old. That was my first

hospitalization with the complications arising from

cystic fibrosis. I thought after the initial

hospitalization that things would get better and I

210

would just go on my merry way with my life, but it

didn't turn out that way. That first year I was

hospitalized over five times and progressing over

the next eight years my lung function went from

approximately 95 percent to 18 percent at the time

of the transplant.

In January of 1999 I was listed for

transplant at the University of Pittsburgh Medical

Center and in the years leading up to my surgery I

faced the reality that my own lungs may not sustain

my body until new lungs became available. In 2002

my health declined to a point so bad that I was on

oxygen 24 hours a day until August of 2002 when I

received my double lung transplant. I was called

four times for transplant. I had three false

alarms until I got the actual call in August of

2002. It was a very emotional ride, as well as a

very physical one, you know, dealing with the trips

to the hospital and all the prep procedures where

you would have your surgeon come in and tell you

that, you know, the operation wasn't a go.

It has been almost three years now since

211

my transplant and in that time I have managed to

reclaim my life and venture forward with my goals.

Less than three months after my transplant I

returned to the ice hockey rink. I was an avid ice

hockey player and I also played golf and, sort of

against a lot of people's wishes, I wanted to go

back and enjoy the sport I loved. I took the

necessary precautions; I wanted to know that I

could do it again.

Less than six months after my transplant I

decided, well, it is time for a career change so I

decided to go back to school and take preparatory

classes to pursue my ultimate goal of being a

physician assistant. The long hours have paid off

and after all the long and hard work that I have

spent for the past two and a half years, I will be

accepted to the class of 2007 physician assistant

studies program this August.

Words cannot express the gratitude and

appreciation I have for the support that was given

throughout my journey by my friends, my family and

my medical team and, most importantly, the gift of

212

life given to me by my donor and the decision by

her family.

I realize that my disease did not allow me

the convenience of making an easy decision

regarding my transplant but in the years that

followed my transplant I have been able to overcome

the hurdles associated with the complexities of the

surgery, and even the care that followed. I knew

going into transplant that infection and rejection

would be issues that I would have to address in

future care. The statistic that was provided to me

prior to transplant was not very impressive, given

that the five-year survival rate was approximately

50 percent, but what was the alternative? I chose

the transplant and took my chances at that point.

I have been very fortunate and have only

had to deal with a few cases of acute rejection

that were resolved with conventional steroids and

adjustments to my immune suppression medication. I

was able to battle through these minor hurdles; I

always worry about what happens in the future, what

happens the next time I get rejection. Is it going

213

to be treatable? Or, what happens if it just turns

into chronic rejection? Do I have something to

look forward to, to help me treat it? Just given

what I have heard with the inhaled cyclosporine, it

just seems like it is a tremendous asset to the

transplant community to have it available for

patients like myself that might run into problems

and conventional therapy might not carry you. I

have seen a lot of my friends be in a situation

where they are in intensive care for months on end.

A few of them have passed away. It is very

heart-breaking knowing that I am well and that they

are gone because there wasn't a drug available to

combat the effects of rejection.

A new drug such as inhaled cyclosporine

will help benefit transplant patients such as

myself and prevent or reduce the probability of

rejection occurring in transplanted lungs. The

drug can also help eliminate some of the

traditional side effects that patients like myself

deal with. My creatinine level is currently 1.5,

1.6 so I am teetering on the sea-saw as to which

214

way I am going to go. So, will inhaled

cyclosporine give me that opportunity to lower my

current immune suppression in the future and maybe

have dual medications to help alleviate some of the

toxicities on the other organs? Those are

questions on our minds and, you know, I am sure

there are a lot of transplant patients who feel the

same way, and I believe the long-term benefits of

the inhaled cyclosporine will provide new hope and

opportunities for many patients allowing them to

live long and prosperous lives without worry of

additional complications. Thank you very much.

DR. SWENSON: Thank you, Mr. Stein. Our

last speaker is Miss Renee Moeller.

MS. MOELLER: I am a double lung

transplant survivor of three years. Although I am

doing very well, I am concerned about the long-term

risks associated with my current rejection drugs.

I feel that taking cyclosporine as a preventative

medicine will benefit my long-term survival rate

and I will tell you why that is important to me.

I am a 29 year-old young woman who for all

215

of my life coped with cystic fibrosis and took care

of myself for years. I lived a pretty normal life

except for the daily routine of taking 50 pills a

day. After I finished college my health declined

dramatically. I thought my life was over. I was

completely devastated knowing that I was so young

and I had to deal with death. A transplant was my

only hope. My whole life I dealt with an incurable

illness. Finally I could breathe like a normal

human being after this wonderful gift of a

transplant. I don't want to risk losing this new

life that I absolutely love and have longed for.

I am afraid of getting rejection. One of

my best friends died because she rejected to the

point of no return. It affected me a great deal

and I don't want this to happen to myself. This is

a huge concern of mine and I would love to have the

opportunity to take cyclosporine. By taking this

drug my other organs can be saved and, hopefully, I

can live a longer and prosperous life. Thank you.

DR. SWENSON: Thank you. At this point I

will turn the meeting over to Dr. Albrecht to give

216

us a charge for the rest of the afternoon's

considerations.

Charge to the Committee

DR. ALBRECHT: Thank you. Before I read

the questions let me just spend a couple of minutes

summarizing some of the salient points and some of

the questions that we still have remaining that we

would like the committee to talk about.

Let me just reiterate, as we have heard,

that a single Phase II study was performed and

Chiron submitted this, and we accepted it, knowing

the size of the study, given the dramatic

difference in mortality that was seen. As you have

heard before, the reason for this is that the

incidence of lung transplants is fairly low. The

current mortality is higher than with other

transplants. There is no approved FDA therapy and,

clearly, there is a need for safe and effective

therapy in this population, as we have heard so

eloquently stated.

In the Chiron presentations you heard

quite a bit of information presented about this

217

study and you heard Chiron's assessment that they

felt that these results were really quite robust

and supported the survival difference and warranted

a positive regulatory action.

During the FDA presentation you heard a

somewhat different perspective or interpretation of

the very same data in the following way: We

acknowledge that there was a difference seen in OB

and mortality. But OB is a histologic finding and

a histologic finding without some clinical signs

and symptoms causing mortality doesn't quite

follow. So, when we looked at some clinical signs

and symptoms, for example characterized by FEV1 or

BOS, and did not see that difference we were

puzzled and continued to do additional analyses.

Again, just to remind everyone, the primary

endpoint of acute rejection also was not

demonstrated to be significantly affected by the

aerosolized cyclosporine.

So, we looked for other explanations that

could possibly say why was there a difference in

mortality without seeing differences in FEV1 or BOS

218

and found a number of characteristics that were

imbalanced in the two populations which, as we

heard, of course, had been randomized but sometimes

the risk of a small study is that randomization may

still not lead to an adequate balance in

characteristics.

One of the main ones was double lung

versus single lung imbalance. Then you heard a

difference in the incidence of early pneumonias

that happened in the single lung in patients to a

greater proportion than the double lung patients.

Dr. Hernandez then admitted that we do not have a

lot of information on the donors but used the

available information that we had to try to get a

sense of the donors, as well as the early courses

in the recipients, and pointed out that the

inotropic to support to donors was longer; the

PaO2/FiO2 was less than 300 in the PG arm whereas

it was greater than 300 in the double lung arm.

Then the recipients also had a longer stay in the

ICU which correlates with their clinical course

post-transplant.

219

So, seeing these imbalances, we thought

could this be part of the explanation because the

mechanism of action of cyclosporine and the

incidence of pneumonia did not seem to be directly

correlated. Then we see from the literature that

there is a strong association between acute

rejection and chronic rejection. The assumption is

that acute rejection episodes through various

cycles do lead to BOS and chronic rejection and

mortality.

We also heard that non-immune causes may

be responsible for this and again, as I mentioned,

we did see that there were differences in some of

the donor and recipient characteristics, as well as

differences in pneumonia, so perhaps this was in

part accounting for the differences we were seeing.

In my reading I actually came across a

statement by the pathology group from Pittsburgh

that occasionally organizing pneumonia-like

reactions in airways and air spaces may induce

bronchiolitis obliterans. So, perhaps these are

some of the known immunologic features that may

220

predispose to bronchiolitis obliterans.

Then you heard about the risks of a small

study, such as the fact that when you have a small

study the small sample size results are highly

sensitive to small perturbations in assignment of

patients, and you heard some of the results of the

sensitivity analyses and their impact on changing

the significance of the detected mortality and,

finally, you also saw that if we looked at patients

who received less than 25 doses, which was less

than 10 percent of the intended two-year dosing

regimen, the difference in survival was also no

longer significant.

So, having said all that, let me now go

ahead and turn to the questions that we would like

the committee to deliberate. Having read them

earlier, I will not read all of them. I will start

with question one. I just did want to mention that

this is also attached to the agenda for ease of

reading and it is now being displayed on the

screens.

So, the first question, is there

221

sufficient information to make the determination

whether the observed survival difference in study

ACS001 is due to study drug or to some other

factors?

In your deliberation we would like you to

keep in mind the information that you heard this

morning, including the statistical issues that were

raised; the differences in baseline donor and

recipient characteristics; the effect that was

demonstrated or the differences or the lack of

differences that were demonstrated on various

endpoints, including the survival endpoint, acute

rejection, BOS, FEV1 and OB; and whether you think

some other endpoint showed a demonstrated benefit

or difference.

Let me just mention parts (a) and (b) of

question 1 which is that if after you deliberate

you believe that the answer to the first question

is yes, what we would be interested in is hearing

about the generalizability or, more specifically

the labeling recommendations or the labeling

summaries that would then evolve from the results

222

of this study.

If, on the other hand, you believe that

the answer to the first question is no, we would be

very interested in hearing a discussion of what

additional clinical studies you would recommend be

conducted. Here we would be interested in specific

recommendations regarding the patient population,

drug dosing and regimens, drug administration and

efficacy endpoints. I will stop there and then we

can return to the second question.

Committee Discussion and Vote

DR. SWENSON: For ease in going through

these discussions, I would ask that you just tap

your "talk" button and we will see the red light go

on and then we will call people in turn.

I would like to first step back and allow

for some potential questions that were possibly not

brought up in the morning session and maybe to

spend some 15 minutes or 20 minutes on that because

I think that will be part and parcel of your

answers to these questions. I know that Dr. Mannon

had some unanswered questions and we will start

223

with her. But anybody else that has new ideas or

something unanswered from this morning, please let

us know.

DR. MANNON: This is a question sort of

involved in Dr. Proschan's question earlier this

morning on page 84 of the Chiron binder. I was

struck by the number of patients that completed

therapy. Maybe I am misinterpreting it but only

about half of the patients, maybe less than half in

the placebo group but about half of the patients in

the CyIS group were able to complete therapy. So,

I question both the sponsor and the FDA about what

were the reasons for the lack of completion of

therapy. Also, from a clinical perspective, how do

you interpret the outcome when half the patients in

your treatment group did not complete full therapy?

DR. NOONBERG: To address the first part

of your question, the reasons for early drug

discontinuation are shown in the table below. The

primary reasons for the placebo group are due to a

variety of adverse events. We have already

discussed the withdrawal of consent. Again, there

224

were some problems with early tolerability that

could be fed into the adverse event group of the

inhaled cyclosporine group. The unsatisfactory

therapeutic response, those are patients that were

taken off study drug in order to cross over into

the open-label protocol. Protocol deviations and

violations were largely due to medical

non-compliance and smoking. So, those are the

range of reasons. There were no patients that

discontinued because they died. They discontinued

for other reasons prior to death.

DR. MANNON: I guess my second question is

when only half of your patients complete the

proposed therapy, what is your interpretation of

the outcome of those patients when only half

completed really the full therapeutic part of the

trial?

DR. NOONBERG: Well, my sense is that

inhaled cyclosporine helps patients early on and

continuously because chronic rejection--it is not

like acute rejection where one day you have it and

the day before you didn't and two weeks later you

225

don't. It is a gradual process that probably

starts very early on and only after a year it is

able to be detected by transbronchial biopsy and

certainly by a decline in 20 percent of FEV1.

Again, there is nothing magical about the 20

percent decline and, therefore, it is not an

episodic process and, therefore, patients who

appear to get more drug did better. How we justify

this really is using an intent-to-treat analysis.

DR. ZALKIKAR: Can I respond to that

question? We agree with the reasons for

discontinuation that were displayed here a while

ago. As for the sensitivity, I have shown you some

sensitivity analyses where we treated the patients

who received very little therapy in three different

manners, one, excluding all 11 patients who

received less than 25 doses; secondly, treating the

cyclosporine patients who received very little

treatment as the control patients; and, thirdly,

defining treatment failure as discontinuation or

very early discontinuation due to adverse event or

withdrawal of consent. All of those sensitivity

226

analyses show that the survival benefit is no

longer significant. So, the interpretation is

really hard.

DR. NOONBERG: Well, I would comment that

one of the reasons that patients didn't get 25

doses is that a couple of them died and, therefore,

couldn't have gotten 25 doses. When we did a

sensitivity analysis and only looked at patients

who had 80 percent of protocol maximum dosing

adjusted for death we found the results were

statistically significant. I don't know if you

want to bring that slide up again just to show the

results of our sensitivity analysis.

DR. SWENSON: I think you have made the

point well and I think we remember it.

DR. ZALKIKAR: Can I counter that? Again,

the few early deaths--is it really possible to

attribute those deaths to lack of cyclosporine?

That is also a question we had a hard time dealing

with.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: Just for the record, I would

227

like to know just a little bit more about how the

randomization actually occurred to the extent that

that is reconstructible. About half of the

patients done during that interval actually were in

the study. Were all approached? If not, what were

the criteria? Who made the decisions, and when?

And was it blocked by two, by four or six? So,

what was that process like?

DR. IACONA: I am the principal

investigator of the study. About 120 transplants

were done at the University of Pittsburgh at the

time of the three-year limited enrollment period.

Out of those patients, about half enrolled.

Unfortunately, we had about 20 percent death rate

during that interval which excluded a large number

of patients, which we could do nothing about. We

did screen through other patients and, to be quite

frank, there were a lot of things going on. We

didn't want to push the drug because we had it for

other studies and it was an open-label protocol.

That was one issue. The other issue was that the

patients didn't like the idea of receiving a

228

placebo. So, when you pushed them, their gut

reaction was why should I go into the study when I

can get the drug if I should reject? So, that is

how it was done. That is how I approached patients

and my colleagues did.

As far as randomization is concerned, I

had no part in randomization. It was done by the

University of Pittsburgh statisticians and I had no

idea as to how blocks were assigned. I never

received the coding for randomization and there was

no way any investigator in the program had any idea

as to who was receiving drug or placebo.

DR. SWENSON: Dr. Hunsicker? I am still a

little bit foggy about exactly how the analysis

plan was constructed. We have a study for which

the primary outcome was something that is not now

really the issue of evaluation. So, the

presumption is that you noticed a very substantial

difference in the death rate and that is what now

powered the rest of the analysis that was going on.

So, my question is, and I don't know how I can put

this quite precisely, but to what extent was the

229

analysis plan developed before the data were looked

at so that you knew what you were looking to test?

Because, clearly, if the analysis plan knew the

outcomes it is no longer really an unbiased

analysis. So, I have to ask at what stage in the

development of this thing was the analysis plan

finally formalized by which the analysis specified

that we were going to look at these things? Was it

after you knew the frequency of BOS and so forth,

or was it simply when you recognized that there was

a difference in the rate of death?

DR. CAPRA: As we have heard earlier in

discussion, the enrollment was for three years in

the randomization portion of the trial, up to

August of 2001. The last subject was followed for

an additional two years for treatment. At that

point the study was unblinded and at that point the

analysis took place, and there was no prospective

analysis plan because it was an

investigator-sponsored trial done at Pittsburgh.

What they had in their protocol was they

had a primary endpoint of acute rejection. The

230

prospective endpoints were chronic rejection and

overall survival duration. There was no

prospective analysis as to what kind of covariates

to include in the survival duration endpoint. So,

the trial was over; the results were this;

treatment assignments were unblinded so we looked

at survival duration from the time of transplant to

when the study was closed in August of 2003 and the

results were unblinded. And, that is why we looked

at a number of analyses. The first thing is

straightforward log-rank test. It was significant.

Then we went from there and started looking at

other sensitivity analyses which basically

confirmed the overall result.

DR. HUNSICKER: The specific issue that I

am getting at is what you chose to use as your

endpoint beyond simply survival. I am going to

assume that that is well defined, and everybody

knows whether you are alive or dead. But when you

create an analysis like this you can have any

number of things that you put into a composite.

You know, you are looking at a whole series of

231

composites and if you know what the outcomes are

before you build your composites, then you are not

blinded as you create your test and it means that

you can't really test it that way. So, I am trying

to get a sense of how you developed what you were

going to do--you understand what I am talking

about.

DR. CAPRA: Sure. The secondary endpoint

was chronic rejection. So, in discussion with the

doctors both at Chiron and then with Dr. Iacona at

Pittsburgh I understood that chronic rejection is

measured both histologically through OB that is on

the biopsies, as well as the BOS which is the

sustained 20 percent decrease. From there, we

looked at time to first occurrence of chronic

rejection, again, first doing it in an unadjusted

analysis, looking by log-rank test, and then

forward from there.

DR. HUNSICKER: But were there analyses

done so that the people at Pittsburgh--and if I had

been there I am sure that I would have done these

things so that as you did this you would have known

232

what the rate was of OB and BOS before you began

putting together your composites. Is that the

case?

DR. CAPRA: I guess I will have to yield

to people from Pittsburgh. I haven't seen that so

I will let them discuss it.

DR. IACONA: So, the question, as I

understand it, is what was prespecified in our NIH

grant. We had an NIH grant that supported the

study at the time. The primary outcome, as written

by Howard Rockette [?] at the University of

Pittsburgh who is the head of our biostatistics

section, states that we would use acute rejection

as our primary endpoint evaluating acute rejection

by Poisson analysis.

We also evaluated survival and freedom

from rejection as secondary endpoints, as stated in

that grant. The freedom from rejection was

specified for both acute and chronic rejection as

determined by Kaplan-Meier and evaluating by

log-rank analysis.

DR. HUNSICKER: So, it was freedom from

233

both acute and chronic?

DR. IACONA: Freedom from acute rejection

was primary--

DR. HUNSICKER: No, no, no, I understand,

but your secondary endpoint was--

DR. IACONA: Freedom from chronic

rejection. It is stated in the grant, yes.

DR. HUNSICKER: And was the definition of

chronic rejection in there? The major issue here

is that you are depending a fair amount on BOS.

DR. IACONA: Yes.

DR. HUNSICKER: You know that because of

the way you did things--you can't use--what do you

call it?--the heart, lung transplant definition

because you didn't have the baselines. Did you

have your definitions in place before you started

building an analysis?

DR. IACONA: Yes, the definitions were in

place as specified in that NIH grant, and we can

certainly provide you the statistical section of

that grant. We evaluated chronic rejection by two

means, by BOS and by histology.

234

DR. HUNSICKER: But those endpoints were

defined before you did the analysis?

DR. IACONA: Yes, in the NIH grant.

DR. CAPRA: I think there is also a

misunderstanding about the baseline BOS. Baseline

is a running average as a function of time so

because subjects were enrolled as early as seven

days after transplant, sometimes a subject didn't

have an FEV1 value available in that first week;

they had one maybe on day eight or day nine. We

were able to calculate a baseline BOS, which is a

running average, and then look at change from that

value for calculation of BOS.

DR. IACONA: Could I make a statement

about the initial PFT? Before these patients go on

aerosolized cyclosporine or placebo they are

postoperative patients, some of whom have

tracheostomies; they have chest pain; they are not

candidates to actually journey to a bronchoscopy

laboratory to get a PFT and if they did get a PFT

they would be highly inaccurate. So, that initial

PFT, in most cases where it was not present, would

235

be impossible to get under the clinical

circumstances of a postoperative transplant

patient.

DR. SWENSON: Dr. Moss?

DR. MOSS: I think this is all really

interesting. I think Chiron has done a great job

in presenting the data and actually the question is

not for you but you can stay up there if you want.

The data that Pittsburgh and Chiron have presented

is extremely interesting and very thought

provoking. There was a comment made that if the

decision was made by this committee/FDA that

further studies needed to be performed, maybe a

larger multicenter trial to really determine the

potential answers, that Chiron would not be able to

do that or was not committed to do that. I just

wanted to understand your reasoning behind that

because if you are this committed to this and you

really, really believe that this really works, then

why would you throw in the towel now? I hope the

answer is more than, you know, it costs a lot of

money. Let me prop this up by saying that there

236

are other ways of funding studies or co-sponsoring

studies like that with the NIH, etc. potentially.

DR. DILLY: The answer is not it costs a

lot of money. The answer is we don't think it is

an appropriate thing to do. Just think through the

practicalities of running another

placebo-controlled trial even in a multicenter

site. That involves IRB approval. That involves

informed consent. Frankly, it would be

inconceivable--you have heard from the patients

already--that patients would be willing to go on

placebo in a randomized, controlled study with this

kind of clinical signal. We believe that that

question is behind us.

What is important is to really address

some of the questions about the relationship of the

endpoint. Now, there is no such thing as absolute

certainty in science. Therefore, we think that the

right thing to do is to run a large group of

patients, prospectively defined, follow them for a

long period of time so we can really characterize

the natural history of patients treated with

237

inhaled cyclosporine so that we can address those

questions once and for all. So, it is just not the

right thing to do, to do another controlled trial

before approval.

DR. SWENSON: Dr. Sampson?

DR. SAMPSON: It is actually a small

point. I just want to follow-up on Larry's

question about endpoints because in the Chiron

report it says chronic rejection as manifested by

OB and BOS, and the variable that you used was OB

or BOS in your primary analysis. Is that right, or

am I just getting caught up in "and/or's" in this?

Again, it is the same issue, you know, about

looking for the right variable to produce the

answer.

DR. CAPRA: The answer is it is and/or.

So, it is OB or BOS or both. I don't know if one

of the doctors wants to comment on the clinical

relevance of the use of the composite.

DR. NOONBERG: Again, I just want to

reiterate that chronic rejection can only be

diagnosed in two ways at present, histologically

238

and clinically. There will be patients that have

histologic OB, and they will have it on autopsy,

that don't subsequently go on to BOS in the time

period of the study. However, like I said, there

is nothing magical about 20 percent. They may have

18 percent decline, 19 percent, or 25 percent

decline but they have an episode of pneumonia. So,

there are also patients that have BOS but, due to

the insensitive nature, it is not picked up. So,

really chronic rejection encompasses both groups of

patients but they are not really distinct groups.

They have the same clinical process. It is just a

matter of how it is detected. And, the whole BOS

criteria became necessary because of the

insensitivity of transbronchial biopsy, not because

of the poor specificity or the thought that these

patients who had it on biopsy didn't really

actually have bronchiolitis obliterans. It is just

that there was a sense that there were other

patients who also had chronic rejection that

weren't coming up as OB.

Again, I want to clarify this question

239

about Chiron's definition of BOS because it is

really not Chiron's. We used the programmatic

definition developed in 2001 by a consensus

committee, and it uses a post-transplant maximum.

As you may remember from the FDA's slides, the

initial FEV1 is rarely, if ever, your

post-transplant maximum. It usually really doesn't

come for several months and, therefore, it doesn't

affect the diagnosis of BOS. So, we didn't come up

with any special criteria for BOS. We used the

same programmatic definition that is used in the

transplant community.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: I want to get back to the

monitoring issue because that is still bothering me

a little bit. It is hard for me to imagine that in

this study that was done at the University of

Pittsburgh there was no group looking at the

results on an ongoing basis. I mean, is that what

you are saying, that there was no data and safety

monitoring board or no group or individual that was

looking to see whether, for example, the mortality

240

was in the active treatment arm?

DR. DILLY: There are two points, one

which I would like Dr. Iacona to comment on, the

one about monitoring of endpoints. One of the

questions that we have been discussing is just how

much did the people that entered the endpoints in

the CRs know about the treatment assignment. I

think there was some confusion in the way this was

communicated this morning. The endpoints that

appeared in the case record forms, that appeared in

the data that constituted the analyses you have

seen, were taken from source patient records,

source documents. The people managing the patients

were blind to treatment assignment, as you have

heard from Dr. Iacona. The people transcribing the

data from the source document into the database

could theoretically have known what the treatment

assignment was. There is no evidence that is the

case. However, both we and the FDA went in an

audited the data in the database against the

original source documentation and it is a matter of

common understanding that the data in the database

241

reflect the source documentation. So, we believe

that the data that you see have very, very little

liability to be biased.

DR. PROSCHAN: No, I am not worried about

that. What I am worried about is that the study

was stopped on a possibly random high. That is,

someone is looking at the data, seeing the results

and then saying, "gee, if we stop now, look, it's

going to be a p value of 0.007."

DR. DILLY: Remember, the study was

stopped on the date that was prospectively defined

for the study stop. There was a completion

enrollment date in August, 2001 and completion of

the study in August, 2003.

DR. IACONA: Correct. So, Dr. Proschan,

the enrollment period went on for a duration of

three years. There was a safety and monitoring

committee during those three-year intervals that

met at yearly intervals, to the best of my

recollection, and they looked at safety and the

primary endpoint, and they reported that safety

events were no different between the groups looking

242

at renal function and infectious processes between

the groups, which is of concern, and they looked at

acute rejection. At the end of the three-year

block the safety and monitoring committee ceased to

meet. The patients who were enrolled at that

three-year interval went on to receive their

two-year course of therapy, and all the patients in

the study were continued to be monitored. At some

point, right before the end of the study in June,

Dr. Corcoran had done lung function analysis and he

was unblinded. At that point Dr. Corcoran also

looked at survival and it became apparent that

there was a difference in survival. Up to that

point we had no idea that survival was different.

I knew that survival was significantly better in

the aerosol group and I wasn't unblinded yet. I

was told of this information. I contacted the

members of the FDA, Dr. Albrecht and Dr.

Cavaille-Coll, and we had a conversation. I also

contacted our IRB. And, the decision was made to

proceed to finalization of the trial in August of

2003 until the last person received two years of

243

therapy as prespecified in our NIH grant.

I would like to make one more comment in

reference to the differences in AA gradient between

the donors, between the immediate post-transplant

patients. Since more of the cyclosporine patients

had double lungs you would expect that their

PaO2/FiO2 ratios to be higher. It may not reflect

anything of the donor per se, just the fact that

they had double the lung surface volume.

DR. SWENSON: Dr. Hernandez?

DR. HERNANDEZ: I am going to make several

comments. The first is regarding the study

termination. I have the impression that the study

was terminated early and what I see is that an

amendment was implemented to terminate the study

earlier, before reaching the 126 patients that were

initially planned. Because of reasons that were

not in the hands of the investigators, the study

needed to be terminated earlier, before 126

patients.

DR. IACONA: Yes, Dr. Hernandez, I

appreciate the point. Logistically, we were not

244

able to proceed with the enrollment. We had

requested additional funds from the NIH and the

funding supply was exhausted at that point. We

recognize that we were not able to enroll the

number of patients as prespecified and extend the

study. I made a specific request to the NIH to

extend the funds and they were not allocated. So,

we were forced to make do with what we had.

DR. HERNANDEZ: This is a very difficult

thing to me, but I think because I am a clinician I

would like to insist on this, when I changed to the

area of transplantation I became a transplant

surgeon and very committed to my patients, and I

believe that most transplant patients are very

educated about what the transplant is. I think

they are getting explained perfectly what is going

on and they understand clearly. The thing is that

I don't want to raise false expectations in my

transplant patients. First, I don't want them to

get the impression that this treatment is a

calcineurin-sparing drug because there is no data

to imply that. This drug has not demonstrated an

245

effect on recurring acute rejection. So, I think

that we need to clarify that with patients where

they can understand exactly what we are looking at.

What matters to me is the function of

these lungs. Histology has several limitations.

Transbronchial biopsy doesn't tell you anything

about how extensive the disease is; FEV1 does.

Transbronchial biopsy doesn't tell you anything

about the clinical course of the disease and, as we

know, chronic rejection can go very, very slowly

over time and just maintain like that and not give

too much disturbances. Other clinical courses are

really, really dramatic that go from a very fast

onset. What is indicated in all this is that there

are several factors that are not only immunological

but are also non-immunological factors, namely,

infections that can, you know, go through this

vicious cycle where the patient has rejection, gets

immunosuppression, gets infection, more rejection

and finally all these stimuli and calcineurin

damage may lead to chronic rejection. But what is

really, really important is the effect on the

246

function of the graft--FEV1 and BOS, and this has

been addressed by the International Society of

Heart, Lung Transplantation that has, you know,

clearly specified. And, when we are looking at the

treatment we have to look at the effect over time

of serial measurements of FEV1 before and after the

treatment in order to assess an effect of this

drug.

DR. DILLY: If I may comment, our

perspective is we endorse--we want to know the

effect of inhaled cyclosporine on lung function,

but we would suggest that the cardinal endpoint is

whether the patient is alive or dead and, frankly,

you know, whether they are breathing easily is

secondary compared to whether they are alive or

dead. And, we have a very strong signal in favor

of mortality here which makes interpretation of

some of the other endpoints rather difficult. That

is why we are suggesting that the right thing to do

is to benefit from that finding, take this drug

forward and study it in a much larger group of

patients where we can really nail what the

247

trajectory of FEV1 is in patients who have their

rejection controlled by inhaled cyclosporine.

DR. ZALKIKAR: I want to make just one

point regarding monitoring the study. The study

report that was submitted to us mentioned an

interim analysis that was conducted by UPMC during

the conduct of the study. However, we did not

receive any report. There was no adjustment.

There was no information about the boundary used or

anything like that. So, we requested that

information. In response, what we received was

that the interim analysis that was mentioned in the

study report was really the so-called final

analysis from UPMC. But prior to that during the

course of the study there was another interim

analysis that was also conducted. The data was

blinded at that point. University investigators

were blinded at that point and that data did

suggest a difference in survival, although not

significant at that point. Again, there were no

formal statistics done on these interim analyses.

DR. CAPRA: Let me comment on that.

248

Again, Chiron came into the study at the end of the

trial basically when the results were already over.

When we had the discussion with Dr. Iacona he

talked about this analysis, and what he was

referring to late and which we learned later was

that this was the analysis looked at by their data

monitoring committee. There was a misunderstanding

between Chiron and Dr. Iacona over terminology

between basically the data monitoring committee

versus formal interim analyses. You know, in the

analysis that was done by the data monitoring

committee no adjustments were made as far as we

could tell or Dr. Iacona communicated to us, and

the study continued as planned.

DR. ZALKIKAR: Also, I want to address an

issue that came up about the definition of the

endpoints. Although the endpoints may have been

defined, on reading of the document, it suggested

that the definition was simply survival, chronic

rejection and lung function in terms of FEV1.

Also, the data analysis plan was created

retrospectively after unblinding of the data as to

249

how to analyze those endpoints.

DR. CAVAILLE-COLL: I want to address some

of the comments or some of the questions by Dr.

Hunsicker. I think that we share with you concerns

about when this data was really looked at, and we

do know that the study was presented at the

International Society of Heart, Lung

Transplantation at an open session. So, there were

some analyses done at least before that

presentation. I don't recall the exact date of

that and I don't recall when that took place with

respect to the involvement of Chiron and this

application.

We do not have a prospectively defined

data analysis plan and, certainly, we were willing

to look at survival because that is certainly an

unequivocal endpoint. But when it came to the

secondary endpoints, such as those used to define

chronic rejection, there really wasn't anything

that was prospectively discussed with us and that

was defined before the information on survival had

become public.

250

DR. PRUSSIN: I have a question as far as

the charge to the committee. Do we go over that

now? Is this a reasonable time to do that?

DR. SWENSON: Let me hold your question.

I have several and we may have one other but we

will get to that. My question is to both sides

here, and that is that in all of this we haven't

discussed any issues around the potential toxicity

over a longer period of time of these very high

concentrations of drug on the airway. The animal

data rest largely on one-, two- and three-month

data. As I look at those data, I see that

transiently at peak there are 100-fold greater

concentrations of drug applied to the airway

epithelium. It does tail off but it still remains

high. And, the risk, as I see it in this field, is

the issue of malignancy developing and the problem

of post-transplant lymphoprolific disorder. So, I

wonder if both sides might touch on this issue

about this dosing and down the road possible

adverse consequences.

DR. JOHNSON: Dale Johnson, from Chiron.

251

One of the things that we did, of course, was to do

toxicology studies in normal animals at high doses

and look at those particular findings. What you

actually saw on the listing, for instance, doesn't

actually describe the severity effects which are

barely detectable. So, from an acute standpoint it

is fairly clear it is not an issue. Chronically,

there have been studies and they have been done

with monkeys, and what I would like to do is to

refer you to Dr. Allan Singer, who is from Battelle

Institute, who actually has knowledge of those

studies.

DR. SINGER: I am Al Singer and I am from

Battelle, which is a not-for-profit organization.

We actually do very little work for Chiron so I

don't really have a whole lot to gain one way or

the other here. They are not paying my salary,

Battelle is. They are reimbursing Battelle for my

time for today.

The monkey studies were actually run with

propylene glycol. Those were run over a period of

13 months at a saturated solution. They caused no

252

effect. But your question really relates to

cyclosporine. The main contribution I can make

here--I was not the pathologist, veterinary

pathologist, toxicologic pathologist; I was not the

pathologist in either of those studies but I did

peer review both of those studies, the rat and the

dog study. The lesions which were diagnosed--and

there were lesions--there were minimal

inflammations, sometimes mild inflammations in the

alveoli and in the interstitial areas of the lungs

and, frankly, it is within the realm of normal. We

did not run an air control on the dog study, and

that is simply because we have run so darned many

air control dogs through the years that it is just

a waste of dogs. At some point you have to decide

why you are just putting more animals on a study;

it is just a waste of animals.

The lesions that were seen in the

propylene glycol controls are typical of what you

would see in an air control in that study. The

pathologist reviewed those dog slides and we cut

35, 40 slides. He spent most of his time on 40X

253

looking for a few cells.

The only thing that we actually had any

trouble with was the pinpoint ulcers in the larynx

of some of the dogs, and we typically find those in

controls as well. It is my belief that it is the

function of the way the mouthpiece works in the

dog. The rats are put into a tube and they have to

breathe through the nose. But in the case of the

dog it is actually a tube that goes in the mouth

and they have to breathe through the mouth, and I

think that is somewhat drying. But they are all

within normal limits. There are no acute findings

within 28 days to speak of.

DR. SWENSON: Well, I can imagine that

they are typical. What we are talking about is a

concern raised in the literature that cancer and

malignancies will be a problem with long-term

chronic immunosuppression, and cyclosporine has

been pin-pointed as a possible risk factor for

that. So, I don't think the animal studies are

going to answer that. Cancer just takes too much

longer to evolve. So, it is going to be an issue

254

only in the humans because what you are proposing

is to take this out for more than two years, maybe

five years or the life of the patients.

DR. DILLY: Exactly right, and it may be

worth showing slide PK-26. First of all, there are

few safety endpoints that trump survival and

patients have to survive long enough to see the

toxicity. Second of all, what you are talking

about are going to be low incidence signals. If it

was a high incidence signal it was likely to have

been picked up by now. Those will only be found

with a significant sized study for a long time, and

that is why we say that actually to nail questions

exactly like the one that you are posing, the right

way to do that is a five-year study following a

large cohort of patients through treatment so we

can look at the incidence.

We also have the very nice reference point

of, for instance, the UNOS database, where we can

look at the incidence in people not receiving

inhaled cyclosporine. So, that is why we see in

this context that a postapproval study, running for

255

a long time to gather this kind of data, is

entirely the right way to go.

DR. SWENSON: Before you step down, let me

raise just one issue. If, in fact, this committee

votes positively to proceed here, what assurance do

we have that this study will be done? The track

record, as was highlighted recently in an article

in the LA Times last week pertaining to fast track

approval, and in essence this is something similar

to fast track approval, and many of these

promissory notes have not been delivered and,

therefore, if this does go to approval it is really

a contingent approval.

DR. DILLY: I will give you three answers

to that. The first one is that it is entirely

within the FDA's regulations, FDA's own regulations

to hold us to a postapproval commitment, not

withstanding whether it is accelerated approval or

not.

Second of all, this is part of a much

broader commitment of Chiron to lung disease, and

we have referred to our treatment of cystic

256

fibrosis with TOBI. We followed that population.

One of the reasons we got here in the first place

was patients with cystic fibrosis receiving TOBI

for pseudomonal infections. We have been very

diligent in furthering that treatment, for instance

with our drug powder inhaler program where we

followed through with a program to optimize that

therapy.

Third of all, and probably the most

important, is think about how you commercialize a

drug like this. Trying to get broad adoption of a

treatment based on a single-site study in 26 active

patients versus 30 control patients is an uphill

proposition. This is exactly the study that we

want to do to generate publications, to generate

more data to talk about, and to underwrite the

widespread adoption because if we can do the study,

then we can optimize the dosing regimen. We have

the option to optimize the formulation. We have

the option to just get it right in the long-term

for patients with lung transplantation.

In the absence of this kind of study this

257

could be the sum total of the clinical experience

with inhaled cyclosporine that is interpretable,

for some of the reasons that we talked about

before. So, it is in our mutual interest to do

this study.

DR. HUNSICKER: Just an extension of that,

you argued before that one of the major reasons for

requesting approval now, rather than doing a

definitive study that you just talked about, would

be that it would be both unethical and impossible

to recruit patients to a study if there was this

publication, which is undoubtedly going to be out.

But you just said now that you don't think you can

commercialize this unless, in fact, there is better

data. That would imply that there would be

patients who might be available and that it

wouldn't be unethical. So, is there a

contradiction here?

DR. DILLY: Not really. We are talking

about 250 patients over five years compared to

about approximately 2000 patients treated worldwide

every year. So, during the conduct of this study,

258

say, we take a year to enroll 250 patients and then

five years to follow them up, that is six years

worth of treatment and that is 12,000 people

worldwide getting transplanted. It is a relatively

small subset of the overall population that we

would be putting in this study. We do see that

having a robust, ongoing program of research to

optimize the drug is the right thing to do because,

as we said from the get-go, not all the questions

have been nailed down by the single study right

now.

DR. ZALKIKAR: If I may just say something

that came to my mind as I looked at this slide,

PK-26 that the applicant put up, we saw this slide

and an effort was made to match the placebo

patients to the UNOS data, but we didn't see any

effort to match the cyclosporine patients to the

UNOS data in terms of baseline factors.

DR. DILLY: In fact, you did see that

slide during the presentation this morning, and the

p value and the point estimate were almost entirely

the same as in the original analysis.

259

DR. ZALKIKAR: That was a comparison of

the cyclosporine arm in the study to the UNOS

matched controls.

DR. CAPRA: As Dr. Zalkikar was

mentioning, we did compare the cyclosporine

subjects to the UNOS matched controls and we used

the same matching criteria. We matched by

transplant type, CMV match or mismatch, early acute

rejection, age where we took the ages in brackets,

and sex and, not surprising--I mean, this result is

positive given that the comparison from the placebo

to the UNOS was nearly identical. So, here the

p value is 0.19 and the relative risk estimate of

0.252 is nearly identical to what we saw in the

primary analysis of 0.213.

DR. SWENSON: Dr. Tisdale?

DR. TISDALE: I had a question that was

percolating some time ago. We seem to be inferring

from the analysis of this study that it is all post

hoc and the primary endpoint was not met. But I

imagine the primary endpoint was decided upon

because it was felt that it was more likely to be

260

impacted by this.

But I want to be sure that I understand

that in the original study that was written for

three years--it wasn't re-funded, probably because

the primary endpoint wasn't met and there was no

difference--survival was in fact one of the

endpoints, one of the secondary endpoints, and in

the analysis of one of the secondary endpoints that

was a planned part of this study there was a highly

statistically significant difference, and that is

the reason why we are all here.

DR. IACONA: Unfortunately, I don't have

the statistical section of the NIH grant with me to

show the audience. It is written as an endpoint of

survival as a secondary endpoint, as is chronic

rejection and bronchiolitis obliterans syndrome.

One of the analyses that I did independently was to

actually look at change in FEV1 from peak, as is

conventionally done, and calculate individual

slopes. I calculated individual slopes between the

cyclosporine and the placebo patients and, at least

by my independent analyses, I am showing a

261

difference between the rate of decline in the

cyclosporine versus the placebo. Now, I don't have

the background that Chiron does, but that was also

mentioned as part of the analysis. I am not sure

why that is not being presented or accepted, and I

can show you how I did it independently. But the

chronic rejection is a secondary endpoint and we

looked at chronic rejection in our study by

bronchiolitis obliterans syndrome and by

histological rejection. If one should read through

the transplant literature, our pathology department

is probably the best in the world in diagnosing

chronic rejection by histology and we really

emphasize that in our grant, that we are going to

look at histological OB.

The second point that you made was what we

should pick as a primary endpoint. Well, when you

look at transplant drugs it is believable and

acceptable by the NIH, if one should mention acute

rejection as a primary endpoint and that was our

thinking, Dr. Griffith's and my own thinking, that

acute rejection is a conventional endpoint for a

262

transplant drug. It is taken as an endpoint

because it is a surrogate marker of chronic

rejection. If I went and I suggested that

aerosolized cyclosporine would be the first drug

ever to prevent chronic rejection my grant would

not get funded.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: I would like to just explore

the alternative to the proposed study, which would

be perhaps a smaller number of patients, a

randomized trial. I think a lot is being hung on

the perception that around the country it would not

be possible to do that. I am not totally

convinced. I think there is obviously a great deal

of interest around the country in this potentially

radical advantage. But I think that a lot of

patients don't complete the course; don't get very

far in the course. It is a huge expense--there are

a lot of things about it I think. I would like to

hear perhaps more of the argument that a randomized

trial, much smaller in scale but powered to provide

capacity to see the difference that we are hearing

263

is believed this trial gave us from the data we

have now, why that wouldn't be a viable

alternative.

DR. DILLY: There are several points.

First of all, our analysis of the data, as we have

said from the very start of our session today, is

that there is a robust survival advantage for

inhaled cyclosporine. Therefore, we think the

right thing to do is to make this treatment

available to patients with lung transplantation.

Therefore, we actually do not see withholding

therapy, even in the context of the clinical trial,

as a desirable way to go if there is an

alternative.

We believe the very strength of the

available data on the natural history of survival

after lung transplantation means that we don't have

to randomize patients to placebo. So, we took what

we saw as a much more sound approach of saying

let's do a big study rather than a small study

which will allow us to also look at some of the

secondary phenomena like the effect on pulmonary

264

function, like the effect on chronic rejection, as

well as survival. So, we felt it was a more

elegant way forward than another placebo-controlled

study and a more appropriate way forward.

We also had advice from our advisers that

it would, in fact, be rather problematic, and we

did our own internal soul searching around how

would you write an informed consent form with that

Kaplan-Meier shape. And, drawing on my own

personal experience in oncology where, in the face

of this kind of survival endpoint, you do

everything you can to get patients onto active

therapy.

DR. BURDICK: So, in essence, what the

proposal is--the point that it is effective is

proven and we are going on from there to look at

the details. I think that that happens a lot,

especially in transplantation where the numbers are

small and there are a variety of sort of opinions

around the country about exactly how to best treat

patients and you end up with a series of papers

written showing exactly how this or that effect is

265

optimized by this or that approach, and a lot of

good things, and ultimately truth comes out of

that. But that would happen anyway if the FDA just

said, okay, approve it.

The trial you propose with an OPTN

control, which is going to have some problems--I am

not sure exactly what is in the OPTN database that

would provide you with what you need for your

control group. Maybe it is good. Maybe you could

address that. But I am concerned that we will have

a series of opinions about details around the

treatment but it is not going to extend how

convincing the big picture is, which is does it

make a difference or not since you are hearing some

concerns about whether that really has been proven.

DR. DILLY: Our take on that is that

currently the five-year survival for lung

transplantation is quite well nailed down at around

50 percent, and that has not been a point of major

contention. The control group in the ACS001 study

behaved very like a control group in external

controls. It has all been about the remarkable

266

trajectory of the patients who received inhaled

cyclosporine, and what we want to do in the

confirmatory study is confirm that remarkable

trajectory. Therefore, we can draw statistical

plans around the point estimate and the confidence

intervals of one year, two years, five, and so

forth, and we see that as the most powerful way of

generating the data that are necessary to address

this question.

DR. BURDICK: I don't mean to argue this

extensively, but you are caught in the same

situation as we are in transplantation otherwise.

By the time you are calculating your endpoints you

are going to have patients on MMF being moved back

and forth on rapomyacin and you are going to end up

with a series of observations that characterize

certain subsets or certain areas and seem

convincing, and it is not again going to provide

you further strength against the critics who might

say this is very interesting but we haven't seen

that it is really making a difference that is

proven.

267

DR. DILLY: If in seven years time we are

looking at data that says that the point estimate

on five-year survival with inhaled cyclosporine

really is 85 percent, it will be absolutely clear

that that is different from the current practice.

And, we are confident enough in these data having,

as you have seen stress tested them every way, that

we could think of that as appropriate, that we are

going to see an effect that is clearly different

from past practice and that is what we are

interested in pursuing.

DR. GOLDBERGER: Dr. Swenson, I was

wondering whether it would be helpful--the company

has Dr. Golden here and another expert, if maybe it

would be helpful to the committee to hear their

views on the types of trials that could be done

with and without prior approval because they are

the kind of people who actually have to do those

trials practically.

DR. SWENSON: Fair enough. Dr. Golden, do

you want to take that?

DR. GOLDEN: I got most of your question.

268

Do you mind just summarizing it?

DR. GOLDBERGER: Yes, there has been a lot

of talk about what kind of trial could be done. In

particular, whether a placebo-controlled trial

could be done at this point in time with this

information already public and and probably will be

more public when an article comes out about it, and

what your take is about that and about the

situation for further studying this therapy.

DR. GOLDEN: I have to believe that given

the change in survival in this study that that is,

(a), going to be sustained in another study and

(b), it will be very hard to look at my patients

and ask them to be in a placebo arm. This is

always the problem with any study. But I happen to

think that in my institution my IRB will likely

say, especially after a publication, that this

information is already out there in abstract form

and otherwise. I have to explain to a patient that

this inhaled therapy, a novel approach, has been

the first absolute study to show a change in our

dismal outcome at five years.

269

I must say to the point of rapomyacin

trials, now at 24 months, it hasn't shown any

difference in obliterative bronchiolitis. I think,

as a physician, that I am not going to be able to

entice patients to go in a placebo group in the

context of this inhaled therapy.

I would very much actually like to ask

Bert Trulock his opinion on that question as well.

DR. TRULOCK: Thanks, Jeff. Bert Trulock,

from Washington University. I don't have very much

to add to what Jeff has already said. But

presented with this evidence, I am not sure that

there is an IRB in the country that would approve a

randomized, placebo-controlled trial. Certainly,

at our university when presented with this kind of

information these days, it is very difficult for

the IRB to approve a placebo-controlled trial.

Aside from that, there are the emotions

that Jeff described in convincing patients to go

into a placebo-controlled trial when this

information is already in the public domain. So, I

don't believe that it is practical to do a

270

placebo-controlled study.

DR. SWENSON: Instead of a placebo arm,

what about the possibility of some lower dose that

might achieve at the airway level essentially the

same levels that are obtained with oral dosing?

This would then offer patients at least something

active, and it is still a question that is relevant

because we don't know what the dose-response

relationship is.

DR. TRULOCK: I can't speak for Chiron,

but I think those kind of dose-ranging studies are

obviously important, and there are many things like

that that can and need to be done in a postapproval

study.

DR. SWENSON: And it doesn't seem as if

you would need 250. If this is really as robust as

it is, simply another trial of 50-75 patients, if

it showed exactly the same--I think the question

would be moot about survival advantage. Dr.

Proschan?

DR. PROSCHAN: If I had anything to say, I

have forgotten it now.

271

[Laughter]

DR. SWENSON: Dr. Barrett?

DR. BARRETT: As I was listening,

particularly as the sponsor pointed out what their

plans were next, I am not so sure that an

additional confirmatory trial, ethical reasons

aside, is going to be necessarily informative here.

There are so many other questions with regard to

how often this agent should be given; what dose;

and the disconnect between acute response and the

chronic response data that you see here. There is

some disconnect as far as disease progression. The

FDA pointed out that these two maybe should be

closer linked and the overwhelming evidence that

you have a signal here, although unanticipated, is

very large in magnitude. Those seem to be more

relevant questions that would be addressed not from

repeating this with a bigger N but with a study

design that is perhaps more exploratory in nature.

Maybe just to ask the FDA, you know, you

put in your slides the expectation of the

correlation between acute rejection and chronic

272

rejection but I didn't see any references there.

Could you comment a little bit more about what you

would expect to see there?

DR. HERNANDEZ: Yes, this is well

documented about the relationship between acute and

chronic rejection. This has been documented in

literature and registry data. As a matter of fact,

the sponsor agreed that one of the factors that is

important to take into consideration is to take

into consideration acute rejection. Basically, I

would say the natural history of these patients

will be developing acute rejection; getting

treatment for this acute rejection and infections.

So, this meets the category of the multifactorial

nature of chronic rejection.

If we are looking at a drug that is

supposed to prevent or decrease the degree of

chronic rejection, which is one of the leading

causes after the second year of transplantation, it

is completely reasonable to look at long-term

outcomes and look at correlation with the degree of

disease progression which would be reflected in the

273

histology of the lung. As I pointed out before,

the limitations of defining chronic rejection only

by biopsy and giving it weight similar to BOS, from

my clinical perspective, is not adequate because,

as I said before, it doesn't have the ability to

predict the extent of the disease, the rate of this

disease progression, and those are things that are

very relevant questions. When we don't see this

correlation between acute and chronic rejection,

and if chronic rejection is really prevented, we

would expect to see at least some evidence on the

preservation of lung function and we don't see

that. And that is one of the disturbing things

that put a question mark in this difference in

mortality.

It is not that we are questioning that

these patients are not dying. There is no

difference in the graft. The problem is are the

patients in the placebo group dying because of

other causes, because of the baseline

characteristics of these patients, or are these

patients surviving because they have better

274

starting points and not because of the

cyclosporine? I mean these kind of questions when

you don't see these correlations, when you don't

see that everything is going in the right

direction, then make you think about what is going

on over here.

DR. TRULOCK: There has been an

association between acute rejection and chronic

rejection in most of the multivariate analyses that

have been done. However, many patients develop

chronic rejection without ever having a single

episode of acute rejection. Furthermore, just

because there is a statistical association in

multivariate studies, that doesn't mean there is a

cause and effect relationship between acute

rejection and chronic rejection. That is, it is

not a requirement that acute rejection occurs

before chronic rejection can develop. All of these

things are probably in the continuum of

allo-reactivity that is not well controlled by the

current immunosuppressive medications.

DR. HERNANDEZ: Yes, I agree with that

275

fact. Acute rejection could be not clinically

evident and could be subclinical, and I agree that

chronic rejection could be developed without acute

rejection but that is not the rule. I mean, I

understand that, for example, there are other

factors that could be taken into account for the

development of chronic rejection and acute

rejection is only one but the rule, what you would

like to see, is the patient who had acute rejection

correlating with chronic rejection, not the other

way. It is not the rule that the patient doesn't

have acute rejection and develops chronic

rejection. That is my point.

DR. SWENSON: At this juncture I think we

probably need to get to the questions at hand. Dr.

Prussin, you had a question about the charge and

maybe we could have you ask your question and then

Dr. Albrecht will proceed with the discussion to

those questions.

DR. PRUSSIN: Dr. Albrecht, the charge as

written has a fairly binary yes or no answer to the

question and I think what we have seen here is that

276

this is a fairly unusual application. There is a

lot of grey area. We were talking about p values

and the fact that while these p values give you an

indication they really shouldn't be thought of in a

quantitative sense. So, I guess my question for

you is if you could elaborate a bit and

clarify--and I know from statute that approval of a

drug such as this has the same requirements as

drugs for larger patient populations that are not

orphan drugs, but how should we manage that?

Clearly, this is not the typical binary situation

where we have Ns of thousands, and this is a

population of patients that clearly has a huge

mortality. Can you give us a little more

instruction on how to factor that into our

thinking? Thanks.

DR. ALBRECHT: You raise good points and

you have very well summarized the challenge before

us. The truth is our decision does have to be

binary. As I mentioned in the introduction, we did

have difficulty reaching the conclusion that would

allow us to make that decision. So we did, in

277

fact, want to bring this to the committee to hear

your perspectives on this with all the challenges

that you have identified.

In the event that it is difficult to come

to sort of a yes or no recommendation, it would be

very important for us to understand both where you

believe the data are convincing and where you

still, in your own assessment of these data, have

questions and where you believe the unanswered

questions are.

I don't know if that helps but I think we

all acknowledge that this is a very difficult

scenario. I think we heard earlier during the day

about there being promising potential here,

something to that effect, and I think we certainly

concur with that. I think we heard some analogies

to gambling and I think, being regulators, we are

not willing to gamble with patients' health and,

therefore, we take these questions very seriously

and are very seriously looking into your

perspectives and how much has been demonstrated;

how confident are we that the questions have been

278

answered about the efficacy of the product, mainly

the safety, or how confident are we that there is

still further information that needs to be

gathered.

Parenthetically, I know we talked about

the pharmacology/toxicology information. I didn't

know if we needed more information on that, but our

pharm/tox review is available. Just to repeat, the

FDA only received those one-month toxicology

studies. I could parenthetically say that for

products that are administered chronically the FDA

actually does request carcinogenicity studies.

Those can be done preapproval or those can also be

done as postmarketing commitments after approval.

But we do not at this point have an aerosolized

cyclosporine carcinogenicity study. There were

carcinogenicity studies done with the systemic

formulation.

DR. SWENSON: Dr. Venitz?

DR. VENITZ: I have a follow-up question,

not regarding the process as much as the

consequences. Let's assume that the committee

279

votes in favor of approving the product and let's

assume you follow our recommendation, what are your

tools to enforce a follow-up study as suggested by

Chiron?

DR. ALBRECHT: As you have heard allusion

to accelerated approval, that is a regulation that

allows us to approve a product on a surrogate

endpoint and then request confirmatory studies. At

this moment, I do not believe that is the question

on the table. So, in a setting of approving a

product in the conventional fashion what we can do

is request that a company commit to conducting a

postmarketing study and we put that in the action

letter. We put that in the action letter after

receiving a letter of commitment from the company.

I don't have the data as far as postmarketing

studies for what the record of completion of those

is but, again, our expectation would be that the

postmarketing study would be done as committed to

by the company.

DR. VENITZ: The reason why I bring that

up is that somebody mentioned the survey that was

280

published, I think it was in "The Los Angeles

Times," and only 50 percent of those promises are

kept. I think that is obviously something we have

to consider as we discuss the responses to the

question. You are basically saying a letter is

going to be written that is going to be agreed upon

by both parties, but from that point on there is

nothing that you can do.

DR. ALBRECHT: I am not aware that, other

than having that commitment, there are other sort

of regulatory steps that the agency has available.

DR. SCAIFE: May I just comment on that?

I obviously defer to the FDA regarding legal

requirements but I think it is true, what you say,

that the commitment that the FDA issues to a

sponsor is a legal commitment. This is not "would

you like to do this?" This is not an option.

Whether the Office of the Inspector General, in

other words the chief counsel of the FDA decides to

enforce, that is really a decision of the general

counsel. If you actually look at the trends over

the last few years and if you actually look at some

281

of the congressional activity, there are very

strong signals that they are going to tighten this

up. If you look, for example, at warning letters,

a warning letter is issued by the FDA that is

sanctioned by the OIG which is basically telling

the company you have got to do something; if you

don't there will be a legal consequence. If you

look at the trending over the last few years, those

letters have changed in tenor. So, those letters

now almost invariably are actually issued and go

through the OIG. That is basically saying an

attorney is underwriting this. So, I think if you

actually want to look at the statistics, when those

letters are issued those postapproval commitments

would be enforced. It has a legal meaning. It is

legally binding. Up to now the question has been

whether the FDA has been prepared to enforce it or

not. But if you look at the statistics, OIG is

getting a lot more blunt about it.

DR. SWENSON: Dr. Schoenfeld?

DR. SCHOENFELD: Are we at a point now

where people can begin making their comments on the

282

data, or are we not yet at that point?

DR. SWENSON: We are fast approaching it.

Do you wish to start that? We could go ahead and

focus on question one. You are first.

DR. SCHOENFELD: First I want to talk only

about the mortality endpoint and the discussion

that we have had about various covariate

adjustments of that endpoint and various subgroup

analyses.

First, people should realize that if you

do a randomized study a p value is valid if you

close your eyes entirely to the patient

characteristics. You don't need to look at patient

characteristics to justify a p value. What ends up

happening is that if there is no difference you can

be wrong five percent of the time, and rolled up

into that five percent are all the times that you

get a bad break or a good break with covariates.

So, that is the first thing to realize. Covariates

don't count. You don't have to look at them.

The second thing is if you do look at

them, if you decide to split your data by one

283

covariate and to analyze within each covariate

group and pool the results, in a randomized study

the randomization carries over to each subgroup.

That is very nice. That means that when you split

there is no presumption--let's say you do a study

and you do have imbalance in one group and you

decide, well, I am going to split, you are now

saying I am not going to use the original p value.

I am going to do another p value, and that p value

is also valid which, of course, is a big

contradiction in people's minds. How can two

different p values be valid? But they are. The

fact is that there should be no presumption that

because they are unbalanced in one covariate they

will be unbalanced in other covariates because they

were randomized within whatever subgroup you view,

and this is something else.

Now, people often expect that imbalances

will propagate down subgroups because they are used

to observational studies, and in observational

studies this isn't true. In observational studies

you don't have that factor that randomization

284

protects balance through subgroups, and when you

see imbalance in one subgroup you presume it is

going to be imbalanced in other subgroups and you

presume it is going to be imbalanced in things that

you didn't measure. But a randomized study is not

that kind of study. A randomized study is a study

that if you didn't measure something you should

assume it is balanced in it and not that it is

unbalanced in it.

These are just sort of factors that people

should try to understand. So, I thought that the

survival analysis was robust and the reason is

that, first, all of these subgroup analyses or

these stratified analyses are somewhat post hoc and

you can search for good p values or bad p values.

You can make just as much of a mistake trying to

kill a p value as you can to sort of create a p

value. So, when you have a lot of them they are

all suspect. So, you end up having to use your

reason, watching them and watching them, and it is

clear that the FDA did admit that they were driven

to look for imbalances by another problem, which is

285

the problem that the rationale didn't fit. Okay?

Then they were looking for something that would

throw away the p value, and I think that that is

kind of not a good idea. So, I think that survival

benefit can't be thrown away because of all these

various analyses. I think that you have to see it

as standing. So, I wanted to say that first.

Now let's deal with the other analyses

because I think the thing that the agency was sort

of concerned about was sort of mechanism of action

issues. That is, they said, well, so there is a

survival difference and the mechanism of action

doesn't seem to work because there wasn't an acute

rejection difference. This is probably a harder

problem.

First, one of the things is that I am used

to survival being the primary endpoint and one of

the reasons that survival is often the primary

endpoint in studies is that when there is a

survival difference you never can analyze for

anything else because what happens is that the

deaths cause biases. So, it is important to

286

understand this phenomenon. For instance, if there

were three people who were quite sick and died

right away even if it had nothing to do with the

treatment, those are three people who are bad

actors who have been pulled out of the placebo

group. Okay? That automatically means that if you

just remove those people and look subsequent to

those three deaths every analysis is biased by the

fact that the patients aren't balanced in the two

groups.

In fact, this is a problem in general,

that any analysis that is based on subsets that are

defined after treatment began is biased. Those are

problems that you have in really even analyzing

FEV1, acute rejection, chronic rejection, all of

those things where you try to remove survival. For

instance, I was sort of scratching my head about

the FEV1 because I couldn't really know whether it

was due to the different amounts of follow-up time

in the two treatments. This is also acute

rejection. I mean, the FEV1 is particularly

strange because actually the treated group had much

287

better FEV1 during the whole course of treatment,

but this could actually be a benefit of treatment

but we don't know because we don't have a baseline.

Actually, it is not clear that baseline is even

that meaningful. So, it is difficult to analyze.

So, when you look at these secondary

endpoints, if the deaths that occurred without

these secondary endpoints had nothing to do with

the secondary endpoints, then those analyses would

become unbiased but nobody really believes that is

true. So, we have a bunch of biased analyses, and

most of them actually would be biased towards

placebo basically because I think it is reasonable

to assume that the people who died would tend to be

the bad actors and that would bias FEV. It would

bias acute rejection, and so on.

Anyway, when I sort of count those up,

FEV1 was negative. Acute rejection was negative.

Chronic rejection was positive including both

endpoints. So, I think the situation really is

that we have a fairly robust survival benefit and

our problem really simply is that we don't really

288

understand this acute rejection well enough to

really use it.

DR. HERNANDEZ: Well, my main concern is

acute rejection, of course, but my main concern is

this, if I am following a patient with FEV1's and I

have a drug that is going to graft rejection I

would like to see that this FEV1, which is the

physiology of the lung, to be preserved regardless

of at what level they start, whatever the baseline.

And, what I would like to see is that if the group

that has not preserved that function, I would like

to see the natural history of decline of these FEV1

declines over time. But if I see these two graphs

to be parallel and the slope analysis doesn't show

any significance and the slope is similar, then I

don't see any preservation of the function.

DR. SCHOENFELD: Those graphs are biased

anyway because in one group people are being culled

out by death and in the other group people aren't

being culled out so fast. So, a longitudinal graph

over time where you are just looking at the

marginal comparison isn't actually valid. It isn't

289

a valid statistic. That is, in other words, if you

look at the FEV for all patients at, let's say, two

and a half years you have six or seven people who

are not in one group and who are in the other

group. That is, the only valid analysis would be

somehow to subset the analysis by the people who

would have been alive on both treatments if they

had had both treatments. You can create models to

estimate that but they are all models and nothing

is perfect. But just looking at the graph isn't

really a fair comparison.

DR. HERNANDEZ: The only thing is not only

looking at the graph but also to look at the

incidence of BOS as defined by the sponsor. Really

this is something that is bothering me. If you

look at a drug that is preserving the lung

function, that is preventing chronic rejection, you

need to see a benefit in the function of the lung.

That is something that you would like to see. I

mean, you can't say to the patient I am going to

give you this drug that is going to prevent chronic

rejection but I am not sure the lung function is

290

going to be improved or is going to be maintained.

That is my main concern.

DR. ZALKIKAR: I want to address a couple

of things. There was pre-enrollment FEV1 available

in the patients and the final FEV1 available in the

patients and we took the difference in each patient

between the final and the pre-enrollment FEV1, and

even those differences didn't show any

significance.

DR. SCHOENFELD: But that was already

subsetted. That was only about half the patients

who had pre-enrollment FEVs.

DR. ZALKIKAR: That is right. Of course,

we had to impute the missing data.

DR. SCHOENFELD: I mean, I think it might

be reasonable to say--I mean, I really am

supporting this application now but I would think

it is reasonable to say that there is something

that we don't understand here. Okay? And, that is

true but I think that then the question is do we

have to understand everything in order to approve

drugs? If things were completely the other way, if

291

there was no difference in survival but you did see

a difference in FEV we would be in the same

situation in a sense. We would still have the

question of, well, how come it produced a

difference in FEV and how come it didn't produce a

difference in survival? Especially with a small

study, we can't understand everything. Even with a

big study we tend not to be able to understand

everything.

DR. HERNANDEZ: My problem is this, if you

are going to give a drug it does need to have a

clinical effect. If you are giving this drug to

prevent chronic rejection, this drug should have a

clinical effect.

DR. SCHOENFELD: You mean a physiological

effect.

DR. HERNANDEZ: Exactly.

DR. SWENSON: We should move on to other

members. Dr. Hunsicker?

DR. HUNSICKER: First, I would like to

suggest, Dr. Swenson--I may be totally out of

order, but if we are going to go back and forth

292

between either the FDA or the other side arguing

each point, we are never going to get anywhere, and

I would really suggest that we limit the discussion

for the time being to the committee members unless

we have specific questions of the other people.

DR. SWENSON: I agree. We need to move on

to a vote and I would like to at least open this up

to the rest of the panel members here for any other

questions or observations before we make that vote.

DR. HUNSICKER: I have a technical

response to the question from--I don't know what

your name is--

DR. SCHOENFELD: David.

DR. HUNSICKER: David. There is, in fact,

a way to look at the FEV1 data that hasn't been

done so we can't use it today. You can do a mixed

model analysis so long as you include the last

measurement that was associated with what caused

the failure. And it has been shown that that

unrelieves the bias of informative censoring.

DR. PROSCHAN: That is not true. I mean,

it depends on whether it is missing at random

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versus not missing at random.

DR. HUNSICKER: We can discuss this later

on but there are additional analyses that could be

more informative than what we have.

DR. PROSCHAN: That is true.

DR. HUNSICKER: I would like to give my

approach to this which I offer up because it is

really opposite to yours, Dr. Schoenfeld. Where we

start out in this application is that there was a

very well formulated hypothesis that use of this

agent would affect acute rejection. We didn't find

that. We find now no effect on that. So, we start

with the usual presumption that if you have

something that turns up in a secondary analysis

this is considered hypothesis-generating and needs

to be then retested.

I can practically quote Flemming on this

who says that if you have a secondary outcome that

is significant or if you have a subset analysis

that is significant, almost irrespective of the

p value for it, if you repeat it only about a third

of those are confirmed when they are then repeated

294

because there is an effect of regression to the

mean. You have chosen them because they were

further, more deviant from the mean.

So, we start here with why we should not

or should look at this as being different from the

usual circumstance where the primary outcome was

not recognized, was not achieved, but a very

striking secondary outcome has been found either in

a subset or with a secondary thing.

This really is related to Dr. Helms'

comment where he says that this is sufficiently

strong that it strikes you between the eyes. That

is true. There is a strong thing here. So, how do

you evaluate this kind of a thing when it was not

the primary question?

There are two ways that you look at this.

First of all, does this have a credible underlying

hypothesis? Now, I would say that with respect to

the hypothesis that local administration of an

immunosuppressant agent might be effective in

preventing chronic rejection is credible but it is

certainly not something for which there is any

295

experimental data. This is something that is

really de novo. It is not impossible. It is a

rather attractive hypothesis but it is not based on

the same kind of data that we have for the

assumption that immunosuppression would affect

rejection in a broader sense.

So, that is a weakness in the hypothesis.

Then the second question, and this is why I do

believe that looking at the relationship between

the deaths and all the other stuff is relevant--we

have a circumstance where there is no question; it

is absolutely clear that there were fewer deaths in

the group that was treated. That is not a matter

of statistics; it is a matter of fact. So, then we

can ask ourselves is this difference in fact

something that was the result of the application of

the treatment or is this a fluke, if you will.

This is a small study so flukes are more possible.

We have the problem that I referred to before of

having sort of chosen this to bring forward because

it was an attractive, unexpected finding. That is

why we are here. That is not true for Dr. Iacona.

296

I don't mean to imply that he is in quite the same

situation. He put out the hypothesis that there

would be a good outcome. But we are looking at it

because this is one of the unusual circumstances

where you have a really striking p value in an

unexpected circumstance. So, we have to deflate

the p value for that.

Then we look at the circumstances that

deal with the question of whether, in fact, it is

credible that this thing is affecting chronic

rejection and, thereby, is preserving people's

lives. That the lives were preserved is

unequivocal. Then one question that could come up

is, well, there was no difference in acute

rejection and here I have to say that what I

consider to be an appropriate analysis actually

favors the company rather than the FDA. There is

no reason why acute rejection should be the

prerequisite for chronic rejection. As the FDA

probably knows from other circumstances, I have

argued in the past that what we call chronic

rejection is generally a mixture of immune and

297

non-immune events. Everybody has agreed upon this,

and you don't ever quite know how much of this is

immune and how much is non-immune. In fact, even

earlier failure, whether it is graft failure in the

case of the kidney or death in the case of lung

transplantation, could be the result of a process

added to something, what I have called in my area

which is nephrology interceptant [?] slope. If you

start lower you are going to get to your endpoint

sooner than if you started higher and it has

nothing to do with the rate at which chronic damage

is being done. So, there may be a difference in

chronic rejection or fibrosis that has nothing to

do with acute rejection.

On the other hand, what we have seen is

parallelism with all of the limitations of the

methods that we are using--parallelism in the

outcomes in terms of the FEV1 and other things like

that. So, at the bottom what I wind up with is

that this is a very promising therapy but it is not

a therapy that is now established. This is in a

way very strong hypothesis generating. So, has

298

this reached the status of substantial evidence

from well designed and executed clinical trials, or

something like that? But I don't think we have

gotten there.

I do want to say one last thing, which is

the Helm's comment. I find myself worried about

the idea that we would be chased into approval

because if we didn't approve nothing would ever

happen again. I think that would be a very bad

precedent because then all that a company would

have to do in coming to this group is to put you in

the position where, if you don't approve the drug,

nothing is ever going to happen. There are lots of

ways in which this drug can be studied further. It

is not this group's business to figure out what

happens if we don't approve it. The question we

have to deal with is whether it has reached an

approvable status or not.

DR. SWENSON: Dr. Gay?

DR. GAY: We have been given a challenge

that our cardinal task is to consider alive or

dead. There are significant things, in my opinion,

299

that compromise our ability to decide this. We

cannot underestimate the potential bias that occurs

with the fact that there are more patients who

underwent double lung transplantation in the

treatment group as opposed to the placebo group.

We have different criteria for listing for double

lung transplantation than we do for single lung

transplantation. The patient population is

younger. There can be potential selection bias

because the wait list time tends to be longer with

the double lung transplant population. Thus, if

they can get to transplant they tend to be

potentially healthier at the time that they are

transplanted with a lack of other potential

problems and medical issues that could compromise

their survivability.

I am concerned that this puts into this

process a profound amount of bias, and my concern

is, as optimistic as I would like to be for this to

be a therapy that we should consider, that the

explanation of the change in survivability can't be

easily explained by that and that alone as opposed

300

to factors that we cannot determine with the lack

of change in FEV1, the lack of change in the

presence of acute rejection, and with this I do

feel that a significant amount of increased

investigation is going to be required to make

absolutely sure that the difference we are seeing

between alive and dead are secondary to the

therapy. Because once we move to approve our first

therapy for lung transplantation I think we can

guarantee that it will be utilized in full force

and we must be cautious in doing so.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: You know, this is a very

difficult decision for me. One of the things I was

struck by is that really small trials go both ways.

That is, in this particular trial you would think

that because it is a small trial and you are seeing

more placebo deaths, then those people who are

dying are the sicker patients. Therefore, the

remaining patients in the placebo arm should be

healthier than the ones in the cyclosporine arm.

So, I would expect in a small trial, even if you

301

see a benefit at first, that the curves would tend

to come back together because of that survival of

the fittest phenomenon--you know, you have only the

fittest surviving in the placebo arm and everyone

surviving in the other arm. So, I would expect

them to come back together and the fact that they

didn't come back together is something that I think

influences me when I try to think about is it real

or not.

The statement has been made that no IRB

would allow another randomized trial. Earlier than

that a statement was made that if you were on the

DSMB you would definitely vote to declare treatment

benefit. I think that is not true at all. I think

that a DSMB would be struggling just as we are and

that it would not be a slam-dunk. In the cardiac

arrhythmia suppression trial there were 19 events

in one arm and 3 in the other arm and they didn't

even want to be unblinded yet. They said whichever

way it went, it is too early to tell. So, that was

19-3 and they didn't even want to become unblinded.

So, I think the idea that this is a

302

slam-dunk and the question has already been

answered is not true. I struggle with this and I

do agree that the survival result seems to be

robust to various sensitivity analyses and, you

know, that makes me feel a little better. I agree

with Dr. Schoenfeld. That does make me feel a

little better.

Then the question is what degree of

evidence is required. If it is like a civil trial

where you just need a preponderance of evidence

there is no question in my mind that that has been

shown. If it is like a criminal trial where you

need proof beyond reasonable doubt, I am not sure

that that has been shown. So, to me, it is

somewhere in between those two and, you know, the

question becomes how much evidence do you need.

DR. SWENSON: Miss Drittler?

MS. DRITTLER: I am a lung recipient and

this is sort of getting away from the questions

presented to the committee but what I wanted to

know--the first year and a half after my transplant

I went through approximately three rejections, one

303

very serious one. Of course, nothing was available

at that time. After that year and a half I have

not had a rejection but, as we all know, rejections

can occur at any time. If I were, say, in my

fourth year to encounter this problem, would the

inhaled cyclosporine be beneficial to me at that

time? Because I am assuming that these people who

were in the study were put on the inhaled

cyclosporine immediately after transplant and

followed for the two years. So, I want to know is

it beneficial to somebody--Dr. Suss stated that she

was put on it a year and a half or two years after

transplant. Is this going to be the case, that it

will benefit those of us? If I hit my five-year

survival rate, which I don't believe in, will I be

able to take it to prevent or stop rejection?

DR. SWENSON: Well, I think that is a

pretty hard question because it wasn't studied in

that fashion. Maybe someone from the company might

just spend a minute or two, not any longer, just

answering her question if you think you have

something to either agree or to put a different

304

light on it.

DR. DILLY: Our belief is that we are

preventing or slowing the trajectory of chronic

rejection so our hypothesis, which is worth testing

and we have already seen the RAR data being very

provocative, is that the drug would benefit

patients already some way down the road from their

transplant. But that is not the basis of ACS001.

MS. DRITTLER: Thank you.

DR. SWENSON: Dr. Barrett?

DR. BARRETT: I just wanted to again

reiterate that this was really not designed as a

registration trial. It is a Phase II trial, not

even with the benefit of a formalized statistical

analysis plan prior to proceeding. So, applying

the conventional statistical criteria, as has been

done by both the agency and the sponsor, makes it

very difficult and I think is the cause of all our

unhappiness as we sit here and see the data

summarized.

Having said that, I do believe Dr.

Schoenfeld's assessment of the forgiveness of the p

305

value given--maybe short-sighted--but the attempt

to randomize patients as was done in this trial.

However, I also feel the way the FDA has done their

subset analysis was absolutely relevant in order to

define which criteria are in fact sensitive to

these results. Because of that, it makes it very

difficult. I believe that the signal is, in fact,

valid and robust but I don't know if I would feel

comfortable generalizing the magnitude of this

effect from this one trial in a subsequent study.

DR. SWENSON: At this juncture I think we

should go ahead and take the vote, unless there are

any committee members that feel that they really

need to say one more thing.

DR. VENITZ: Yes, one more.

DR. SWENSON: All right.

DR. VENITZ: I am not a statistician but I

am trying to use informative decision analysis to

approach the problem that we are facing because I

think everybody would agree it is a close call.

The way I approach things like that that are a

close call is that I am going to look at what is

306

the likelihood that we are right or wrong and what

are the stakes. In other words, I do what Helms

suggested. I am a rational gambler. And, I think

to some extent, whether we admit it or not and that

includes the FDA, we are rational gamblers when we

review evidence to decide what the significance is

both in terms of the statistics as well as the

consequences.

So, I think, like most of you, I am

obviously not convinced that this is beyond any

reasonable doubt for proving that the mortality

benefit that was demonstrated was due to the

treatment as opposed to something else that we

don't know about, no matter how much we try.

However, I do think that it is plausible, and I do

think that it meets the civil trial standard. It

is the preponderance of the evidence; not beyond

reasonable doubt but preponderance of the evidence.

So, there is some 30 percent likelihood of coming

up with the wrong answer, that we find a difference

that really doesn't exist.

Counteracting that is the fact that it is

307

a large difference in terms of the mortality. That

is all I am talking about. And, counteracting that

is the fact is what is the competition that we are

trying to beat right now? There are no drugs

approved. It is a dismal disease. Right now we

have a 50 percent mortality rate with the current

treatments. Maybe there are other ones being

investigated. So, I think the stakes are high and

I am willing to take a chance on the likelihood

that this might be a study that doesn't prove

beyond any reasonable doubt that the drug actually

works.

So, in my final summary then, I would

conclude, even though I have this doubt about the

likelihood that this is real, the stakes, to me,

favor saying that this is sufficient evidence.

That is a word that is in the question here, I

think there is sufficient evidence to say that the

survival benefit is due to the treatment that

patients might benefit from.

DR. SWENSON: We will go ahead and begin

the voting. I will ask Miss Schell to give us your

308

vote.

MS. SCHELL: I am Karen Schell and I am

the consumer representative. I would just like to

add one comment before I vote. Looking at the

question on sufficient evidence, I am a practicing

respiratory therapist and I also do perform FEV1

pulmonary functions on a daily basis, and I think

those objective measurements are very important in

a study. And, because of the limitations of this

study I think the study needs to be bigger. I

think that whenever there are unanswered questions

more research needs to be done. So, I am voting as

a no.

DR. SWENSON: Dr. Sampson?

DR. SAMPSON: It is obviously a very, very

difficult decision. I have listened to my

statistical colleagues and my clinical colleagues

and have wrestled with this more than I care to

admit, and I think all I can conclude from this

single trial is that the observed mortality

difference may be due to treatment. There is the

other uncontrolled data, the ACS002, that is

309

supportive but it is certainly uncontrolled.

My basic problem, as has been stated by so

many other people, is if it is due to treatment the

question is why, and what has been demonstrated to

cause the survival difference. I don't see strong

enough evidence, certainly not in acute rejection.

In fact, at least by the sponsor's own analysis,

acute rejection rates are higher in the CyIS

group. And, I think there are a lot of other

statistical difficulties in the analysis of the

chronic rejection data, both in the definition of

the endpoints and the analysis.

DR. SWENSON: Your vote then is no. Dr.

Schoenfeld?

DR. SCHOENFELD: I guess I will be very

brief. My vote is yes.

DR. SWENSON: That was brief. Dr.

Proschan?

DR. PROSCHAN: To me, what you want is

compelling evidence to offset any potential harm

that there might be that is hard to see based only

on 100 patients on the safety data. So, my short

310

answer would be no, that it is not sufficient.

DR. SWENSON: Dr. Barrett?

DR. BARRETT: I am going to key in on two

words, "sufficient" and "survival" and because of

that I am going to say yes.

DR. SWENSON: And I will reserve mine till

the end and move on to Dr. Moss.

DR. MOSS: The thing in making the

decision for me is that based on the small study

the outcome of five or so patients, if they had

gone the other way is going to change the standard

of care for a thousand patients each year based on

that outcome of just a few. I think there is some

precedent with the gamma interferon trial, with the

steroid trial for ARDS of two small studies that

when the companies were able to go ahead and do

larger trials, it showed that those things were not

true.

On the flip side, with the ventilator

strategy for ARDS the paper in The New England

Journal of Medicine it showed that the ventilator

strategy worked and work now shows that, in fact,

311

it was true. So, I think it was possibly due to

the studies. But I don't think we should change

the practice based on a small study where a few

patients can weight the whole outcome so I would

say no.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: I sort of approach this

question in the setting of the thousand shades of

grey that were dealt with by something that others

have said, and that is where is the greatest harm?

I think the tradeoff we have is believing the

survival or believing just about everything else

that would make sense about it. I think, in my

view, the greatest harm would be to not proceed

with approval. So, it is a yes.

DR. SWENSON: Miss Drittler?

MS. DRITTLER: Well, of course, as a

patient I have to look at the survival rate and the

application that it has on chronic rejection, and

my vote will be yes.

DR. VENITZ: I have said my piece. My

vote is yes.

312

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: I have said my piece and

my vote is no.

DR. SWENSON: Dr. Gay?

DR. GAY: Considering all the factors

involved, understanding that this is a therapy that

will be adopted across the board, understanding the

limitations of the sample size and the potential

for a skew on this, I must vote no.

DR. SWENSON: Dr. Mannon?

DR. MANNON: With due respect to the

thoughtful presentations by both Chiron and the

FDA, and I also empathize with the patients for

coming here, as a solid organ transplanter, you

know, facing life and death is a difficult issue

but, be that as it may, my vote is against

approval. Again, it is because, to me, though the

survival effect may seem to be a statistically and

a reality-based issue, it is not clear to me what

caused that and it is not clear that the drug

itself was responsible, particularly when only half

of the individuals on that treatment completed the

313

treatment.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: I usually like to think of

things in mechanistic terms, but in this disease we

don't really understand the mechanisms enough and I

think ultimately the uncertainties are much greater

but ultimately it appears relatively safe. We

haven't seen evidence of toxicity. There is a

potentially huge upside so I will vote yes.

DR. SWENSON: Dr. Tisdale?

DR. TISDALE: Well, I am basing my

decision on the fact that this was a secondary

endpoint in the study, that it did come out in the

original planned analysis of the study. There was

a clear survival advantage. I am not saying that I

believe that there is a connection between the drug

definitively and the survival advantage but, when

considering everything on balance, I am going to

have to vote yes.

DR. SWENSON: Dr. Brantly?

DR. BRANTLY: Having been involved in

treating individuals with rare diseases for the

314

last 20 years, I crossed this bridge about 20 years

ago actually when I first started. My vote is yes

for the reason that I believe this offers probably

the best promise at the present time and has

sufficient data to support that.

DR. SWENSON: My vote is no, not

overwhelmingly no but for reasons that have been

stated here, I don't think it is proven and I think

that the issue could possibly be resolved faster

than what has been stated in a smaller trial. If

this is really as strong an effect as it is, it

should be borne out very quickly. So, I don't

think the evidence is yet there.

What this means is that we have a tie

vote. Dr. Albrecht, how do we proceed here with

the second portion to this question?

DR. ALBRECHT: I think next time we will

invite an odd number of consultants--

[Laughter]

If I may ask you to please move to the

second part of the question, I think it would be

very helpful for us for those who believe the

315

evidence is sufficient to please address the yes

part of question 1(a). For those who feel that the

data are not in, to please give us suggestions

about additional studies. So, please discuss

either option yes or option no.

DR. SWENSON: What I would ask then--and

we will go through the order just as we did--is

that those voting yes please answer (a) and those

voting no to offer their suggestions. So, Miss

Schell?

MS. SCHELL: I voted no and I would like

to have more data concerning the donor and also

post-operation, some of the other factors that

would be sufficient like the FEV1 and less decline.

Basically, I would like to know more about the

donors' lungs before they were donated.

DR. SWENSON: Dr. Sampson?

DR. SAMPSON: I voted no and, as I started

to say before, I think there is a struggle and I

think there are certainly very strong arguments as

to why CyIS would work. But to do another two-year

treatment study with a survival endpoint and

316

reasonable follow-up would be a lengthy

undertaking. I would encourage the agency and the

sponsor to work together to design a prospective,

randomized, blinded trial but with a more

innovative design. I don't know if that means

doing something like low dose versus high dose to

increase enrollment, as has been suggested, or

introducing a reasonable surrogate endpoint for

survival that could be measured earlier than

waiting for it two or three years post treatment.

I have heard arguments pro and con why

FEV1 might be such a surrogate. I think it is

really critical to identify and agree upon

important baseline variables, and perhaps even

employ some sort of stochastic, dynamic balanced

randomization scheme that would try to keep all

these variables between treatment groups reasonably

comparable and maintain the blinding so that we

would not have a discussion like this again.

As is usual in regulatory studies, the

study protocol and the SCP should spell out the

objectives very clearly; the primary variables for

317

analyzing these; and the primary analytical methods

for the primary variables. I also think that this

is the kind of study, given the kind of difference

that we have seen up to now, that would benefit

from some sort of sequential design which would

allow for an early stopping if, in fact, the

differences persist of the magnitude that we are

seeing so that a quick decision could be reached.

DR. SCHOENFELD: I won't be as brief this

time. I am going to look--

DR. SWENSON: I should say that is Dr.

Schoenfeld. We need to keep that for the record.

DR. SCHOENFELD: I am sorry. I think that

in regards to 1(a) it is sort of a difficult

situation because this study would indicate that

the biggest difference created by this treatment

was survival. I mean, this would be the thing you

would want to look at as the thing that would be

the most likely endpoint to show a difference in a

subsequent trial. As I have said before, even

analyzing any of these other endpoints that would

give you a good idea of the mechanism is very

318

difficult in the face of a big survival difference.

This was the big difference, by the way, in the

ARDS. We still don't know why 6 mg/kg works.

Because, in fact, all the oxygenation parameters

and all the various parameters don't really show a

difference between 6 mg/kg and 12 mg/kg--I am

referring to the study of low versus high pressure

ventilation for ARDS. None of those mechanistic

things work because you can't really compare them

because of the difference in mortality.

So, I think that this leaves a big problem

for someone coming to a future trial because their

best shot is mortality and the other things are

going to be probably fuzzy, like they are now. I

think that is something to realize. So, the big

advantage they will get in doing another trial is

that mortality won't be a secondary endpoint and

there will be now two trials, and maybe a

multicenter trial so they will get some of these

other things dealt with.

So, I think that in terms of 1(b) you end

up having to repeat the trial and it would sound

319

very funny if you then argued--you know, you

wouldn't have any of those secondary endpoint

arguments at that point.

I don't know how you could balance it

because I am sure that, no matter how carefully you

stratified the trial, if people were really trying

to knock it down by finding different covariates

you could find some. So, I don't think there is

any way of perfectly balancing a trial. So, it

would be a confirmatory trial and that is probably

what should be done if you want to go forward.

Now, in terms of 1(a), this is always a

problem, how to generalize clinical trials either

from one institution or from--so I just answered

1(b) and I guess the answer to that is you are

going to have to do another survival trial, bigger

and multicenter.

In terms of generalizability, that is

always a problem in clinical trials, generalizing

from the few patients you treated to the patients

you didn't treat. This trial randomized about five

percent of the patients in the United States that

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have this disease. That is, you randomized about

five percent of the people which is much better

than we did in ARDS network. So, I don't know how

you can answer these questions. Nobody knows

whether you can generalize. Usually what you end

up doing with clinical trials is you close your

eyes and you generalize.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: For what additional

information would be needed, to me, I think you do

have to do another randomized trial. I don't think

you can get away with a single-arm trial where

mortality is the primary outcome. And, I don't

agree with a comment made earlier that it could be

much smaller. I think that is an invitation for

disaster again because then you could get a p value

that is 0.10 or something and you might also get

the baseline imbalances. So, I do think it has to

be a larger trial, perhaps multicenter.

I am not as concerned about the issue of

generalizability. To me, the issue of

generalizability is, you know, University of

321

Pittsburgh does a lot of these and maybe they have

learned something about how to deliver this

aerosolized cyclosporine and maybe other centers

that are just starting might not know that. So, to

me, that is the issue of generalizability. Is

there anything special that Pittsburgh learned and

other centers that try to do this might learn the

hard way? So, to me, you have to do another trial

where survival is the primary outcome, a randomized

trial.

DR. SWENSON: Dr. Barrett?

DR. BARRETT: I voted yes. However, as I

mentioned before, I think there is very little that

you can generalize from the previous study, and for

all of the analyses that the FDA showed there are

several factors which make the existing data,

primarily due to the small sample size, very

suspect.

One of the most important things I thought

was the idea that the acute rejection doesn't

necessarily correlate with the chronic rejection.

And, one of the things that I am more suspicious of

322

is the maintenance of the survival benefit in the

face of limited dosing and/or exposure. It simply

may be that we don't understand how to dose that

particular facet of rejection progression. It is

an interesting finding. I don't know if I would

walk back into the quicksand and do another

survival study though. I think there are better

studies to do now with the idea of really figuring

out how to dose this agent.

I think there was a rationale for inhaled

cyclosporine at the very beginning that prompted

this trial, which I think is probably still there.

There is, for sure, a regional delivery advantage,

however, it is probably not maintained by

conventional pharmacokinetic behavior so we simply

don't understand what is the local exposure

requirement in order to maximize the benefit of

this route of administration.

So, as far as studies go, I think a

combination of preclinical models as well as

different dosing scenarios where you consider low

and prophylactic regimens to be more beneficial.

323

DR. SWENSON: I voted no, and I have

mentioned my thoughts here. I think another trial,

maybe two to three times larger than this one that

might incorporate several centers and, of course, I

think with the problems that develop in the design

and then ultimately coming here could be corrected

from the start. That is, we would have all the

preliminary data. There would be no question about

loss of data in a prospective study. I think

another study of that magnitude would be what would

be necessary, and possibly a stopping point could

be agreed upon early. If, in fact, this major

survival advantage persists the study could be

concluded earlier on the basis of that, given what

we have seen with this study. Dr. Moss?

DR. MOSS: I really don't have a lot to

add to what Erik just said. I think that the

results need to be confirmed in a larger

multicenter study where the study is performed more

rigorously and, of course, add some longer-term

outcomes that won't preclude people from voting yes

to approve the drug, but that that would be kept in

324

mind in terms of carcinogenic possibilities.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: The big issue in

generalizability is what was observed before, that

about two-thirds of the patients in this trial

weren't on up-to-date immunosuppression. So, for

all programs, including Pittsburgh, I think that is

a question that remains in terms of using this

regimen today.

I think the other major issue is that if

this is effective, if the results of this trial

haven't misled us due to happenstance, or whatever,

then there needs to be some inventive thought about

how to look at it with things other than biopsy,

FEV1 and other things which have not correlated

with the outcome.

DR. SWENSON: Miss Drittler?

MS. DRITTLER: Again from a patient

viewpoint, I feel that what I am reading in the

data with the survival rate, the safety problems

don't seem to exist. I just think that having been

very sick for ten years, hoping something would

325

come along as many patients are doing, grasping at

straws actually, this seems to be something that

could be very profitable to the lung transplant

population. And, I just feel that it is an

important thing at this particular moment not to

preclude necessarily further studies. I think that

could be necessary but in the meantime there will

be patients dying who might profit from this.

Thank you.

DR. SWENSON: Dr. Venitz?

DR. VENITZ: Obviously, I voted yes so I

am down to "yes-(a)" I guess. Confirm efficacy;

establish mechanism of action; expand safety; and

optimize the dose. Those would be the outstanding

issues in spite of the fact that I did vote yes.

Confirm efficacy in a larger, more heterogeneous

population. I think mortality is definitely going

to continue to be an outcome that is of interest

because you have to come up with labeling language

that reflects whatever the committee recommendation

is and the FDA final judgment on this is going to

be, but I think also an assessment of mechanism of

326

action would look at FEV1's. It would look at the

relationship between some of the markers of disease

progression relative to survival to understand what

actually happened in this study. Expanding safety,

I think that is question number two, is to look at

long-term safety five-year safety data. It was

already mentioned that there is a concern about the

incidence of cancer as a result of chronic

immunosuppression even though you would think, due

to the low systemic exposures, that is minimized

but, nevertheless, you would like to have some

empiric data.

Lastly, I don't think the dose--and I

agree with Dr. Barrett on that, I don't think this

is the optimal dose, as it usually is not. I would

like to believe that it is a safe and effective

dose but I don't think it is an optimal dose. So,

I think in addition to efficacy, safety and

mechanism of action, additional dose optimization

studies are appropriate. In particular, what I

would be interested in would be the dosing

interval. Right now I don't know whether the drug

327

has to be given three times a week. It could well

be that you could give it once a month. It could

well be that you don't have to give 300 mg and

expose patients to the hassle and the inconvenience

of being bronchodilated, getting lidocaine and then

sitting in front of a nebulizer for ten minutes.

So, I think there are some dosing questions that

should be addressed in clinical as well as possibly

some of the preclinical studies as well.

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: I was a no voter. One of

the committee members down the line there, whose

name I can't see, suggested that we should not

exclude the possibility of preclinical studies. I

am, for one, not absolutely sure that we have an

established mechanism that we are working towards.

It may be that it is obvious to some that locally

administered immunosuppression should work. It is

not so obvious to me. So, I would not forget the

possibility of doing preclinical studies that are

really properly designed to see whether topical

administration of this in the lung transplant

328

setting--which you can do and it is really unique

in the lung transplantation that you can do

this--is effective in preventing chronic rejection.

I think this is a very interesting question and

that shouldn't be forgotten.

With respect to the clinical trial, it

seems to me very straightforward, as has already

been said, that the next trial should have

mortality as its major endpoint. That is where we

are, and if the next trial shows an advantage in

mortality it doesn't make any difference what else

is shown. That confirms it. At this point, this

is now starting from "we think that this might

work" and that would just nail it down. But I

would hope that that trial would have defined in

advance very well how to at least look at the

issues of fibrosis and function, these being the

two major things that are involved in chronic

rejection of lung, as well as the other organs.

So, I think of things like the endobronchial biopsy

that was being discussed--some knowledge of what is

actually happening to the lining of the bronchi

329

which is where the fibrosis is going on would be

very helpful in eventually being able to analyze

this.

Finally, with respect to the study size, I

would just caution you that virtually always when

you have a striking effect like this the next time

you look at it the effect is much smaller. So, do

not assume that you are going to get this size of

effect the next go around even if this is a real

thing. You have to power the next trial

sufficiently to be able to detect a difference that

would be convincing to you and important to you

irrespective of it is the size that we see in this

trial. So, I think it is going to wind up being a

fairly large trial.

Then you get into the issues of can you

ameliorate the ethical quandaries by having a

different randomization scheme, 2:1 rather than 1:1

and things like that. These are well within

Chiron's and Pittsburgh's ability to figure out and

I don't think it is going to help us any for me to

go on about it. So, basically, it needs a new

330

clinical trial and I would love to see some basic

studies.

DR. SWENSON: Dr. Gay?

DR. GAY: I voted no because of the

problematic nature of attempting to define

mortality in the transplant population and the

causes for mortality. Unlike the oncology studies

where mortality usually results from progression of

the primary malignancy, with factors related to

both rejection and infection and side effects from

the immunosuppression, I believe mortality becomes

very hard to power for. Where a significant impact

may be present is the fact that we have no therapy

whatsoever that intervenes on chronic rejection,

and if we can have a proven theory that affects

BOS-free interval, if we can show that you can go

longer without developing BOS with a therapy as

opposed to without it, I think you will find a

therapy that will have significant positive benefit

and a reasonably easy course for possible approval.

So, I would attempt to put together a randomized,

controlled trial that would deal as the primary

331

endpoint with BOS-free interval in enrolling a

patient population post-transplant.

DR. SWENSON: Dr. Mannon?

DR. MANNON: Again, I was a no vote. To

reiterate, I think a proper prospective collection

of data, so a randomized trial, and also with

balance of the two critical components, that is

double versus single and acute rejection rates. I

think that is a big sticking point for me in the

analysis of the initial data.

I also think it would be important to have

a spelled out standardization of immunosuppressive

strategies whether it is one center or multicenter,

as well as standardized strategies for patients

with acute rejection so that all patients are

receiving similar therapies. Then, if they fail

those therapies there are appropriate outcomes.

Obviously, a formal safety data monitoring

board, with an appropriate stop point, the endpoint

being survival. But I also think, as Dr. Hunsicker

pointed out, an opportunity to collect mechanistic

data as additional information, including

332

standardized time points for FEV1 and bronchoscopy,

but also maybe localized as well as systemic

measurements of allo-immunity because you have a

small group on specific therapy and that may

actually shed some light even if the study is not

huge.

Finally, I think we need some long-term

safety data. There was a discussion of potential

malignancy from this drug, but cyclosporine also

stimulates TGF-beta and whether this local effect

may in the long term actually promote fibrosis

indirectly, which we don't know, is something else

that I think needs to be answered.

DR. SWENSON: Dr. Prussin?

DR. PRUSSIN: Most of my comments have

already been addressed. In terms of

generalizability of the study, I think the

population that is being looked at could be more

ethnically diverse than the small study in

Pittsburgh, and that probably would be addressed if

it is a multicenter study.

Also, the whole issue of an inhaled

333

formulation in terms of SOPs for nebulization. I

gather that inhaled lidocaine is not approved so

that whole usage and how that is delivered should

certainly be standardized.

DR. SWENSON: Dr. Tisdale?

DR. TISDALE: I was a yes but, as I said

the first time around, my decision was based mostly

on a risk-benefit assessment. Here the risk seems

to be extraordinarily low and the benefit is

possibly extraordinarily high. So, that weighed

me. I sat right on the fence the whole way around

the table until it came to me, and the whole

morning as well.

But when it comes to the question of

generalizability, that is the yes-man's question.

Certainly the control group correlated well with

the experience that is out there, the broad

experience for transplant. This represented a very

sizeable fraction of the transplant patients over

that period of time. So, any new therapy that is

tried, for example in bone marrow transplant, is

always a very small fraction. A hundred things are

334

different about each protocol so in this I was

actually encouraged by the fact that there was a

big percentage of patients that were studied and

that the control group looked just like the broad

experience of transplant patients. So, I felt like

there was at least some generalizability of this

information.

We have had a lot of people bring up the

issue of the collection of the data being

problematic in this study and, certainly, the study

wasn't designed as a pivotal study for FDA approval

of this drug so there are a lot of problems with

the collection of the data but the endpoint that we

are looking at, which is survival, was a secondary

endpoint and this is not a subtle endpoint. I

mean, you are alive or you are dead so that is

simple to look at. And, whether you look at it a

week after the study closed, a year after the study

closed, there is no arguing about whether or not

there is a survival advantage. So, to design

another randomized study with a survival endpoint

is the study that we already have. It was a

335

randomized study with a survival endpoint, and the

survival endpoint was statistically significant.

So, you know, what is necessary for me to

move it on--you know, not everyone is going to

adopt this. People will look at the study when it

comes out and realize that there are problems with

the study and not everyone is going to do it.

Certainly, it requires further validation in

another study I think which doesn't necessarily

need to be, in my mind, a randomized, controlled

trial. There are many different ways to get at the

questions that still remain beyond the survival,

and the survival can be compared, I think, to the

existing survival data because we have heard over

and over again that this survival curve has not

changed in more than a decade.

So, I certainly feel comfortable with

comparing whatever is seen in a subsequent trial to

the existing 50 percent survival rate. I don't

think that is likely to change in a big way, and if

the next study is a negative study everybody is not

going to be giving inhaled cyclosporine. It is a

336

pain for the patients; it is a pain for the

placebos. They have all demonstrated that it is

not something that people are going to wildly run

to without further information. So, I think a

subsequent trial that is not randomized is

certainly sufficient to get at the questions that

weren't addressed in the original randomized,

controlled trial.

So I agree that the things that need to be

addressed next is that we need a study that

confirms the efficacy on survival. That is easy

enough to do in a study that is not randomized. We

need to better establish the safety. That is easy

to do in a study that is not randomized. And then

optimize dosing, which I think would be very

difficult to do in another randomized, controlled

trial. So, those are what I would see as the ways

to move forward on whether or not this is actually

generalizable.

DR. SWENSON: Dr. Brantly?

DR. BRANTLY: I was a yes voter, and I

think that, number one, my greatest concern with

337

the study was the fact that there was an imbalance

in the double lung/single lung transplants and that

that plays strongly into survival benefit.

As far as generalizability, I have

questions about how generalizable these studies

are, and I believe that that should be expanded in

a good controlled study in the future. I would

recommend basically having four arms, which would

be double lung, single lung, a low dose versus the

standard dose, which would answer some of the

questions regarding both the ethics since we really

don't know what the dose is in this particular

study group. I think it would be acceptable to the

patients and probably get to the answer about

survival.

DR. SCHOENFELD: I just want to say

something because this keeps coming up as double

lung and single lung. I think that the

stratification by double lung and single lung as

was done in the analysis pretty much shows that the

benefit occurred in both groups, and when you

control for single and double lung the relative

338

risk stays exactly the same and the estimates stay

the same. So, to consider that as a major problem

with the study I think is not borne out by the

data. I think that the FDA would even agree with

that, that that isn't the primary problem with this

data. Their stratified analysis on that simple

stratification was still highly significant. If

that was the problem, it would just go away, the

significance.

DR. ZALKIKAR: The model that included

just the single versus double lung, yes, the data

was significant, just that one factor at a time.

DR. SWENSON: Dr. Albrecht, hopefully, we

have satisfied your charge here on this question.

It looks like it is a split and I don't think the

yes/no are really that far apart. We all have

concerns and we all have, obviously, great hopes

for something like this to work and hope that a

speedy answer could be obtained. Shall we move on

to our second question?

DR. ALBRECHT: Yes, please, and I think I

will elaborate a little bit on it to see if I can

339

probe for some more comments and advice. The

second question is fundamentally focused on safety,

specifically, has the safety of the product been

adequately characterized for its intended use?

I know we have heard some of these

comments already during the past discussions, but

in these deliberations please consider both the

amount of preclinical information and the clinical

information that is available on the administration

of cyclosporine, as well as the vehicle, through

this route, and the number of patients that have

been exposed to the inhaled cyclosporine in this

application at the proposed recommended dose.

Here is where I would like to just

elaborate a little bit more, if I can, which is if

you answer yes to this, and especially this in

addition to question one, here is where I would

really like a lot of comments from you, if

possible, about what you would envision in the

labeling, I think both the positive as well as what

kind of cautionary or negative language you might

include. So, specifically for what population

340

would you suggest, if you are advising that the

product be approved, that it be labeled for what

patients perhaps should receive the product and

where the data may in fact be limited or absent as

far as patients that perhaps shouldn't at this

point be advised or recommended to receive the

product.

Also, it would be very beneficial if you

could comment on the dosing regimen, the

preparation, the administration route, the dosing

intervals and the duration, again basing this on

the information that we have in the application.

How comfortable would you be summarizing the

information in labeling and, again, what kind of

cautionary information do you believe or would you

recommend that we consider putting in the labeling

regarding what isn't known about the product.

Also, if you could, because I think as we

have heard and has been stated, the difference in

mortality that has been presented is fairly

dramatic and, at the same time, there are not

differences in some of the other endpoints like

341

acute rejection, BOS, FEV1--how much of this

information would be valuable in labeling; how much

of the information might not be ready for labeling

based on the comments you made about need for

corroborative data, and so forth.

So, I would like to hear as much

discussion as you can give to the "yes" part of the

question. I notice that we were getting

recommendations both on "yes" and "no" so on the

"no" side it would be really useful--and I know we

heard a lot of comments about traditional studies,

both efficacy and safety and dosing and

preclinical, but if you could just elaborate in any

way that you can specifically on study designs. We

heard some suggestions for randomized, some

non-randomized, but if you could perhaps give some

further details about study designs that may be

coming to mind as you go around the table.

DR. SWENSON: Well, we could do it in the

same fashion as before, a vote, but maybe as much

as we have talked already, if the committee would

be willing just to go ahead and take both in turn

342

individually. Do I have any strong dissent for

that? Just for fairness, we will start on the

other direction and I will ask Dr. Brantly to start

off.

DR. BRANTLY: Well, if yes, I would argue

based on the study I read--I would say the

population is lung transplant. I would make it no

more specific than that.

As far as the dosing regime and dosing

intervals, I think they have to stick closely to

what was done in the original trial. At the

present time we have no other information.

Regarding 2(c), I believe that this can

only be labeled as having a survival benefit.

There is no evidence to suggest that the other

things were changed by this drug.

DR. SWENSON: Dr. Tisdale?

DR. TISDALE: I think I would have to echo

almost identical statements. If yes, only for

prolongation in survival in recipients of single

and double lung transplants.

The same dosing regimen should be listed

343

in the labeling even though it wasn't completely

followed by all the patients.

There should be I think no expected

benefit with respect to the other endpoints since

they weren't shown definitively to be altered by

the cyclosporine inhalation.

I think there also should be caution that

there is no safety data regarding carcinogenesis

effect on lung scarring or that sort of thing. So,

I think there should be caution that there is

incomplete data on carcinogenesis in laboratory

animals and in humans, and that it is too early to

know in the recipients that have been treated with

this regimen whether that is a concern.

DR. SWENSON: Dr. Prussin?

DR. PRUSSIN: Along the same lines I

guess, you could put for the dosing 300 mg three

times a week as tolerated. In terms of duration,

obviously the study was for two years and so you

would put in some caveat that use of this has not

been shown to be of value beyond the two-year

point.

344

There is the whole quandary of the

lidocaine use and how do you put that into the

labeling since that is an integral part of the drug

but is not an approved drug itself. I think, other

than that, that is the only unique thing.

DR. SWENSON: I should step in here and

say that another party has entered this position

about lidocaine and I am not sure that 100 percent

of patients had to have lidocaine as pretreatment.

It was a large fraction. Could the company just

comment on that? Did everyone get lidocaine as

part of this or was it only as needed?

DR. NOONBERG: It is my understanding that

most, if not all, patients were initiated on

inhaled lidocaine without butyryl. However, how

long they continued with it was variable. We don't

have exact information on duration but certainly it

wasn't uniformly continued.

DR. SWENSON: So, this probably should

just be a point for further discussion and

decisions about how lidocaine might fit in this and

whether it needs its own labeling. Dr. Prussin?

345

DR. PRUSSIN: Obviously, these people have

been followed closely but, because this has been

used in such small numbers of patients, something

about follow-up and close follow-up and long-term

safety has not been established.

DR. SWENSON: Dr. Mannon?

DR. MANNON: From the perspective of

long-term safety, we do now have a patient

population that is available that has been on the

therapy for a number of years, and perhaps we will

be able to incorporate them insofar as giving us

some of the more long-term data rather than relying

on a dog model or a rodent model where the dosing

is different. You know, the opportunity to keep

dogs around for five years may not be feasible.

I am not really sure how to address the

tolerability of dosing. It wasn't clear to me what

was the cut-off. Were patients having either

sufficient bronchoconstriction that they had to

stop, or coughing or wheezing, whatever? But I

think that we need to have a better understanding

of the tolerability of dosing and what is

346

appropriate pre-medication. As we alluded to, it

is not clear to me what the dose escalation

guidelines are. It sounds as if you got 100 mg and

you tolerated it, then you went to 200 and by 10

days you got 300. But I think that those

guidelines need to be defined and it is not clear

to me whether there was additional intolerability

or bronchospasm or cough or wheezing due to a

higher dose, or whether it was the vehicle itself.

It would be helpful I think to know what

the tissue levels are. We have DTPA and

scintigraphy that suggest that there are very good

levels but it would be nice to know what the actual

levels are because I am not really sure how you

dose the drug. We are talking about can we get

away with one time a month. I mean, I think we

need to know what the level of the drug is and get

a sense of the outcome of the drug. Since

obviously systemic levels appear to be lower by

inhalation, I am not exactly sure how to do that.

DR. SWENSON: Dr. Mannon, could you

clarify which patient population?

347

DR. MANNON: It would be lung transplant

recipients. You know, how would you label it?

Preventing death? I mean, I think that would be

really the only thing that you could honestly put

in the label. Clearly there was no prevention of

rejection. There clearly was no prevention, based

on the data presented, of BOS, and there may have

been an effect on OB but it is not clear to me that

it was that, or whether you can say these are the

limitations of this on the label.

DR. SWENSON: Dr. Gay?

DR. GAY: Most of my comments actually

echo Dr. Mannon's. I think short-term safety seems

to be reasonable. I have concerns about long-term

safety issues, and with the fact that this will be

a long-term drug I think that needs to be studied

more fully and evaluated more fully.

It would have to be labeled for lung

transplant patients and at this point, yes, clearly

for improving survival. But with future studies it

will probably be more for prevention of chronic

rejection.

348

Dosing regimens have to be standardized at

some point. With the concern that half the

patients did not receive really long-term therapy,

greater than 24 doses, that has to be looked at

more closely with potential long-term risk of

therapy associated with the disorder.

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: First, the question put to

us is, is the agent safe? I just have to comment

that if the survival benefit is real the drug is

safe with reference to its benefit. But if the

survival benefit is not real, then we have

substantial issues, or if the benefit is much

smaller than it seems we have substantial issues

with local tolerability because, as has already

been commented, it is striking that half the

patients couldn't tolerate it for the long term.

With respect to what should be done further--

DR. SWENSON: Let's get your vote. Yes or

no on that?

DR. HUNSICKER: I would vote, since I

voted no on the first, that I don't think that it

349

is shown to be safe relative to its known efficacy.

If the efficacy is repeated and is there, then

obviously it is safe because being alive is better

than being dead.

DR. SWENSON: And this is a no vote?

DR. HUNSICKER: It is a no vote for the

question or whether that issue has been answered.

With respect to what more should be done, first of

all, I think that there does need to be some more

animal data specifically with respect to the lung

toxicity of cyclosporine, and it is striking that

there is no really long-term animal data on the

tolerability of cyclosporine. That should be easy

to be done. It isn't a definitive thing but it

certainly is something that should be done along

the way.

I am one who believes that things like

cancer can really only be answered in postmarketing

surveillance. I think it has to be done as part of

postmarketing surveillance, along with all sorts of

other bad things but I don't think there is any way

that kind of question can be answered prior to its

350

approval.

With respect to question one, for which

population, I agree with everybody that it should

be lung transplants.

What information should be included on

dosing, we have only had one dosing regimen and,

therefore, I think we can only talk about one

dosing regimen.

I do think that for duration we should say

that this has only been shown to be useful up to

two years. I think we can add on that there is no

reason why the sponsor could not give us evidence

about tolerability after two years. But right now

what we have is data on tolerability, which seems

to be actually sort of marginal, up to two years

with half the patients going off of it at that

time.

What information should be included on the

labeling, I have sympathy with those who say the

only thing you should say is that it prolongs life,

however, it seems to me that to say that it

prolongs life but we don't have any information

351

about what it does to chronic rejection or acute

rejection is a little naive. I don't see how we

can say that and not sound silly. So, if the

agency is going to approve it, we should say that

the outcome is that it prolongs life presumably due

to suppression of chronic rejection. I think that

would be the way I would phrase it. And, I think

that you need to have an explicit statement in

there that there is no evidence that it affects

acute rejection because I am afraid that some

people will think that this is something you should

use for acute rejection, and if there is anything

we do know is that it does not seem to affect acute

rejection.

DR. SWENSON: Dr. Venitz?

DR. VENITZ: Again, I am a yes-man so I

would vote in favor of safety having been

demonstrated. I agree that the population would be

the population of lung transplant patients at

large. I don't think there is any evidence for

subpopulations at a particular risk but, hopefully,

that is a question that can be addressed in the

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follow-up study that we alluded to.

As far as the dosing regimen is concerned,

I think the dosing regimen that should be labeled

should be the dosing regimen that was used, and

that does include the initial escalating dose study

to get patients up to 300 mg before they then start

their three times weekly maintenance dose.

Something that I found interesting is that

one of the patients during the open session

mentioned that, because of seizures, he was put on

phenytoin and he developed a rejection. Obviously,

phenytoin is a known enzyme inducer which increases

the clearance of drugs such as cyclosporine and

lowers their systemic levels. So, as far as drug

interactions are concerned, I do think that you

have to stick with the current cyclosporine label

for oral use even though we think the systemic

experiences are low and unlikely to contribute to

this effect.

I also have some concerns about the fact

that at least the studies that we looked at were

done with the same nebulizer. So, I think you are

353

looking at a fixed drug-device combination here. I

don't think we can extrapolate that beyond any

other devices since I have no clue what the aerosol

dynamics--the mean diameter for example--might be

in a different device. So, I think the device is

pretty much locked in, and you have already heard

some of the comments about the lidocaine briefly.

As far as 2(c) is concerned, I agree with

my neighbor to the left. I believe they have

demonstrated survival benefit. They have

demonstrated no benefit on acute rejection and,

therefore, maybe a benefit on OB.

A couple of additional comments, being a

kineticist by training, I guess I miss some

exposure measures in the preclinical studies that

allow me to compare--and I am talking about

pulmonary exposures, not drug levels or PG

levels--some of those studies in the lung so I can

make some extrapolations as to what that might be

in humans. Is there any way that we can use some

of those biopsies from lung to actually measure

drug levels and to ascertain in humans what the

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relative ratios of systemic exposure over topical

exposure are?

On the last question that Dr. Albrecht

wanted us to address about the study design, again

given the fact that I am a yes-man on both

questions, I don't see any reason why the follow-up

clinical trial could not be an open-label trial. I

happen to be a member on an IRB and I would think

that most of my committee members, probably as a

consensus, would not approve a randomized,

placebo-controlled trial with this product. So, I

do think an open-label trial ethically is more than

justifiable, and I think most of the information,

at least that I am looking at, especially as far as

dose optimization concerns, could be gotten out of

a non-randomized, open, prospectively designed

trial.

DR. SWENSON: Miss Drittler?

MS. DRITTLER: On 2(a), I don't know what

else to say except transplant patients. What

information should be included on dosing regimen--I

question whether each patient might have a

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different dosing regimen as opposed to what has

been shown in the study with the 300 mg for all

patients. I just wonder if each patient could be

different, and in that case it would have to be as

directed.

Included in the labeling regarding

expected benefit--so, that has not been proven. I

agree that it should refer to longevity. As far as

the carcinogenic impact, I pay little attention to

that because everything I take has carcinogenic

impact so we know that we are at greater risk for

cancer when we are taking these drugs but that is

one of the benefits of still breathing and living.

That is it.

DR. SWENSON: And your answer to the

original question is yes?

MS. DRITTLER: Yes.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: Well, presuming

approvability, the answer to the first question is

yes. It would be for long allo-transplant

recipients.

356

For 2(b) I think it would be important to

note that it would be used in the setting of

standard systemic immunosuppression, perhaps with

an insert noting that the data were essentially in

patients on azathioprine, which is not going to be

the standard practice now.

For 2(c) it should say that this may

improve survival. It is not expected to be

beneficial for acute rejection, and leave out

anything else.

Can I just mention that postmarketing--you

know, the FDA has one advantage here that you have

built in 100 percent postmarketing surveillance

through the OPTN. So, that is different from

looking towards approval of other drugs where you

sort of lose control of things a little more, and

that is an important dimension to keep in mind.

DR. SWENSON: Dr. Moss?

DR. MOSS: I kind of agree with Dr.

Hunsicker. I am not as concerned about the safety

as whether there was really efficacy demonstrated

in this trial. So, I would say no but I thought

357

the safety data was reasonable.

I really don't have a lot to add to what

the other people said, except I think it is a good

idea that there is already a cohort of patients you

can follow-up for long-term follow-up.

There was some data about irritability and

irritation of the airways and that could just be

followed up better in a better controlled,

randomized, multicenter trial.

DR. SWENSON: I will vote yes on this

question and all the points that I would raise have

already been raised by preceding members. Dr.

Barrett?

DR. BARRETT: I will vote yes to the main

body and for the population of lung transplant,

like has been mentioned earlier.

With respect to parts (b) and (c), I

think, again if we are going to recommend approval

based on a single Phase II study, the description

of the experimental findings unique to this study

have to be clearly stated. However, in addition to

that, I think there has to be information that says

358

explicitly that dose response has not been shown

with this product, and I think it is going to be

very important to decide how much of the oral or

other route of administration of cyclosporine gets

added to this label because I think we are going to

have to make some choices. Dr. Venitz pointed out

that in some cases the drug interaction piece will

be very pertinent, but with others I don't think

you can confer some of the information that is

contained with the other routes of administration

to this product. We are specifically fighting the

issue of very limited patient exposures with this

product and I think that is where the primary

safety liability comes from.

Having said that, on (d), even though I

answered yes, I think we still need to do more

follow-up studies with respect to the propylene

glycol as well as the product itself in longer term

tox studies.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: On the safety, I don't

really feel like I have a lot to say on the safety.

359

I would feel a lot more comfortable with more data

than is available so far. I think that if there is

an additional randomized trial that is larger, that

would go a long way toward establishing safety.

So, to me, I am not convinced that the safety has

been adequately characterized.

I guess I would label it for survival and

chronic rejection-free survival for lung transplant

patients.

In terms of additional information, I sort

of changed my mind on what kind of study would be a

good follow-up study if, in fact, this is not

approved. So, the question is what would you do

next if it is not approved. I think that the

essential uncertainty here, in this group, is due

to the fact that is one study; that it is a small

study; it is a single institution study; and that

the endpoint was this unexpected endpoint. It

seems to me that, given the actual data, you would

choose a follow-up trial using the most powerful

possible endpoint and that is basically chronic

rejection-free survival. That had the lowest

360

p value. If you use that as an endpoint you would

have the additional advantage that if patients then

rejected, had a chronic rejection, you could give

them drug so you wouldn't actually necessarily have

to treat people until death. Treating people until

death is a very unpopular way of running a study.

DR. SWENSON: Dr. Sampson?

DR. SAMPSON: I actually don't have much

to add to what has already been said. I voted no

on number one and I am ambivalent about the amount

of safety data. I would certainly like to see more

information on dosing to understand the

relationship of the severity and occurrence of the

adverse experiences that the patients experienced

relative to dose.

DR. SWENSON: Miss Schell?

MS. SCHELL: My vote is no also, mostly

because of the limitations of the study, including

the variable dosing when the patient fell out and

didn't take medication anymore, and also the length

of the study, the long-term effects. So, it is no.

DR. SWENSON: Well, that concludes the

361

official questions and I will turn it back to you,

Dr. Albrecht, for any further thoughts that you

might want to pose to us. We are a little ahead of

schedule--no one is going to complain, but we do

have a bit of time for other pressing issues to be

raised by members of the committee.

DR. ALBRECHT: If I could just ask a

follow-up question, and I know I have heard a lot

of discussion on this but I wanted to actually just

specifically ask this one more time in case there

were further comments. As you heard, Dr. Dilly

proposed that the company, in the event of

approval, would commit to conducting an open-label,

multinational study of 250 patients. I know going

around the table I heard different opinions about

open-label studies, not comparative studies. I

wonder if perhaps we could go around the table to

see if the committee members would believe this was

enough, or this in addition to comparative studies,

randomized studies, dose-ranging studies. Could I

ask the committee to sort of think about the

proposal versus other studies that I sort of think

362

I heard mentioned, either dose-ranging studies or

some other randomized studies?

DR. SWENSON: Well, if I could at least

try to paraphrase the company's plan, it was 250

patients. Certainly it would be a broad number of

patients that would address issues of confounders

and all of that, but there really wasn't any

explicit discussion of dosing either as to

frequency per week or absolute amount per dosing.

So, those questions sort of remain. I am sure the

company probably doesn't know exactly what the

answers are. Please?

DR. DILLY: We explicitly suggested 300 mg

inhaled cyclosporine three times a week or the

patient maximum tolerated dose. So, our explicit

suggestion was--

DR. SWENSON: Just the way the first study

was performed?

DR. DILLY: Yes.

DR. SWENSON: Okay.

DR. HUNSICKER: But it says for five years

and, at this point, we have no information on five

363

years and at least a presumption that you don't

need five years since the people who got short

courses seemed to have benefited similarly. So, I

would not agree with five years at this point.

That is something that you might look to change as

you accumulate more information.

DR. DILLY: One consideration here is we

put in a single dosing element, if you like, 300

mg, three times a week for five years. It is

perfectly within the realms of appropriate design

to take a 100 mg arm into this design. It is

perfectly appropriate to have a two-year cohort and

a five-year cohort so we can actually test.

Because, you know, we do agree that providing

patients with access to potentially efficacious

therapy is entirely appropriate at this stage so

comparison of 100 versus 300 would be a very

appropriate way to go; a comparison of two years

versus five years we would see as both addressing

our concerns about the ethics of withholding

therapy, but also answering some of the key

questions around safety of long-term administration

364

and what is the right dose for these patients. So,

we are willing to refine this design.

DR. SWENSON: Rather than go around the

table, I will just look to anybody with comments.

Dr. Hunsicker?

DR. HUNSICKER: There are two issues and,

therefore, I am not quite sure how to answer your

question. One is what, in my mind, would be needed

for approval given that I voted no. Then, the

second is what is needed by the community, assuming

that this does eventually become approvable for

intelligent use. We have to keep these things

separate.

With respect to approval, what I want is

more evidence that, in fact, there is a real

benefit here. I would actually agree rather

strongly, surprisingly perhaps to some, that it

need not be necessarily a placebo-designed study.

I would be willing to accept, because there has

been no change in chronic rejection if there is no

change in chronic rejection over the next little

while, an active treatment study against a

365

registry, contemporaneous registry control. I

don't think that it really is needed to set it up

as a placebo-controlled trial. So, that might ease

the issue of doing another study if, in fact, the

drug does not get to be approved.

In terms of its intelligent use, I think

the outstanding issue is the amount of the drug and

the duration of the drug. Actually, what is to me

a rather attractive design is what has just been

discussed which would be 100 mg, or some other dose

that was designed to be somewhat similar to what

you would have given with oral dosing as opposed to

respiratory dosing, versus the higher dose. If you

get a dose response--you know, if 300 is better

than 100 then you have a clear answer to the other

question as well.

The second is duration. I personally

would like to see a trial that has two years--how

shall I say?--if you are going to approve, I would

approve for two years and then let them design a

trial to take it to five years and see if there is

an additional benefit.

366

DR. TISDALE: I just wanted clarification

on your question. I think your question was,

assuming approval, what study design would you

envision as being appropriate as the next step, or

did I understand you wrong?

DR. ALBRECHT: I apologize. I said that.

Actually, I was thinking that the company's

proposal was for a postapproval study but I was

more interested, because the company had proposed a

study that was an open-label study comparing to the

registry, whether that type of study would be

convincing to the committee or whether, when I

heard discussion around the table about randomized

studies, in fact, the committee felt that while

that study might be informative, randomized

studies, in fact, were what I was really hearing as

the preferred approach to gaining further

information, regardless of whether it be

preapproval or postapproval.

DR. TISDALE: Well, I happen to agree that

it would likely be problematic--you know, putting

on my other hat as an IRB member looking at a study

367

that is a randomized study design, to repeat a

randomized study that has already shown a striking

survival benefit. I think most IRBs are not going

to be capable of doing the post hoc analysis of the

statistics and understand the limitations as they

have been put forward today, and the majority of

them would say, "look, you've already got a

striking survival benefit, how are you going to go

back?" So, I would look at that investigator and

say, "hm, I wonder what it is they're trying to do?

They want to look at mechanism. They want to do

something else. And, they're going to take these

poor patients and randomize them to placebo so that

they can look at lung biopsies and try and figure

out how cyclosporine is working locally when the

question for survival has already been answered."

I would really be wondering at that point whether

they were putting their science ahead of the

patient's benefit. So, putting on that other hat,

I think it would be very difficult for me to look

at a randomized, controlled trial in this setting

with the survival being the primary outcome, with

368

my IRB hat on.

So, I think it is perfectly appropriate to

go forward, either preapproval or postapproval,

with a study that compares to contemporary

patients. There will be plenty of patients who

don't go on trial. I mean, I think it is striking

that you got 50 percent. I think that is a really

high percentage of patients to go on a clinical

trial so I don't think you will have any trouble

having controls. They will be the majority.

DR. SWENSON: Dr. Burdick?

DR. BURDICK: I mentioned this before, I

am concerned that the sort of study that was

proposed by the company, using cohort controls

through OPTN data and so forth, is going to leave

one, no matter how carefully it is put together,

with a series of confounding variables to be

interpreted and a more or less random conclusion

that certain clinical settings work and certain

others don't unless it is an extraordinarily

positive benefit which is being predicted. And, as

we have said, probably the next time around there

369

won't be quite such a big difference, then you are

not going to be able to have the fundamental

information about basic utility of the drug.

So, I think another randomized trial is

the way to find that out. The argument that there

is a huge difference in the trial we have been

considering is true but, remember, we have seen

that huge difference based on just a few patients

because the numbers were so small. And, it is not

quite as convincing as everybody is making it out

to be. It is just too convincing to ignore but it

is not that convincing. The way you really find

out for sure is to do another randomized trial,

somewhat larger numbers, pick your power, and then

the rest of what is proposed in sort of cohort

study, no control group study or dose escalation

will go on in the transplant community anyway and

we will get that information. It will evolve as

immunosuppression evolves. It will have to be

redone every two or three years, just as everything

else works.

DR. SWENSON: Dr. Proschan?

370

DR. PROSCHAN: I think Chiron has done as

good a job as you could possibly do with this data

that they have, and I am still not convinced. So,

for me, I would need to see another randomized

trial. I think the analyses that they have done,

the sensitivity analyses, are very good and that is

what made this so difficult for me. You pushed me

right to the edge but you didn't quite push me

over, although I am sure some of you probably want

to push me over a cliff. But, to me, it is not

strong enough and, to me, I would need to see

another randomized, controlled trial. It would not

be sufficient to see a one-arm trial for example.

DR. SWENSON: Dr. Moss?

DR. MOSS: Actually, I like the suggestion

that Dr. Schoenfeld recommended. You know, I think

the people that voted no, they would need to say

that a randomized clinical trial needs to be done.

I think having the endpoint be chronic

rejection-free survival makes a lot of sense to me

in the sense that then if people did develop the

endpoint they could be done with the study, and if

371

they wanted to then do something off-label that

would be a reasonable thing to do. So, I thought

that was an excellent suggestion for a randomized,

clinical trial.

DR. SWENSON: Dr. Hunsicker?

DR. HUNSICKER: It is always preferable to

do a randomized clinical trial and my endorsement

of the possibility of a one-arm study does not take

away from the fact that is always preferable to do

a randomized clinical trial. Sometimes it is not

possible or feasible, or whatever you want to call

it.

A way to get around the problem that Dr.

Burdick raised, which is that if you use a registry

control you are going to have some explanation to

do, and if you have a close call it is going to be

very unconvincing. One way to get around this is

to stipulate a minimum difference. You know, what

we are trying to do now is to see whether this idea

that there is 70, or whatever it was, 75 percent

reduction in mortality is credible. If you say

that the mortality absolute difference--let's say

372

between 20 percent and 50 percent, I don't remember

exactly what the numbers were--that there has to be

at least a 15 percent difference in mortality that

is observed, that will take care of an awful lot of

messes in non-equality and will also get at the

issue of whether this is really a robust finding.

So, I think that there is, in fact, a rigorous way

that one can do a single-arm, registry controlled

trial by defining exactly what your outcome is.

DR. SWENSON: Dr. Proschan?

DR. PROSCHAN: In terms of the single arm

or the non-placebo study, if you did dose ranging I

would suggest trying to actually decrease that

volume of propylene glycol. It seemed that even in

the placebo patients it was poorly tolerated. So,

rather than decreasing--you know, it is a small

point--the concentration of cyclosporine, actually

try to decrease the volume--it is something like 5

mL, which is a lot of stuff to inhale even though

most of it is not being inhaled.

A second point is that if you are going to

compare to the registry, is there a way to control

373

or at least partially control for systemic

immunosuppressive drugs so that at the end of this

clinical trial you don't have radically different

systemic immunosuppression?

DR. HUNSICKER: The registry data on doses

of immunosuppression is non-existent and is very

low quality. I think all you can get is sort of

what they were on.

DR. SWENSON: Dr. Schoenfeld?

DR. SCHOENFELD: I think, first, if you

think that it is unethical to do a randomized trial

we should approve this. I think if you can't do a

randomized trial, then the drug should be approved

now.

As a postmarketing study, I think the

single-arm study is a great idea because basically,

to use a baseball metaphor, the postmarketing study

would tell us whether we hit a home run or just got

to first base and that is an important thing to

know because you want to know where to go from

here, and a long postmarketing study would show us

that. If survival was really, really good compared

374

to historical controls we would know that we had

gotten a home run.

On the other hand, the fastest way to get

approval has got to be a randomized, controlled

study organized to be as quick as possible, with a

sequential stopping rule, with an endpoint that

occurs as early as possible. In this case it would

be chronic rejection with lots of biopsies done so

you can see it. If they do a single-arm study it

will be a long, long, long time and then I think

the results will be somewhat confusing.

DR. SWENSON: Dr. Sampson?

DR. SAMPSON: I just wanted to echo again

the controlled, randomized, double-blind trial.

DR. MANNON: I just wanted to make a

comment regarding the number of comments made

around the table and also by the investigators

regarding the ethics of this and what an IRB might

potentially go along with. But I have to tell you

that if I were sitting on an IRB and an

investigator wanted to present a double-blind study

and said, "I have this initial study and look at

375

the striking event," I don't think that I would

find it inappropriate if I understood that the data

presented represented some concerns and flaws and

how the data was interpreted. And, look at us.

There are 18 of us sitting here and we can't even

come to an agreement one way or the other. We are

all sort of split. So, that clearly means a number

of intelligent people are interpreting this data in

a variety of ways. So, I think that a standard

IRB, presented with that kind of information, would

understand the necessity for going on.

Then, as far as the patients, I think if I

presented my patient with what they should take--we

use a lot of things off-label--I shouldn't even say

this but we use a lot of drugs in immunosuppression

for transplant that are off-label based on a couple

of case series, and you if present it to a patient

and say this is the option and we are going to try

this. Most will do what you recommend and it is

not clear to many of the patients that this is the

beneficial therapy. Therefore, I don't feel that

everybody is going to run and say I can't be on

376

placebo.

DR. SWENSON: Dr. Moss?

DR. MOSS: I just want to echo what Dr.

Mannon said. I think there is a lot in the

literature about smaller Phase II trials which show

that there appears to be efficacy and in a lot of

those cases, or most of those cases, there were

then larger multicenter studies done and they all

got through IRB committees. So, I think there is

very good precedent in the literature for orphan

diseases, such as idiopathic pulmonary fibrosis,

where this same scenario has happened where IRBs

approved larger multicenter, randomized clinical

trials. So, I agree with you, Dr. Mannon. To say

that no IRB is ever going to approve a multicenter

trail based on the data that we were presented

today I think is incorrect.

DR. SWENSON: Well, that being the extent

of comments here, Dr. Albrecht, anything more?

DR. ALBRECHT: No, just to thank everybody

very much for all your thoughtful comments. You

have given us a lot of food for thought and we will

377

take them back and discuss them internally.

DR. SWENSON: I would like to reiterate my

thanks to everyone, the company, the FDA, the panel

members, the audience and the patients who came

here.

[Whereupon, at 4:30 p.m., the proceedings

adjourned.]