UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

IMMUNOLOGY DEVICES PANEL OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

NYMOX URINE NEURAL THREAD PROTEIN (NTP) KIT (P040010)

Friday, July 15, 2005

The hearing came to order at 8:30 a.m. in the Grand Ballroom of the
Holiday Inn Gaithersburg, 2 Montgomery Village Ave, Gaithersburg,
Maryland. Clive Taylor, MD, D. Phil, Presiding.

PRESENT:

CLIVE R. TAYLOR, M.D., D. PHIL., CHAIR

SUSANNE M. GOLLIN, PH.D., VOTING MEMBER

JAMES L. GULLEY, M.D., PH.D., VOTING MEMBER

TERRANCE R. LICHTOR, M.D., PH.D., VOTING MEMBER

WILLIAM DUFFELL, JR., PH.D., INDUSTRY REPRESENTATIVE

VELIA BUTCHER, J.D., CONSUMER REPRESENTATIVE

JOSEPH PARISI, M.D., DEPUTIZED VOTING MEMBER

AVINDRA NATH, M.D., DEPUTIZED VOTING MEMBER

OSCAR L. LOPEZ, M.D., DEPUTIZED VOTING MEMBER

BRENT BLUMENSTEIN, PH.D., DEPUTIZED VOTING MEMBER

RUFINA CARLOS, B.S., EXECUTIVE SECRETARY

STEVEN GUTMAN, M.D., FDA

A-G-E-N-D-A

Call to Order and Introductions

Dr. Clive Taylor 4

Conflict of Interest Statement

Ms. Jenny Slaughter 7

Opening Remarks

Ms. Rufina Carlos 9

[Special Topics]{.underline}

Critical Path Initiative

Dr. Sousan Altaie 11

Role of OSB in the Review of Postmarket

Study Designs

Dr. Susan Gardner 18

[Open Public Hearing]{.underline}

Dr. Stephen McConnell 26

Alzheimer\'s Association

[Sponsor Presentation]{.underline}

Dr. Paul Averback 28

Dr. Daniel Bloch 36

Dr. Patricio Reyes 43

Dr. Ralph Richter 52

Panel Questions 71

[FDA Presentation]{.underline}

Dr. Robert L. Becker 86

Dr. Marina Kondratovich 101

Dr. Ranjit Mani 119

Panel Discussion 138

Question 1 183

Question 2 190

Question 3 201

Question 4 202

A-G-E-N-D-A (cont.)

Open Public Hearing 215

[Summations]{.underline}

FDA 216

Sponsor 216

Panel Deliberations and Vote 219

P-R-O-C-E-E-D-I-N-G-S

8:34 a.m.

DR. TAYLOR: Good morning. My name is Clive Taylor and I am now going to
call this meeting of the Immunology Panel to order. With regard to the
record, the voting members present constitute a quorum required by 21
C.F.R. This is the majority of voting members. The minimum is normally
seven. At this time I would like to ask each panel member sitting at the
table to introduce him- or herself, and to state his or her specialty,
position, title, institution, and status on the panel. We begin with
Mrs. Butcher on my left.

MS. BUTCHER: Good morning, I\'m Vicky Butcher \-- Velia. I am the
consumer rep on this panel, and I represent the ANMA, the auxiliary to
the National Medical Association, as well as my non-profit Water for
Children Africa.

DR. DUFELL: Good morning, I\'m Bill Duffell. I\'m the industry
representative on the panel. I work for Gambro BCT in Denver, Colorado.
My area of expertise is clinical trials, biostatistics, behavioral
sciences, and product development.

DR. GOLLIN: My name is Susanne Gollin. I\'m a professor at the
University of Pittsburgh Graduate School of Public Health in human
genetics. My areas of expertise are public health genetics biomarkers,
and cancer.

DR. LICHTOR: My name is Terry Lichtor. I\'m a neurosurgeon at Rush
University in Chicago. And my research interests are in developing brain
tumor vaccines.

DR. GULLEY: I\'m James Gulley. I\'m a medical oncologist working at the
National Cancer Institute. My area of interest and expertise is in
immunology and immunotherapy for cancers.

DR. TAYLOR: And I\'m Clive Taylor. I\'m a Professor and Chair of the
Department of Pathology and Laboratory Medicine at the Keck School of
Medicine, University of Southern California. In my spare time I\'m Dean
for Student Education. My research interests have been over the years in
immunology, immunodiagnostics, and lymphoma leukemia.

MS. CARLOS: I am Rufina Carlos, and I am the Executive Secretary of the
Immunology Devices Panel of the Medical Devices Advisory Committee.

DR. LOPEZ: I am Oscar Lopez. I am a Professor of Neurology at the
University of Pittsburgh, and my area of expertise is Alzheimer\'s
disease and related dementias.

DR. BLUMENSTEIN: I\'m Brent Blumenstein. I\'m a biostatistician working
privately.

DR. NATH: I\'m Avi Nath. I\'m a neurologist at Johns Hopkins University,
and the Director of the Division of Neuroimmunology, and I do both
clinical and basic science research on multiple sclerosis as well as the
neurological complications of HIV infection. A minor correction to my
name tag. I\'m only an M.D.

DR. PARISI: Good morning. I\'m Joseph Parisi. I\'m a Professor of
Pathology at the Mayo Clinic. I do neuropathology. That is my specialty.
And I have a special interest in Alzheimer\'s disease and the dementias.

DR. GUTMAN: I\'m Steve Gutman. I\'m the Director of the Office of In
Vitro Diagnostics at FDA, which is the unit which is sponsoring this
event.

DR. TAYLOR: Thank you. At this time I\'d like to ask Ms. Jenny
Slaughter, who is the FDA Supervisory Program Integrity Officer, to make
a statement.

MS. SLAUGHTER: Thank you Dr. Taylor. I\'m here today to read the
conflict of interest disclosure statement. The Food and Drug
Administration is convening today\'s meeting of the Immunology Devices
Panel of the Medical Device Advisory Committee under the authority of
the Federal Advisory Committee Act of 1972. With the exception of the
industry representative, all members of the panel are special government
employees \-- and I will now refer to you all as SGEs \-- or regular
federal employees from other agencies, and are subject to the federal
conflict of interest laws and regulations.

FDA has determined that members of this panel are in compliance with
federal conflict of interest laws, including but not limited to 18
U.S.C. 208, and 21 U.S.C. 355. Under 18 U.S.C. 208, the regulation
applicable to all government agencies, and 21 U.S.C. 355, which is
applicable only to FDA, Congress has authorized FDA to grant waivers to
special government employees who have financial conflicts when it\'s
determined that the agency\'s need for a particular individual\'s
services outweighs his or her potential conflict of interest. Members
who are special government employees at today\'s meeting, including SGEs
appointed as temporary voting members, have been screened for potential
financial conflicts of interest of their own, as well as those imputed
to them by their spouse, minor child, and it\'s in relation to the
discussions of today\'s meeting.

Based on the agenda for today\'s meeting, and all financial interests
reported by the panel participants, it\'s been determined that all
interests and firms regulated by the Center for Devices and Radiological
Health present no actual or appearance of conflict of interest for
today\'s meeting. Today\'s agenda includes a premarket approval
application for a laboratory assay designed to measure levels of neural
thread protein in urine specimens from patients presenting with
cognitive complaints, or other signs and symptoms of suspected
Alzheimer\'s disease. Dr. Duffell, as he had just mentioned, is serving
as the industry rep on the panel today, and he is employed by Gambro
BCT. In the event that the discussions involve any other products or
firms not already on the agenda for which FDA has a financial interest,
the participants are aware that the need to exclude themselves from such
involvement, and their exclusions will be noted for the record.

Finally, with respect to all other participants, we ask that in the
interest of fairness, that they address any current or previous
financial involvement with any firm whose products they may wish to
comment upon. Thank you.

DR. TAYLOR: Thank you. Ms. Rufina Carlos, who is the Executive
Secretary, will now make some introductory remarks.

MS. CARLOS: Good morning again. First, some housekeeping matters. If you
haven\'t already done so, please sign the attendance sheets that\'s
available on the table outside the door. Information for today\'s agenda
is at this table. Upcoming panel meetings are announced in our advisory
panel website, and in the Federal Register. Finally, as a courtesy to
others in the room, please turn off your cell phones during the meeting.
And before I turn the meeting to Dr. Taylor, I am required to read into
the record the deputization of temporary voting members statement.

Pursuant to the authority granted under the Medical Devices Advisory
Committee Charter, dated October 27, 1990, and amended August 18, 1999,
I appoint the following as voting members of the Immunology Devices
Panel for the duration of this meeting on July 15, 2005: Dr. Joseph
Parisi, Dr. Oscar Lopez, Dr. Avindra Nath, and Dr. Brent Blumenstein.
For the record, these people are special government employees, and are
consultants to this panel or another panel under the Medical Devices
Advisory Committee. They have undergone the customary conflict of
interest review, and have reviewed the material to be considered at this
meeting. Signed, Daniel Schultz, M.D., Director, Center for Devices and
Radiological Health, June 29, 2005. I would now like to turn the meeting
over to our chairperson, Dr. Clive Taylor.

DR. TAYLOR: Thank you. This panel is here today to discuss, make
recommendations, and vote on a premarket approval application PMA
P040010 for Nymox Urine Neural Thread Protein (NTP) Kit. This is a
laboratory assay designed to measure levels of neural thread protein in
urine specimens from patients presenting with cognitive complaints, or
other signs and symptoms of suspected Alzheimer\'s disease. Results from
this test are intended for use in conjunction with, and not in lieu of,
current standard diagnostic procedures, to aid the physician in the
differential diagnosis of Alzheimer\'s disease.

The first item on the agenda is a presentation by Dr. Sousan Altaie. She
will discuss the Critical Path Initiative. Dr. Susan Gardner will then
discuss the role of the Office of Surveillance and Biometrics \--
that\'s OSB \-- in the review of postmarket study designs. Dr. Altaie?

DR. ALTAIE: Thank you. On my daytime job I am the Scientific Policy
Advisor for the Office of In Vitro Diagnostics, and in my spare time I
advocate for Critical Path. It\'s an endeavor that the Center took on
and is determined to see through. So let\'s see if I can get the
presentation up. All right, we\'re in business.

All right. For an outline, I\'ll first tell you what the Critical Path
is about, and then I\'ll go through the differences between the Critical
Path in CDRH versus what\'s in CDER, in the drugs. And then I\'ll
describe some of the projects that we have in the Center that we\'re
trying to see through in fulfilling Critical Path needs. And then I\'ll
ask you to participate and take part in this effort because it\'s a
leveraging effort. And I\'ll give you information as to where to and how
to participate.

Critical Path is a serious attempt to make product development more
predictable and less costly. Okay, that\'s an overview. Obviously these
slides are a bit out of order, and I apologize. Critical Path, if you
look at the development of the devices, you will be looking at basic
research prototyping in preclinical and clinical development, and
industrialization of the devices. Critical Path Initiative deals with
the prototyping all the way through the marketing, but not dealing with
the basic research.

You might wonder why FDA is interested in Critical Path. Well, because
we realize the significant benefit of bringing innovative products to
the public faster. Because we have a unique perspective on product
development, we see successes, failures, and missed opportunities.
Because Critical Path will help us develop guidance and standards that
foster innovations. We want to work together with the industry,
academia, and patient care advocates to modernize, develop, and
disseminate solutions. These are tools to address scientific hurdles in
device development.

What are Critical Path tools? The tools are methods and techniques used
in the regulatory three dimensions. And those are, in assessment of
safety, the tools predict if potential products will be harmful. In
proof of efficacy, the tools determine if a potential product will have
medical benefit. And in industrialization, the tools help in
manufacturing the products with consistent quality.

At the FDA, we think of Critical Path tools to be biomarkers, Bayesian
statistics, animal model biomarkers, clinical trials designs, computer
simulations, quality assessment protocols, postmarket reporting, and any
other suggestions you might give us that might fall under these
categories. We\'re open to your participation. In the medical devices,
if you consider the vast majority of the devices we regulate, they
actually have a complex \-- and a whole array of complexity, starting
from being scissors, surgical scissors, to a heart valve, to a glucose
monitor, to a CT scan, a PET scan. So we are looking, actually, at the
diverse sets of products, and each one of them has a certain need. So
that\'s why we are actually different from the drugs, and we\'re
different by the complexity of the components of the devices, by the
biocompatibility issues that we have to deal with. We are looking at
durable equipment, and rapid product cycles. They get upgraded, and made
into a new model very fast. We are dealing with device malfunctions, and
user errors, and we\'re dealing with bench studies as well as clinical
studies. And we do put a lot of weight on our non-clinical studies as
well. As far as the regulations, we deal with the quality systems regs
and ISO 9000, rather than the GMPs that the drugs deal with. So, we\'re
totally a different beast as far as Critical Path concerns.

And I want to just go through now some of the medical device areas that
we are interested in CDRH to pursue. Under safety tools, we look at
biocompatibility databases, and effects of products on disease or
injured tissue. Under the effectiveness tools, we\'re looking at
surrogate endpoints for cardiovascular device trials, and computer
simulation modeling for important devices. We are looking under
industrialization tools to practice guidelines for follow-up of
implanted devices. And we\'re looking at validated training tools for
devices with a known learning curve.

These are some of the projects that are being pursued in the Center. And
all of these things are not funded. We\'re trying to go through
leveraging, and using the partnerships with the industry and the
interested public to see these projects through. For validation of
biomarkers, we\'re looking at blood panels to assess sensitivity and
specificity. For peripheral vascular stents we are working to develop
computer models of human physiology to test and predict failures before
going into animal and human studies. In intrapartum fetal diagnostics
devices we are developing clear regulatory path with consensus from
obstetric community, and NIH is playing a good role there. And we are
collaborating with NIH on pharmacokinetics and image-guided
interventions. We are working with CDC and Johns Hopkins to develop a
well-defined serum panel to test sensitivity and specificity for new
hepatitis assays. We are working on pathways for the statistical
validation of surrogate markers. We are working with medical
specialties, organizations, to develop practice guidelines for
appropriate permanently implanted devices. And we are determining the
extent of neurotoxicity for neural tissue contacting materials. So these
are some of the projects that we\'re dealing with.

And this is how you could get involved. There\'s two ways for you as an
interested individual to get involved. That is that you can send in your
comments to the Critical Path Initiative through our dockets, and I\'ll
give you the docket number in the next slide. And we are also compiling
a national Critical Path opportunities list that is being developed now.
We\'re almost there, so if you have an idea of what should be an
opportunity to be pursued under Critical Path you can contact us and
tell us under that comment, in the docket comment as well. So these are
the webpages and the docket number that I was mentioning. And you can
always contact me if you need something that\'s related to CDRH
specifically because I\'m the Center rep, not the entire FDA rep.

So at this point I want to leave you with this thought. At CDRH, we
believe in the total product lifecycle, and we believe that ensuring the
health of the public through the total product lifecycle is everyone\'s
business. With that, I\'d like to have a question if there is one.

DR. TAYLOR: Are there any direct questions? Thank you.

DR. ALTAIE: Thank you.

DR. TAYLOR: Next will be Dr. Susan Gardner.

DR. GARDNER: Okay. Technology\'s working. I\'m going to spend just a few
minutes this morning telling you about a fairly major programmatic
change in CDRH, and what that means to us, and what it might possibly
mean to you. The basis of the change is the movement of the conditions
of approval studies from the Office of Device Evaluation, ODE, to the
Office of Surveillance and Biometrics, which is called OSB.

Briefly, the functions of OSB are that we do have a major supporting
role in the premarket activities by virtue of the fact that the
statisticians are in our office, and also the epidemiologists. We\'re
also responsible for signal detection of adverse events by having a
number of the major monitoring tools in our office, the Medical Device
Reporting Program, and the MedSun Program. We\'re responsible for
characterization of risk by doing analysis of these adverse event
reports, and using our other monitoring tools, for coordination of the
Center response to public health problems through communications to the
health care professionals, and also for interpretation of the MDR
regulation.

So, the condition of approval studies. The regulation, which is in 21
C.F.R. 814, etc., tells us that post approval requirements can include
continuing evaluation and periodic reporting on the safety,
effectiveness, and reliability of the device for its intended use. The
basis of this change actually came from an internal review that we did a
couple of years ago to look at our condition of approval program. We
went back and we looked at all the PMAs that were approved from 1998 to
the year 2000. There were 127 PMAs, and 45 of those had condition of
approval studies. When we began this project, what we were really
looking for was to assess the quality of the studies. We found out that
we actually couldn\'t locate a lot of the studies, that we had a very
limited process, and no standard procedures for tracking these studies.
There was, as one might expect in any organization, a turnover of the
lead reviewers, and that of course has also resulted in a lack of
follow-up. And essentially, over in the premarket shop, they didn\'t
really have the resources while they were doing these heavy premarket
review tasks, to focus on the postmarket studies once the product had
been approved. So we decided to attack this problem.

The goal of changing the program is to obtain better postmarket
information as the device enters the market, which is obviously a really
critical time as it moves from clinical trials into real world use. We
want to better characterize the risk/benefit profile again as it moves
into community practice, and of course add to our ability to make sound
scientific decisions, and communicate back, obviously, anything that we
find in the immediate postmarket period.

So, as I said, we officially transferred the program from ODE to OSB.
That happened on January 1, although we had been doing a pilot for about
two years before that time. So when we made the official transfer, we
had some really good experience on how our procedures were going to
work. We had developed, and in fact it\'s up and running, an automated
tracking system so we know where every study is. We have information on
the date the product was approved, what the condition of approval
requirements are, and we\'ll track the studies, and we\'re going to
acknowledge the receipt of mandated reports, and obviously we\'re going
to let people know when they haven\'t sent in the additional
information, or the required information.

We\'re also adding an epidemiologist to the PMA review team when we
expect that there\'s going to be a condition of approval study. The
epidemiologist is tasked with the development of a postmarket monitoring
plan during the premarket review. So as the product\'s moving along this
premarket review path, there\'s somebody on the team that\'s sort of
thinking postmarket as it goes. The epidemiologist is going to have the
lead in developing, and this is really important, and it\'s something
that we felt we were also missing, really a well-formulated postmarket
question. If we don\'t do those, these studies are not going to be
important to anybody. They\'re going to have the lead in the design of
the condition of approval study protocol, and in the evaluation of the
study progress, and the results after approval. So we\'ll follow the
studies, and again, we\'re going to be giving feedback on the studies.
And of course, the PMA team will continue to work throughout. It\'s only
the lead that will be switching, not the members of the team.

So we think this is going to be better for a number of reasons. First of
all, I want to emphasize again that we want to be very careful when
developing important postmarket questions, and a really good, solid
study design, so that everybody\'s who\'s involved will think that this
is an important activity to be done. Second of all, acknowledgement and
feedback on the work they\'re doing is important to industry, and it\'s
also going to be important to us. And we think it\'ll be a motivating
factor, again, for getting these studies done. We will be posting the
study status on the CDRH website. So for industry that is doing the
studies and have them on time and cooperating, that information will be
available. But if they\'re not being done, that information will also be
available. And also, we do have the ability through Section 522 to
mandate a postmarket study if these studies are not done, and there are
penalties for not doing that.

How might this impact the advisory panel? Well, during the approval
process, often first of all, postmarket questions come up pretty
naturally, and sometimes the epidemiologist will be speaking, and will
bring up postmarket issues. As this happens, of course as always we\'re
going to look for your advice, because what you say during the panel
process about issues that you\'re concerned about postmarket, advice on
methodologies, whatever, will be extremely important as we develop the
protocol if the product is approved and we decide to do a condition of
approval study. And also, we\'re committed to having either FDA or
industry come back to the advisory panel and update you on progress of
any condition of approval studies that have been instituted for approved
devices. Now, let me just also mention that because Dr. Gutman\'s
office, the Office of IVDs, is set up a little bit differently, with
premarket and postmarket activities going on in the same organization,
the process will be a little bit different. But we do have an
epidemiologist that is what we call a shared hire, works part-time in my
office, and part-time in Steve\'s office. And the basic principles of
committing, if we are going to have condition of approval studies, to
having a well designed study, to tracking them to follow-up, and
interacting with industry, and giving feedback, remain the same. So
again, the process may be a little bit different, but the commitment and
principles are the same. Do you have any questions? Thanks.

DR. TAYLOR: Okay, thank you. Now we have an opportunity, one of two
opportunities in fact, for our open public comments. And we\'ve had one
official notification of intent to comment. This is Dr. Stephen
McConnell, Ph.D., from the Alzheimer\'s Association. Dr. McConnell?

DR. McCONNELL: My name is \--

DR. TAYLOR: Could you just hold one moment?

DR. McCONNELL: Sure.

DR. TAYLOR: We\'re just going to first read the open public hearing
statement from the Executive Secretary.

MS. CARLOS: Both the FDA 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, FDA
encourages you, the open public hearing speaker, to advise the committee
of any financial relationship that you may have with the sponsor, its
product, and if known, its direct competitors. For example, this
financial information will include the sponsor\'s payment of your
travel, lodging, or other expenses, in connection with your attendance
at the meeting. Likewise, FDA encourages you at the beginning of your
statements 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. Dr. McConnell?

DR. TAYLOR: Go ahead, sir.

DR. McCONNELL: Okay. My name is Steve McConnell. I\'m Senior Vice
President for Advocacy and Public Policy with the Alzheimer\'s
Association, and I have no relationship to the sponsor, financial or
otherwise.

First of all, I want to start by acknowledging the dedication and
expertise of this panel, and the excellent work that you do to advise
the FDA on making critical decisions about interventions, devices, and
tests. Second, I\'m here representing the Alzheimer\'s Association. I am
not an expert, a deep expert, on this issue. The Alzheimer\'s
Association is advised by an expert panel, a medical and scientific
advisory council made up of scientists and clinicians who are the
leaders in the field of research in Alzheimer\'s disease. So the
statement I will read this morning has been approved by the Medical and
Scientific Advisory Council, as has all public statements that we make
about such issues.

The AlzheimAlert NTP Test, AD7C Urine NTP Test, marketed by the Nymox
Corporation detects levels of neural thread protein in urine. The
Alzheimer\'s Association does not recommend use of this test either for
diagnosing or ruling out Alzheimer\'s disease. Studies supporting the
validity of the test for such purposes have not been replicated by
independent laboratories, or conducted in an adequate number of
individuals. At this time there is no consensus among Alzheimer\'s
experts that this test is valid or useful, and its use is not part of
any recognized diagnostic guidelines developed by professional
organizations.

Currently, there is still no single test for Alzheimer\'s disease, and a
diagnosis is a multifaceted process that must be administered and
evaluated by a skilled health care professional. To date the Urine NTP
test has no established clinical utility in the diagnosis of
Alzheimer\'s disease. Thank you.

DR. TAYLOR: Thank you. Are there any other speakers from the floor who
have not previously notified us? There will be another opportunity in
the afternoon agenda. At this point we are in fact scheduled to take a
short break. We\'re running well ahead of schedule, but I think
nonetheless we will take a 15-minute break at this point in time. That
would mean reassembling at let\'s say 9:20. Thank you.

(Whereupon, the foregoing matter went off the record at 9:07 a.m. and
went back on the record at 9:20 a.m.).

DR. TAYLOR: Thank you. We will now proceed with the Nymox presentation
for their device. The first speaker according to my agenda will be Ira
Goodman, the Chairman of the Department of Neurology, Orlando Regional
Healthcare Systems. Please, sir.

DR. AVERBACK: First of all, I\'m not Ira Goodman. The draft changed. We
apologize for that.

DR. TAYLOR: That\'s fine.

DR. AVERBACK: Good morning. I\'m Paul Averback, and I\'m the CEO of
Nymox. On behalf of Nymox I want to thank the panel members and the FDA
for coming here today to hear about NTP. We\'re very happy to have this
opportunity to present to you the device which we believe is entirely
safe, and a very effective technology to assist physicians in the
evaluation of cases of suspected Alzheimer\'s.

By way of introduction, Nymox is a small biotech company. We\'re based
in Maywood, New Jersey, and Montreal, Quebec. My personal background is
I\'m a U.S. board certified neuropathologist. I\'ve been in primary care
for close to 30 years, emergency room, and neuropathology for 25 years.

Right at the outset we\'d like to emphasize three things which we
believe are important concerning the safe and effectiveness of the NTP
measurement. First, NTP is not a stand-alone diagnostic. It\'s entirely
safe, can\'t hurt anybody, there\'s no downside, it\'s a urine sample,
there\'s no bodily risk, there\'s no radiation, there\'s no lumbar
puncture, there\'s no downside to anybody. There\'s no decision that
directly gets to anything invasive from this. But it\'s not a
stand-alone diagnostic. It\'s not like a liver biopsy. It\'s not like an
HIV test. It\'s a measurement that adds useful information. It\'s
similar to like a urinary dipstick for urinary tract infection. A
urinary dipstick is not definitive, but it helps move the diagnostic
along. It\'s absolutely useful, as every practicing physician knows.

Second point at the outset is that comprehensive specialist evaluation
is a higher diagnostic standard of truth than primary care evaluation.
I\'ll say that again. Comprehensive specialist evaluation is a higher
standard of truth than primary care evaluation. And we are going to show
you today that NTP has a very high percentage of agreement with
comprehensive specialist evaluation. So if this agrees closely with a
comprehensive specialist evaluation, it\'s going to be helpful to the
primary care physician who has accuracy that\'s perhaps half what a
specialist is.

The third point at the outset that I want to emphasize, when you
consider safe and effectiveness today, each individual in this study,
each subject, had only two data points. They had an NTP level, and they
had a diagnosis. Two data points, NTP and diagnosis, and the diagnosis
was according to conventional standards and criteria. Our thesis is
twofold. First, the statistics, we believe, are very clear. We will go
into this more as the talk progresses, but basically in this clinical
study, 96 percent of the people with elevated NTP had disease, that
being probable AD, possible AD, or MCI, and there was a 78 percent
improvement in the negative predictive value by using this measurement.
For the primary care physician, these are extremely compelling, and I
think these are exciting improvements. The second part of our thesis is
that this device is extremely safe. There is no downside for anybody.
It\'s a urine sample. There\'s no bodily risk whatsoever, and it\'s
going to provide very useful information for the primary care physician.

I don\'t want to put this laser beam into anybody\'s retina, but if I
could ask you to ?. This is the basic scatter plot from this study. And
as you can see, 96 percent of the points here that are above the cutoff
are in the disease groups. 96 percent. And 89.5 percent of the probable
ADs are above the cutoff, and 91 percent of the definite non-ADs are
below the cutoff. We believe that this shows lots of usefulness for the
primary care physician who detects Alzheimer\'s, according to experts
and published studies, in the 15 - 25 percent sensitivity range.

If I could have the next slide, please. The Division was kind enough to
provide us with the questions for the panel, and we\'ve had a chance to
look at these. And we just wish to clarify that in the third question
here, \"Does the NTP test add certainty to the diagnosis or
exclusion?\", we would like to clarify that the device is not
confirmatory, but it adds useful information to help in the evaluation.
And in the fourth question, where it says \"Is the test safe and
effective for the diagnosis?\" we would clarify that the device adds
useful information to help in the evaluation.

Now that I\'ve said the introductory points, I\'d like to proceed into a
more formal introduction. Our agenda today in our talks, I will be
followed by Dr. Daniel Bloch from Stanford University who will make a
couple of comments about some statistical issues. He will be followed by
Dr. Patricio Reyes from the Barrow Neurological Institute who will talk
about utility and design. And he will be followed by Dr. Ralph Richter
from the University of Oklahoma who will describe this study and its
results. And then Dr. Ira Goodman will give some illustrative case
examples showing the utility of the device. Next slide, please.

There has been some evolution in the intended use in the course of this
PMA, but the core concepts have not changed. We have tried to clarify
things, but we haven\'t changed anything. I draw your attention to \"The
results are intended for use in conjunction with and not in lieu of
current standard diagnostic procedures to aid the physician in the
diagnosis of definite non-AD versus probable AD, possible AD, or MCI.\"
I would like to emphasize that this is intended to supplement and
augment existing procedures, not to replace them. Next slide, please.

Here is the kit. Urine NTP device is an indirect ELISA format assay
which measures NTP in a first morning urine sample. Coated plates bind
NTP in urine in competition with labeled rabbit anti-mouse IgG. Next
slide, please.

We first came to the FDA in the year 2000. It\'s been five years that
we\'ve worked on this study. And as you can see, the Alzheimer\'s
Association doesn\'t know about any of this work in the past five years.
We\'ve been working with FDA for five years on this, and the theme of
the clinical design is that the test is \-- to test this device in a
realistic clinical context of the intended use population, with real
patients in a real study. And this design, beforehand, up front, was
agreed to by FDA. Next slide, please.

Going back to the beginning, what is NTP? NTP is derived from
Alzheimer\'s disease brain, definite Alzheimer\'s disease brain. The
CDNA was derived from Alzheimer\'s brain. And immunohistochemical
studies have shown that NTP can be detected in the hallmark brain
lesions, and it has pathophysiological relevance to tangles and plaques,
and cell death, and apoptosis. Next slide, please.

In developing the device, the criteria that we were interested in were
that it be simple and readily accessible. This means that no new
infrastructure is needed, no great cost outlays, no new training, no new
personnel, something that could be readily accessible to most
laboratories. It\'s non-invasive and it\'s a urine test. It\'s
non-invasive. And to show that it has significant effectiveness that
could help the physician in the evaluation of patients with these
problems. NTP has limitations. It\'s not a stand-alone diagnostic, and
it is not something that will help in the diagnosis of mixed,
incompletely understood, or controversial, difficult, neurological
entities. Next.

Safety, safety, safety. No invasion. It\'s a urine sample, and it\'s not
a stand-alone test. No invasive decisions result from it. It adds useful
information. We will show more about this as we go on. With NTP is
significantly better than without NTP. And this, I go back to the logic
of the primary care physician who, using prior prevalence, and their
well documented levels of accuracy, if they use NTP, they\'re going to
be significantly improved.

So to summarize the benefit/risk, we have an urgent unmet need. We have
a device that has absolutely no downside to anybody. It\'s non-invasive.
It can\'t hurt anybody. And it adds extremely useful information. And
the data shows 96 percent of people with elevated NTP are in the disease
groups. Thank you. I\'ll now call on Dr. Daniel Bloch from Stanford
University.

DR. BLOCH: Thank you, Paul. So my name again is Daniel Bloch. I\'m a
Professor of Biostatistics at Stanford. I have no financial interest in
the company, but I am paid for my time on an hourly basis.

I would like to start by presenting a statistical description of what
Paul referred to in terms of positive predictive accuracy in his
introduction, if I could have the first slide, and how a statistician
interprets positive predictive value, or negative predictive value, but
I\'ll illustrate with positive predictive value. If someone has no
knowledge at all, accepting that the prevalence for a person to have
probable AD or a mental impairment condition that is to be improbable,
possible, or MCI mild cognitive impairment groupings, that prevalence is
78 percent. And if that\'s the only knowledge that a person has, and
that person decides to classify everyone as having that condition, then
you would be wrong 22 percent of the time. That\'s called the
no-knowledge diagnosis. Maybe you would call it the dumb diagnosis. But
the fact is just knowing the prevalence, you\'ll be right 78 percent of
the time. And of course, you\'ll be wrong 22 percent of the time.

In contrast, among those patients that have NTP elevated, that is above
22 micrograms per milliliter, the probability of correctly placing a
subject into probable, possible, or MCI, raises from 78 percent to 95.9
percent, almost 96 percent. That is, instead of having 22 percent that
are misclassified, now only 4 percent are misclassified. Notice that the
interpretation of positive predictive value does depend upon the
prevalence in the population. And I\'ll come back to that later on in my
last slide that I\'ll present here this morning.

Now, I would like to address some of the comments that were made in the
statistical and medical reviews regarding statistics. And there are so
many instances that I was somewhat dismayed with that I just chose one
or two to illustrate with. And here on this slide, I\'m referring to the
statistical reviews, references, and quite extensive references to the
Blacker paper that was published in 1994, wherein the 1984 criteria were
applied to a group of patients with suspected Alzheimer\'s disease. The
Blacker paper used the three diagnostic categories of 1984, which
include probable, possible, and definite non-AD. Our study uses the
modern four diagnostic categories, which include MCI. And of course, by
including a fourth category, and the four categories now combined are a
mutually exclusive and exhaustive partitioning of all patients, just
like the three were before, but by doing so the definitions of the other
groups have changed, especially the definite non-AD group has a
different definition than it did in the Blacker publication. This is
critical because in the statistical presentation, there\'s great lengths
played about taking those kinds of criteria, trying to fit our data into
the criteria, making assumptions about how that might be done. It\'s all
irrelevant, really. We are not using those criteria. We\'re using the
modern criteria which include MCI. Also in the Blacker paper the
classification was based on definite AD or non-definite AD, and definite
AD was possible because all patients, all patients, were autopsied. That
is, all patients died and they had the autopsy diagnosis. Well, in a
clinical diagnostic criteria for early-stage populations, the chronic
disease, you don\'t kill people and get autopsies to get a definite AD
classification. And in fact, with the FDA it was agreed that the gold
standard evaluation would be the probable AD group.

Also, in the statistical review, references made to so-called best case
and worst case scenarios, this is misleading, it\'s fabricated. And in
fact, as we would know, a best case scenario I would think would mean,
if it\'s supposed to be a best case scenario for NTP, it would mean that
if you did follow everyone, and you could get autopsies, and all the
other information to get a definite diagnosis, then all NTP pluses would
have Alzheimer\'s, definite Alzheimer\'s. That\'s the best case scenario
for an NTP. And the worst case scenario is that all that were negative
would be found to have not Alzheimer\'s. Of course that\'s not going to
be the case, and it\'s \-- and the data that is presented is very
unclear with regard to that point. We\'ll go to the next slide.

This, as Dr. Averback has said over and over again, is that the intended
use is that this is not a stand-alone diagnostic criterion. And if we
could have the next slide, I wanted to drive that home with a scenario
that was presented in the medical reviewers packet, where he
hypothesized there\'s a middle-age individual, say a male, who might be
40 years old I guess. It\'s not clear what \"middle-aged\" means. I
guess when you\'re really young middle age starts at 30, but when you
get a little older it\'s not clear when it starts. But at any case,
there\'s a middle-aged individual, and the workup showed that with the
physical and the neurological exams as well as the mental status is that
the assessment\'s inconclusive. And the two scenarios that he presents
\-- so these facts are the same, represented by these three bullet
points. But the two scenarios, one is where the NTP is elevated above
22, and the second scenario he presents is when it\'s not elevated. And
the question is, well, what utility is it? Well, I would say in this
particular case it\'s clear that with a younger person it\'s very
unlikely, we know that the prevalence of Alzheimer\'s in middle-aged
people is low. How low is it? Well, three possible scenarios, perhaps,
are as low as 1 percent, it\'s probably not as high as 5 percent because
the prevalence among 65-year-olds isn\'t even that high. But notice that
that\'s not the prevalence in the study population. The intended use
population has a prevalence which is much higher than that of having
either probable or possible or MCI 78 percent. But for this hypothetical
patient, it\'s going to be much lower than that. And if you have an
elevated NTP with the scenarios, if you could go back to the past slide
again, that are bulleted here, which lead to an inconclusive diagnosis,
but you have an elevated NTP, then I think that would be extremely
interesting for a physician. It would probably drive him to get further
tests. That is, it\'s not a stand-alone test. This is a good example of
where it would not be a stand-alone test, and you would want to try to
find out and do more workups to see if perhaps the person had probable
AD for some reason that you\'re not finding. On the other hand, the less
than or equal to 22, there\'s inconclusive evidence it might be, so the
primary care physician would say, well, I\'m going to wait, and maybe I
can only see him once a year, rather than next week. Everything\'s so
inconclusive, the NTP is low. I think you get the point. But again,
it\'s not a stand-alone treatment, but the strategy going forward has
been influenced by NTP.

This last slide here that Jack has here, I just want to make the point
that, again, positive predictive values and negative predictive values
depend upon the prevalence. The sensitivities and specificities for NTP
are 60 and 91 percent. The 60 percent drives home the point that Paul
made, that in the primary care setting where with the information
available the sensitivity is documented to be between 15 and 25 percent,
with NTP it goes to 60 percent. One might say, well, 60 percent isn\'t
very good, but you have to put it in the right perspective. And given
that the sensitivity and specificity is, as we have shown with our
study, been with various prevalences, for example with the middle-aged
scenario, the positive predictive value is not going to be 95 percent,
96 percent. For example, if the prevalence is 1 percent, the positive
predictive value will only go up to 6 percent. But the way to interpret
that would be to say you get a six-fold gain knowing NTP than without
it. So I think I\'ll just stop here with those few comments for now, and
give the floor over to Dr. Patricio Reyes. And he\'s going to talk about
the diagnosis of Alzheimer\'s disease.

DR. REYES: Good morning. I\'d like to take this opportunity \--

DR. TAYLOR: Could you state your name, please, and your institution,
etcetera?

DR. REYES: My name is Dr. Patricio F. Reyes. I am Director of the
Alzheimer\'s disease, Cognitive Disorders, and Research Laboratory of
Barrow Neurological Institute in Phoenix, Arizona. Five months ago,
before I took this job, I was Professor of Neurology and Pathology in
Psychiatry at Creighton University, and Director of the Center for Aging
and Alzheimer\'s disease. Prior to that I was a Professor of Neurology
and Pathology in Neuropathology at Jefferson Medical School in
Philadelphia. I have served as Chair of the Medical and Scientific
Advisory Board of the Alzheimer\'s Association in Philadelphia, and I
continue to serve as a member of this board in Arizona. I feel that my
role as a member of this board, as a teacher, as a caring physician, and
as a researcher, my role is to encourage research, support research so
that my patients who suffer from this dreadful disease could have hope
and better lives in the future. I will continue to raise money for
Alzheimer\'s Association which I think is a good partner in this
endeavor. I do not receive any financial compensation \-- or I do not
have any financial interest in Nymox. Next slide, please.

Why do we talk about Alzheimer\'s today? It was Dr. Robert Katzman from
Albert Einstein several years ago who really placed Alzheimer\'s disease
in the front line of medical research. It is a disease that affects
millions of Americans, and the incidence and the prevalence are supposed
to increase in the years to come. It has become a major health problem
in our country. Next slide.

It affects late middle age and older people. And as the population
increases in this segment, we\'re going to have more health care
problems with degenerative disorders of the nervous system such as
Alzheimer\'s disease. Because they\'re older patients, we have to deal
with comorbid conditions that are common in this age group. We all know
that patients in this age group receive multiple medications that
confound the assessment of patients with cognitive deficits.
Unfortunately, to date, because of the lack of a reliable biomarker
antemortem, diagnosis is only confirmed by autopsy.

In looking at the data at present, we know for a fact that primary care
physicians, and even some specialists, because of limited time,
training, and experience, have difficulty diagnosing Alzheimer\'s
disease, particularly in its early stages. Another challenge that we
face is that Alzheimer\'s disease is a neurodegenerative disorder. It\'s
main clinical domains are three: cognition, behavior, and impaired
activities of daily living. All these clinical domains are necessary to
diagnose a dementing disorder such as Alzheimer\'s disease. This is what
we assess when we follow-up as we treat or follow-up patients. Yet the
symptoms that we deal with are not as specific. They are frequently
mistaken as normal aging. And there is truly a need to develop a
reliable, non-invasive biomarker for this disorder. Next slide, please.

But we have a major challenge that we face in everyday life in our
clinics, and even as a neuropathologist. Many times Alzheimer\'s disease
is difficult to distinguish from other dementing processes, such as
vascular dementia, Parkinson\'s disease with dementia, dementia with
Lewy bodies, fronto-temporal dementia, and so on. Let me tell you that
several investigators, and including our own team, have now found out
that vascular dementia frequently is associated with changes similar to
Alzheimer\'s disease. In addition, what we have called Alzheimer\'s
disease clinically, if you look at them neuropathologically, frequently
have vascular lesions as well. This adds to the complexity, both in the
clinical diagnosis and neuropathological confirmation of the disease.
Parkinson\'s disease also, if accompanied with dementia, is a difficult
entity to face. You could have Parkinson\'s disease with dementia per
se, or you could have by age alone because Parkinson\'s disease and
Alzheimer\'s disease affect both older individuals. The chance for
having two diseases is not uncommon.

Dementia with Lewy bodies is a subject that\'s direct to my heart
because in the mid-?80s we were one of the first to describe the
clinical and neuropathological abnormalities in patients with
Alzheimer\'s disease with Lewy bodies. To date, there is quite a bit of
confusion how to call this disease. Some investigators call this Diffuse
Lewy, Lewy body dementia. In our hands we call it, in many instances,
Alzheimer\'s disease with Lewy bodies. And the neuropathological
correlates are poorly defined as well. These are patients who usually
have dementia with Parkinsonism. Not Parkinson\'s disease, but
Parkinsonism. Who have fluctuating moods from day to day. And if you
treat \-- with visual hallucinations so they hallucinate visually. And
if you treat them with regular medications for Parkinson\'s disease,
many of them get worse. If you treat them with regular doses of
antipsychotics, they get worse. So again, there is tremendous complexity
in the diagnosis and neuropathological confirmation of this disease.

Fronto-Temporal dementia is equally difficult to diagnose, although
these patients are usually described as having symptoms referable to
affect, changes in affect, depression, with memory loss, usually in the
younger age group. But we do not have a marker. And the
neuropathological correlates could vary from patient to patient. So with
this challenges, the reason I mention this is because in this study, we
did not include vascular dementia, Lewy body dementia, fronto-temporal
dementia, because of the major controversies that exist in the clinical
and neuropathological diagnosis of these different entities.

It is also true that the presence of neurofibrillary tangles, and the
related plaques, which are the histological hallmarks for Alzheimer\'s
disease, can be found in other neurodegenerative conditions. So with
these challenges, we also have opportunities in understanding
Alzheimer\'s disease. We have to use validated and standardized clinical
criteria. We have to do comprehensive assessment of each patient to
exclude other neurologic and/or systemic disorders. We must develop a
non-invasive and reliable antemortem measure that will provide useful
information and can serve as a biomarker for this disorder.

How did Nymox approach these challenges? Nymox has devised a prospective
blinded study to determine the safety and efficacy of the NTP device. By
that I mean that these patients who were included in these studies were
newly referred patients to memory disorders clinics all over the land.
The technical people who analyze the urine samples were blinded as to
the diagnosis and demographics of each patient. And I think \-- I
strongly believe that it\'s a safe procedure, and as the data unfold
later, I believe that it is also effective in providing useful
information in diagnosing Alzheimer\'s disease and related disorders.

The study utilized subjects representative of the intended use
population. They have employed established and qualified investigators.
To my knowledge, all of the principal investigators were board certified
in American boards of neurology and psychiatry. Many of them are
directors of memory disorders clinic, and some of them are even
chairpersons of the department of neurology. The study utilized accepted
diagnostic criteria for probable, possible Alzheimer\'s disease, MCI,
and definite non-AD. Probable Alzheimer\'s disease, without going into a
lengthy discussion of the criteria, these are patients who are assessed
comprehensively by each investigator, and they have excluded other
conditions, either systemic or other neurologic conditions that could
give rise to dementing symptoms. Possible dementia cases are cases who
have dementia that could be due to Alzheimer\'s disease, but yet the
patients have comorbid conditions, such as hypertension, diabetes,
little stroke. MCI, on the other hand, as Dr. Bloch has referred to, is
a relatively recent concept, which it stands for mild cognitive
impairment. These are individuals or patients who may be members of our
community. They may have subjective complaints of memory loss. On
careful testing they may have mild symptoms of memory loss, or even
visio-spatial disorientation. But they are not demented because they are
able to do their activities of daily living. Their deficits do not
impact on their social or professional functioning. The non-definite AD
are those that do not belong to either of the three categories. The
reason, again, why we do not include a specific category for
fronto-temporal dementia, vascular dementia, Parkinson\'s disease with
dementia, and Lewy body dementia, is because we have considerable
controversy in the diagnosis and neuropathological aspects of these
disorders. Next slide, please.

If we approach this simply by giving pathologic confirmation, it is
obvious that this approach is not viable. It is important, however, if
possible to do pathologic confirmation. Next slide.

So in summary, the NTP assay is a laboratory tool that is non-invasive
and simple. The sample we are talking about here is readily accessible.
It\'s urine. Assay is devoid of adverse body reactions. It is a reliable
test. It has a sound scientific basis. However, it should not be used as
a stand-alone test. I will now give the floor to Dr. Richter.

DR. RICHTER: Well, nice to be here with you today. I appreciate the
opportunity to present results of an interesting study which I think has
really good possibilities for assisting the clinician. I\'m Ralph
Richter \--

DR. TAYLOR: Could you please \-- good. Thank you.

DR. RICHTER: I formally served as Clinical Professor of Neurology at
Columbia University. For 12 years I directed the service at Harlem
Hospital for Columbia, and then was part of the founding of a branch of
the University of Oklahoma in Tulsa, and then have been very active in
clinical affairs. I\'ve been doing a great deal in clinical
investigation in Alzheimer\'s disease. I have also been very active in
the Alzheimer\'s Association. I was one of the founders in Oklahoma and
served as Vice President for a number of years. That\'s why I was a
little surprised to hear Dr. McConnell make comments that I would say
judge not, lest ye be judged. Because we\'ve contributed a great deal to
that association, and to make those comments based on not even reviewing
the data is not fair play. Let me put it on the table.

Now, the \-- could we begin our talk. The study itself was a blinded
clinical study. It was to demonstrate the effectiveness of the NTP test
in the diagnosis in a realistic clinical setting. The individuals that
were worked up came out of our own, like in our own clinical research
unit. As they came in, we would ask, I\'d see seven or eight new memory
patients a week, you know, and have a team that helps work them up. We
would then offer if, you know, once we\'d begin the work we\'d say
?Would you like to participate?\' So it\'s kind of not \-- we didn\'t
pre-select. They selected in the sense would they be willing. And there
were people certainly who were not willing or able to participate, even
in a limited study like this. There were only two data points: the
clinical diagnosis, and the NTP measurement. Next.

So as we mentioned, the other two centers that were involved here. The
other eight also included individuals who were very well qualified in
neurodiagnosis, and had extensive experience so that the \-- one can
rely on the evaluation as being clinically efficient and effective. We
gave it our best shot in terms of helping to work up these individuals.
Next.

The NTP test itself was a first morning sample. And not everybody is
able to give a good first morning sample. That\'s why some of the urines
were inadequate to begin with. The laboratory determination was blinded
to gender, to age, to name, to location. There were unacceptable urine
samples that might contain glucose or protein. These were then not
included. If the creatinine concentration was less than 50 mg/dL it was
felt that this was then not a first morning specimen. Also, those that
were not included were where the creatinine level was more than 225
mg/dL. As mentioned, the investigators that took part in this study are
all very reliable, well trained clinicians. And the workups were then on
a standard basis per protocol, but we did our own full workup as per
each unit, but then included the way the protocol was set up as well. So
this was not an independent \-- in other words, we didn\'t do just this
study. We were doing this to help individuals with their disease and
their families. Next.

So the comprehensive medical history, physical exam, and complete
neurological exam, a psychosocial evaluation. I have the Master\'s
psychologist who helps in interviewing the patients. The Mini-Mental
State Exam was done on each as it is on all of our patients, and the
imaging as listed, a blood workup which would be standard in all of our
units. We\'re trying to exclude those individuals who have correctable
neurological conditions leading to dementia. And we, by gosh we do find
some as we all, those who are clinically oriented, hear. There are going
to be correctable conditions that lead to dementing symptoms that are
not Alzheimer\'s. Next.

The outcome measurement was then the urinary NTP measurement. The
clinical diagnoses followed. We would then put them into categories of
probable AD, possible AD, and mild cognitive impairment. The criteria
were the NINCDS-ADRDA criteria for Alzheimer\'s as possible or probable.
And the mild cognitive impairment category, actually, is some of the
guidelines developed by Ron Peterson of Mayo Clinic, an old colleague of
ours that was a subcommittee of the American Neurological Association.
And the final category, those who were felt not to have Alzheimer\'s
disease. That group ended up as with high Mini-Mentals who in a number
of instances, nine that I can think of, actually had pseudodementia, who
were depressed. And then there are other groupings of patients in that
category.

The flow chart here of the urines. There were urines here that are
listed that were then discarded, or that were not adequate. So there is
a sampling that these patients then, the data then is not included in
the 200 individuals who were included in the database. The diagnoses of
probable Alzheimer\'s disease were found in 28.5 percent of our
database, the possible AD of 28 percent, and MCI of 21 percent, and the
definite non-AD as 22 percent. This kind of a spread would represent, I
think, kind of community-based studies, you know, as serving all comers.
I think that spread would be typical for that. So we\'re not
pre-selecting in this study. Next.

Here again the data. The cutoff point was the NTP of greater than 22
micrograms per mL were those that we felt were significant \-- this was
a significant marker, and those below 22 micrograms per dL. And the
dividing group as you see here, 51 out of 57 of probable AD had this
elevation. And also interesting is that the MCI patients, there was an
even split in the definite non-AD, only 4 out of 44 had an elevation of
the NTP. Next.

Here again is the scatter plot that has been shown several times. The
probable AD are clearly higher than the definite non-AD cases. And there
is very little overlap between these two groups. The possible AD and MCI
groups are in between, which is exactly what we would expect because
these two groups contain a significant number of cases of AD and non-AD.
But it is not possible to be certain on clinical grounds in any given
case. Next.

This slide summarizes the prevalence of definite non-AD versus not
definite non-AD, which would then be the MCI, possible AD, and probable
AD. The prior prevalence for definite non-AD is 22 percent. Next. This
slide shows the performance characteristics of definite non-AD versus
probable AD and possible AD plus MCI. The percentage of those that are
diagnosed in this category of definite non-AD with normal NTP levels is
90.9 percent. The percent of patients diagnosed as not definite non-AD,
of MCI, possible AD, and probable AD is 60.3 percent. The positive
predictive value here as outlined, that the \-- in the group here, there
is the percent of elevated NTP levels as probable Alzheimer\'s, or
possible Alzheimer\'s, or MCI, is 95 percent. The prevalence here is 78
percent. The use of the elevation in the NTP, the utilization, actually
raised the clinical acumen by 23 percent. The utility of the NTP
measurement showed the significance as listed here that your percent of
potential recognition of those with Alzheimer\'s who had elevations were
23 percent. Next.

The performance characteristics are outlined in this slide. The negative
predictive value here is 39 percent. The prevalence, again, of 22
percent. And that compared to the prevalence without NTP there was an
increase in recognition of the potential improvement in diagnosis of
some 78 percent. So there is a utility of the NTP measurement with
significant improvement utilizing the data derived from the NTP.

The clinical study shows that the NTP measurement provides useful
diagnostic information to the diagnostic. It adds a measure of strength
to the diagnostic workup process for suspected Alzheimer\'s disease.
There are, then, ongoing reviews which will be taking place. We hope
certainly to continue to study other individuals, and develop even new
database. And I would hope that our distinguished panel could consider,
give us the opportunity to make this diagnostic test available. Many
thanks. I\'m going to introduce Dr. Ira Goodman, who is from Florida,
and is a leading clinician and a clinical professor at the University of
Florida, who has a very large database also of patients.

DR. GOODMAN: My name is Dr. Ira Goodman, and I have no financial
interest in Nymox. I\'m an adult neurologist, Director of the Orlando
Regional Healthcare System\'s Memory Disorders Clinic, and clinical
faculty at the University of Florida School of Medicine. We are one of
13 state-funded memory disorders clinics, part of the Alzheimer\'s
Disease Initiative begun several years ago by the Department of Elder
Affairs in an effort to support the thousands of people with cognitive
impairments and their families who reside in the State of Florida. The
mission of the memory disorders clinics is to provide evaluation and
treatment, education, as well as research. The State of Florida has a
disproportionately large number of people with cognitive impairment,
secondary to a disproportionately large number of elderly residents.

Patients are referred to our clinic by primary care and other
physicians, as well as referrals by local agencies, sometimes through
neighborhood screenings offered by the local agencies. Patients are
evaluated and treated regardless of their ability to pay, and efforts
are made to reach out to minority communities. In our clinic, after the
evaluation and testing are complete, each patient is then presented at
conference attended by the examining physician and other physicians,
social worker, neuropsychologist, psychopharmacologist, as well as
geriatrician. A diagnosis utilizing the NINCDS-ADRDA criteria is then
established for each patient, at which time \-- the diagnosis is then
established. The patients come back with their caregiver, told about the
diagnosis, and then a treatment plan is formulated. We do follow the
patients longitudinally over the years to monitor their course which
aids in confirmation of the clinical diagnosis. In addition, each
patient is offered the opportunity to enroll in the brain bank program
which allows for pathological confirmation of the diagnosis at the time
of death.

I would now like to briefly review several cases in which the urine
neural thread protein was measured, which I hope will illustrate the
utility of the test. These patients participated in the prospective
blinded study which was just discussed. Because our time is limited,
I\'ll only present the salient features. The first patient is AS, who
was referred from her primary care physician. She is a 73-year-old white
female who presented with a four to six month history of forgetfulness.
Her husband who also accompanied her stated that she was also having
some difficulties with ADLs. Past medical history was positive for
hypothyroidism, and her family history was positive for memory loss in
her mother. The evaluation in the clinic demonstrated an MMSE score of
27. She had an unremarkable neurological examination, other than severe
chronic kyphoscoliosis. MRI revealed atrophy and small vessel changes.
Her extensive laboratory screens were unremarkable, and formal
neuropsych testing suggested early Alzheimer\'s disease with depression.
The urine neural thread protein measurement was elevated. This was taken
before clinical evaluation was begun. After her clinical evaluation, the
diagnosis of probable AD was established. In the two years of follow-up
that we have, she\'s demonstrated significant decline which now has led
to institutionalization despite treatment with cholinesterase inhibitors
and memantine. Next slide. The utility \-- the value of the neural
thread protein in this patient can be seen. The patient presenting with
only mild symptoms, an elevated NTP level, will provide the primary care
physician with additional useful information that may indicate earlier
follow-up or referral for more comprehensive evaluation.

The next patient is SM. He is a 72-year-old white male who presented in
November of 2002, again referred from his primary care physician. He has
a one to two year history of cognitive decline. Past medical history was
positive for hypertension and prostate cancer. Family history was
negative for dementia. Evaluation at clinic revealed and MMSE score of
30. He had a normal neuro exam. There was no evidence of MCI or dementia
on detailed neuropsych testing. His MRI was felt to be normal for age,
and extensive laboratory screens were, again, normal. His urine NTP
measurement was normal. After evaluation, the clinical diagnosis of
normal or the probability of age-related memory impairment was
established. For purposes of the study, the patient was categorized as
definite non-AD.

About two years later, at the insistence of his daughter he came back to
the clinic because she felt that he was showing a clear-cut cognitive
decline, and actually specifically asked to be placed on cholinesterase
inhibitor. We went ahead and reevaluated him with detailed exam, which
was normal. Repeat MRI was normal, repeat labs were normal, and repeat
detailed neuropsychological testing was normal. Next slide.

Again, the utility of the NTP measurement can be seen. This presentation
of the worried well is a common scenario in the primary care
physician\'s office. The normal NTP measurement offers useful
information for the decision whether to refer the patient for specialist
evaluation, or just to continue close clinical follow-up.

The next patient is MM. He is a 39-year-old white male who was referred
to evaluate for about a six month history of cognitive decline. We first
saw him in March of 2003. His primary care physician actually felt that
he was demonstrating depression related to a divorce that he was going
through after 15 years of marriage. His medical history was
unremarkable. However, his family history was suggestive of early onset
familiar Alzheimer\'s disease, with his brother, his father, and
paternal aunt dying in their early forties with a diagnosis of dementia.
Unfortunately, we had no confirmatory family medical records to look at.
Evaluation in our clinic revealed an MMSE score of 18. He had a normal
neurologic examination. Detailed neuropsych testing was consistent with
Alzheimer\'s disease and mild depression. The MRI demonstrated brain
atrophy. EEG was disorganized and slow, but there were no periodic
discharges, and extensive laboratory screens were unrevealing, other
than positive ApoE 4 allele, and elevated homocysteine level, which
actually normalized with a high dose vitamin supplementation. His urine
NTP measurement was elevated. Because of his age and his family history,
we elected to proceed with a genetic analysis for the PS1 mutation. As
you know, there\'s a rare inherited autosomal dominant form of early
Alzheimer\'s secondary to genetic mutations on Chromosomes 21, 14, or 1,
the most common being a mutation of the presenilin gene on Chromosome
14. The patient did have a unique mutation on PS-1, and this confirmed
the clinical diagnosis of probable AD.

Unfortunately, MM passed away last March about at the same time as other
family members, in their early forties. Next slide. The PS-1 mutation
analysis provided independent confirmation of the clinical diagnosis of
probable AD. The urine NTP measurement agreed with the PS-1 mutation
result and the clinical diagnosis of probable AD, and the elevated NTP
measurement added useful information for \-- could add useful
information for the primary care physician to increase suspicion of AD
in a young or middle-aged patient.

And the last patient I want to talk about is PS. He was seen about two
years ago, again, referred from his primary care physician for a second
opinion concerning the diagnosis of Alzheimer\'s disease. He is a
54-year-old white male with about a two and a half year history of
progressive cognitive decline. This actually presented with \-- he kept
repeating himself, and it eventually led to more serious symptoms. His
primary care doctor went ahead and worked him up, and got a brain
imaging study revealing ventriculomegaly which was out of proportion to
atrophy. He, however, on presentation had no clinical symptoms that
would have suggested NPH. His past medical history was negative, social
history was negative, and family history was negative.

Evaluation in our clinic demonstrated an MMSE of 24. He had a normal
neurologic examination, including an entirely normal gait. His detailed
neuropsych testing was consistent with AD. Extensive laboratory screens
were negative. He did not have an ApoE 4 allele. Lumbar puncture was
performed, which revealed a mild CSF pleocytosis. He had eight white
cells, normal protein, normal glucose, negative cultures, negative
cytology. And his EEG demonstrated mild slowing. His urine NTP
measurement checked initially was elevated.

Now, this patient, we were following up, and he developed a severe
cognitive decline, with an MMSE deterioration of 24 to 8 in one year. He
also developed significant behavioral changes that required the
institution of a neuroleptic agent. Subsequent to that he started
developing a very, very severe gait disorder, as well as urinary
incontinence. And we weren\'t clear whether the gait impairment was
related to a central nervous system disease, or was related to his
medication. Well, after awhile it was elected by the family to proceed
with a V-P shunt and simultaneous brain biopsy. The family wanted to
establish a diagnosis as certainly as possible, and also wanted to see
if there would be any clinical improvement with the placement of the V-P
shunt. The V-P shunt and brain biopsy were performed in early 2004
without complication. The results of the brain biopsy confirmed definite
AD, and for the purposes of the study he was categorized as a probable
AD. Next slide.

This is the brain biopsy, with the tangles and plaques. He clinically
did not show any improvement or response to the V-P shunt. So, since
over the last year and a half or so. Next slide.

The utility NTP measurement in this patient. The elevated NTP
measurement adds useful information for the clinician to pursue further
investigations for Alzheimer\'s disease before proceeding to more
invasive procedures.

These patients that have just been briefly presented I believe represent
a spectrum of the types of patient that present to the primary care
physician\'s office. Measurement of the urine NTP offers a reliable,
useful information that can be utilized by the clinician as part of the
evaluation of the patients who present with cognitive symptoms. All
physicians who evaluate patients with cognitive symptoms have their own
individual levels of expertise and comfort based on their training
experience. It is these variables that will determine how best the
clinician will utilize the proven, accurate, added information supplied
by the urine NTP measurement. The result of the urine NTP measurement
along does not prove or disprove Alzheimer\'s disease, nor does it
indicate treatment or no treatment. It does, however, provide additional
useful information for the clinician to use in the process of arriving
at a clinical diagnosis. Thank you.

DR. TAYLOR: Thank you. Dr. Averback?

DR. AVERBACK: Can we have the next slide, please? I\'d like to give the
conclusion now. And the good news is it\'s a very short conclusion. I
also want to thank our speakers who have presented a very good case, and
thank you very much.

Our conclusion is that urine NTP adds useful information for an unmet
medical need. And we have a twofold thesis that this is useful
information. We\'ve tried to show you how it\'s useful, and that it\'s
entirely safe. There\'s no bodily risk to anybody. There\'s no downside.
There\'s no conclusive invasive action that can come from it. Next
slide, please. And I leave you with the scatter plot again, which we\'ve
shown frequently today, that demonstrates the difference when the NTP
was done with these different diagnoses. Thank you very much.

DR. TAYLOR: Thank you. I would like to thank the Nymox presenters for
concluding their presentation well within schedule. So that\'s laudable,
right? And difficult. I\'d like to ask the panel members if they have
any specific questions that they would like to pose at this point in
time to any of the presenters for Nymox this morning. Okay, Dr. Lopez
has a couple of questions.

DR. LOPEZ: I have two questions. One is regarding the \-- can you hear
me?

DR. TAYLOR: Just state your name, please.

DR. LOPEZ: I\'m Oscar Lopez. I\'m a neurologist and Professor of
Neurology at the University of Pittsburgh. My question is regarding the
severity of the dementia in the cases with probable Alzheimer\'s
disease. Have you broken down the group by severity? It\'s possible that
all these results are driven by more severe cases. You showed before
there were some cases that they have early symptoms of disease. That
would be important to know if the test is positive in cases of moderate
and severe to moderate, and if they\'re less sensitive in the mild
cases.

The other question is regarding the possible cases, the possible
Alzheimer\'s disease cases. According to the NINCDS criteria, these
cases are patients with dementia that they have an atypical progression,
or cases that have Alzheimer\'s disease and other conditions that by
itself can cause a cognitive impairment. So in that group, so this is a
group that\'s supposed to have two conditions, Alzheimer\'s disease plus
something else. And I was expecting to see a much better sensitivity of
the test in the group of possibles. And this is the group that goes to
the PCP. This is the group that goes to the family doctor. This is the
group that has comorbidities, and is a group that is going to be
followed by \-- is the group that sees the PCP frequently because of all
these comorbidities. So this is the trouble group. And for what I can
see here, it\'s almost half of the group was identified by the test. So
it would be important to clarify who were those possible AD cases.

DR. RICHTER: And Dr. Lopez, in answer to the first question, there was
some sorting out by the Mini-Mental in terms of severity. So that the
mean \-- the ones with probable AD, if you look at kind of their mean
value of the MMSE, it was 19, in that range, versus the ones who had,
the MCI had in the range of 28 - 27, so only milder one. And the ones
that were possible all had a higher Mini-Mental in the low 20 range, so
that it was sifted out on that basis.

In terms of your question relating to other diagnoses, I think we did
our best to try to distinguish one from another, but you really can\'t
unless you have pathological confirmation. All my patients had brain
SPECT scans, which were of some help in diagnosis. A number of them now
are getting PET scans. But even there you can be misled as to the, you
know, as you know, to the findings, the validity. If their change is
more frontal, they\'re going to be parietal-temporal to a greater
extent. What if you have asymmetry? Does the disease begin more on one
side in some individuals than others? You know, are there vascular
components? None of them had \-- there were no clear-cut stroke patients
that were in the possible. Does that answer in a limited way? Thank you.

DR. REYES: Mr. Chairman, could I address that question?

DR. TAYLOR: Yes, go ahead. Please again state your name.

DR. REYES: Thank you, Dr. Lopez. Those are good questions. The thing of
the \--

DR. TAYLOR: Could you state your name again, please, for the record?

DR. REYES: I am Dr. Patricio Reyes.

DR. TAYLOR: Thank you.

DR. REYES: The objective of the study was to correlate NTP measurement
with the diagnosis of Alzheimer\'s disease. The severity of the disease
was not a major objective of the study, but it\'s a good point that you
raise. So, what they did was classify patients with probable/possible
according to accepted NINCDS-ARDRA criteria, and not the severity. And
also MCI, because current evidence indicates that MCI patients \-- this
came from Mayo Clinic investigators \-- a significant number of them can
convert to Alzheimer\'s disease. About 11 - 15 percent per year. The
recent physician study indicates 33 percent, after three years, a
patient with MCI, may convert to Alzheimer\'s disease.

DR. TAYLOR: Thank you. Any other comments?

DR. AVERBACK: Paul Averback. I agree with Dr. Reyes, it\'s a very good
question from Dr. Lopez. I would just point out, but I\'m sure you know,
that the specifically of possible AD is generally considered to only be
50 percent. So while the sensitivity is high, and I echo your sentiment,
with a specifically that\'s low, we would expect that possibly up to
half the cases would in fact not be Alzheimer\'s. To directly answer
your specific question, your second question.

DR. TAYLOR: Thank you. I believe, did Dr. Blumenstein have a question?
No? Dr. Parisi?

DR. PARISI: I just have a comment \--

DR. TAYLOR: This is Dr. Parisi for the record.

DR. PARISI: Dr. Parisi. First of all, I can\'t underestimate the
importance of the autopsy in confirming the diagnosis in these cases.
And I wonder if any of your cases have come to postmortem exam, and
what\'s that shown?

I also have to take a bit of an issue with Dr. Reyes\' comment about the
uncertainty of the pathology. I think we do a pretty admirable job of
classifying these disorders at autopsy. And I think certainly the
studies have shown that the clinical diagnosis is correct probably 80 or
85 percent of the time, and we often turn up with something different at
postmortem. So.

DR. TAYLOR: Response?

DR. GOODMAN: I\'m Dr. Ira Goodman. Concerning autopsy material, in our
group, the only autopsy material that we had the correlating urine was
with PS, the last patient that I showed. The patient with the presenilin
mutation we did not get autopsy results. And so far, all the patients
that are in the study are registered in our brain bank program, but
it\'s only been about two or three years, and fortunately they\'re still
\-- we\'re still following them.

DR. TAYLOR: Was there another question? Yes. Please, again give your
name.

DR. NATH: Avi Nath. And I was wondering if you have any longitudinal
data on any of your patients? Do you know if as they deteriorate, does
the level change, or stay the same, or what happens to it?

DR. AVERBACK: Paul Averback. Do you mean for this clinical study?

DR. NATH: In this or outside.

DR. AVERBACK: In other studies? We have done some published studies that
have followed people up for longer periods. And it\'s an area that
we\'re very interested in, and it\'s something that we are looking into
quite a bit. But to say something controlled and conclusive, I would be
hesitant.

DR. NATH: And the second question I had was with regard to the point
made about the difficulty in diagnosis of Alzheimer\'s, and that a lot
of these patients may have mixed diseases, which is either with
Parkinson\'s or Lewy body disease. I was wondering why in your study
design you didn\'t consider the possibility of maybe taking pure
Parkinson\'s Disease, or pure NPH patients, or Huntington\'s, just to
see if they would have NTP levels detectable above the norm range or
not.

DR. AVERBACK: That\'s a very good point. The design was supposed to be
all comers to the clinics. So there could be no selection. And of
course, no study is perfect. People with clear-cut strokes aren\'t
referred. So a case that would be, for example, a definite vascular
dementia, where there\'s a clear-cut stroke, they don\'t tend to get
referred to studies like this to dementia clinics. So the fallout of the
cases is purely consecutive new cases as available.

DR. NATH: But you understand my concern is that if you have any other
neurodegenerative diseases, it\'s possible that maybe \-- I\'m wondering
if this could be just it being released from the brain itself
irrespective of whatever the neurodegenerative condition might be.

DR. AVERBACK: Well, we were testing it \-- sorry, go ahead.

DR. NATH: And it may not be specific for Alzheimer\'s disease, even
though you know, in your probable Alzheimer\'s you see a difference
compared to others. And it may be that if you had a similar number of
Parkinson\'s patients, you\'d probably see similar levels.

DR. AVERBACK: Two answers to that question. It\'s supposed to be the
realistic clinical context. So we had to take a realistic consecutive
group of patients. So that\'s \-- we had to do that. There is a study
published in the Journal of Clinical Investigation in 1997 that had a
control group neurologicals using this marker with a different assay.
But there was no significant positivity in some of the conditions that
you mentioned. And there are a couple of studies that we have published
that have found the same thing as well. But I wouldn\'t be so bold as to
say that it\'s impossible that all conditions might not have some
overlap.

DR. TAYLOR: Thank you. Were there any other? Yes.

DR. GULLEY: James Gulley. I have a question for Dr. Bloch about the
performance characteristics of the test. I just was, just for my
edification, where were the numbers for prevalence for both the positive
predictive value and the negative predictive value obtained from?

DR. BLOCH: Well, the positive predictive value through Bayes\' theorem
is directly related to the sensitivity, specificity, and the prevalence
of the disease. So that\'s not a number you get directly from the data.
It has to be derived through a formula that relates sensitivity,
specificity, and prevalence in a certain way, and that is the definition
of positive predictive value. And so, the way you derive it, so where
the numbers come from, is that there is, for example, for positive
predictive value, the prevalence of 78 percent, sensitivity was 60
percent, and so on. Those are the numbers you need to plug into the
formula to obtain positive predictive value.

DR. GULLEY: Right. The 78 percent, where did that come from?

DR. BLOCH: That\'s the study percent of patients that had possible,
probable, or MCI.

DR. GULLEY: Right, okay.

DR. BLOCH: Okay.

DR. TAYLOR: I think Dr. Gollin was next.

DR. GOLLIN: I have a more technical \--

DR. TAYLOR: Okay, name please?

DR. GOLLIN: I\'m Susanne Gollin. I have some more technical questions,
possibly for Dr. Averback, about the protein and the antibody. Am I
correct in stating that the antibody was prepared against an inferred
peptide sequence from the CDNA?

DR. AVERBACK: Paul Averback. The statement we made about the CDNA was a
statement that NTP was initially characterized based on CDNA that was
derived from postmortem human AD brain. Not the device. This is the
background research.

DR. GOLLIN: Okay.

DR. AVERBACK: We were pressed for time. I didn\'t want to \-- we just
didn\'t have enough time.

DR. GOLLIN: Okay, so the antibody used in the test, was that derived
against a peptide inferred from that CDNA, or was it from an isolated
NTP protein from normal brain?

DR. AVERBACK: The exact construction of the test is some proprietary
information that we\'d have to go into another room to give you answers,
which we\'d be delighted to do.

DR. GOLLIN: Okay. Now, I\'ll ask another question, and this is referring
specifically to a 2005 paper in the literature. Does the CDNA sequence
isolated from the Alzheimer\'s brains correspond to the genomic sequence
of this alleged gene?

DR. AVERBACK: Jack, could you please put a slide up? We\'ll have an
answer for you for that in a second.

DR. GOLLIN: Okay.

DR. AVERBACK: The background of NTP, it started in research done at Mass
General Hospital and Harvard Medical School, and then at Rhode Island
Hospital and Brown University in teams led by Dr. Jack Wands and Dr.
Suzanne de la Monte. And they have been working on this for close to 15
years. And your specific question, the answer to that paper is that \--
I would refer you to this paper in PNAS, which is considerably more
authoritative, which explains some of the issues that you\'ve mentioned.

The sequence that the Harvard people derived was from an Alzheimer\'s
brain, and it was work with real test tubes. The paper that you quoted
is a software analysis of the human genome. These are not strictly
comparable. And we quote a couple of papers here that have worked with
the same sequence that we\'re working with. And one in particular, the
Britten paper, gives a good explanation for some of these sequential
elements.

DR. GOLLIN: So have you evaluated the population frequency of the
variation in the various human populations? This would be important in
terms of testing the general human population. Are there polymorphisms
that may lead to altered results on the test because of altered
proteins?

DR. AVERBACK: That\'s a very good question. We have not. The percentage
difference that\'s been hypothesized \-- and we don\'t accept the
hypothesis, nor do these other papers \-- is so small in terms of the
total peptide count that I would say it\'s extremely unlikely.

DR. GOLLIN: It wasn\'t clear to me the percentage of minorities in the
population studied. The examples that were given that said what the
rates of the individual was were all Caucasians. So would there be any
evidence in the population data that would lead to false negatives, or
false positives, due to sequence polymorphisms as a result of race, for
example?

DR. AVERBACK: Here\'s our race data. I mean, in this limited study of
all comers, it was pretty representative in the populations that we
studied. But we don\'t have tools to detect these 3 percent snips that
you\'re talking about. And as I say, other workers don\'t buy into that
hypothesis anyhow. So our opinion has been corroborated by American
studies published in PNAS. Yours was a software study out of Germany.

DR. GOLLIN: So, do any other proteins cross react with your antibody? Is
it very specific for only the neural thread protein, and not any others?
Did you do precipitation studies, for example?

DR. AVERBACK: We tested the ones that are listed in the panel package. A
goodly list of the usual suspects. And in this assay, there\'s no cross
reaction. This assay does not perform well if there is too much solute.
That\'s why the urine creatinine concentration has to be less than 225.

DR. GOLLIN: Thank you.

DR. AVERBACK: Thank you.

DR. TAYLOR: Thank you. In the interest of remaining on schedule I\'m
going to ask Dr. Lichtor to hold his question till after lunch, and we
will proceed at this point in time with the FDA. So the first speaker, I
believe, for the FDA is going to be Dr. Robert Becker, who is Director
of the Division of Immunology and Hematology Devices. And then I will
ask Dr. Becker to introduce the other FDA speakers in turn. Thank you.

DR. BECKER: I am Robert Becker. I\'m Chief of the Division of Immunology
and Hematology Devices in the Office of In Vitro Diagnostic Devices. I
have no commercial affiliations.

The presentations today from FDA will be from three individuals in four
parts. First, I will describe the general nature of issues identified by
FDA regarding performance of the urine NTP test, given its proposed
intended use. I will also give a short treatment of the challenges that
exist for any Alzheimer\'s diagnostic test due to the natural history of
the disease, and the usual unavailability of histological specimens for
test validation. Last, I will discuss FDA\'s evaluation of
pre-analytical and analytical data in the sponsor\'s PMA submission
relevant to precision, and the cut point selected for this test. The
second presentation is from Dr. Marina Kondratovich, mathematical
statistician with the Division of Biostatistics in our Office of
Surveillance and Biometrics. She will discuss our findings from the
clinical data that the sponsor submitted for review. The third
presentation will be from Dr. Ranjit Mani, a medical reviewer and
practicing neurologist with the Center for Drug Evaluation and Research.
He will discuss the clinical effectiveness of the urine NTP test. For
the final presentation, I will summarize the earlier presentations and
pose discussion points and questions for the panel to consider.

As with any in vitro diagnostic device, our evaluation begins with the
intended use. The latest of several versions provided by the sponsor
during the course of our review is projected here. The first notable
element is the intended use population. That is, patients presenting
with cognitive complaints or other signs and symptoms of suspected
Alzheimer\'s disease. No distinction is made as to the setting in which
these patients present. Therefore, we conclude that the test is meant
for patients at any stage of the diagnostic workup. As the sponsor makes
clear elsewhere, this includes patients seen by general practitioners
and other non-specialists, as well as by neurologists or other
specialists trained in the diagnosis of AD.

The second important point is that the test is for use in conjunction
with, and not in lieu, of current standard diagnostic procedures. More
specifically, the test is for use as an adjunctive aid for differential
diagnosis. Current diagnostic procedures for the most part apply the
criteria from the National Institute of Neurological and Communicative
Diseases and Stroke for probable and possible AD, and the Quality
Standard Subcommittee of the American Academy of Neurology for mild
cognitive impairment, or MCI. For brevity, I\'ll call the NINCDS-ADRDA
criteria just the NIH criteria for the rest of my presentation.
Sometimes I\'ll substitute the phrase \"clinical criteria\" or
\"clinical diagnoses\" for the combination of the NIH and AAN criteria
for diagnoses.

The NIH criteria and the AAN criteria are applied with varying rigor and
skill by differently trained health care professionals. Therefore, an
important review issue is how well the urine NTP test results work in
combination with the usual clinical criteria to inform both primary care
and specialist diagnosticians. Characterizing the urine NTP test as
adjunctive is an important element to this device\'s claim. An
adjunctive test is subordinate to a parent diagnostic process. For
Alzheimer\'s disease, the parent diagnostic process is the clinical
diagnosis determined using the NIH and AAN criteria. The adjunctive test
is applied to clarify results from the parent test. It might be used to
improve on the sensitivity that is provided by the parent test alone. To
be useful in this role, it must improve sensitivity without significant
loss of specificity. Alternatively, the adjunctive test might be used to
improve specificity while avoiding a loss of sensitivity. And sometimes,
improvements in both sensitivity and specificity are sought.

It is essential to recognize that there is only one way to establish
improved sensitivity or specificity for the combination test relative to
the parent test. That is to compare results from the parent test, alone
and combined with the adjunctive test, to results from a higher
standard, such as histology in the case of AD. Without such a
comparison, it is possible to determine bounds within which the
combination test performs perhaps better, perhaps the same as, or
perhaps worse than the parent test alone. However, it is not possible to
know which state of affairs occurs when using the combination test.

The next point to consider is that the sponsor\'s intended use and the
indications for use define a particular distinction that the urine NTP
test is to help us make. The test is designed to help distinguish
patients who do not fit the criteria for possible AD, probable AD, or
MCI, from patients who do fit the criteria for one of these categories.
Patients not fitting any of the NIH or AAN categories are designated
definite non-AD patients. It is well known that patients outside the
definite non-AD class vary substantially in their cognitive state and
prognosis, and so the further distinction of such patients is also
important. Indeed, the original intended use put forth by the sponsor
concerned distinction of probable AD patients from those meeting
criteria for possible AD, for MCI, or for none of the clinically defined
AD-related classes. However, the currently proposed labeling aims only
at distinguishing definite non-AD from not definite non-AD. And our
remarks mainly address this distinction.

The last point we consider from the proposed indications for use
concerns the refinement of diagnostic workups. This is in wording that,
quote, \"An elevated urine NTP level may help the clinician\'s decision
for the need of further diagnostic workups, such as specialist
consultations, imaging, in depth neuropsychological testing, EEG, and
other testing procedures.\" Since the urine NTP test can be used by
general practitioners and specialists alike, FDA takes this wording to
mean that test results will help the general practitioner to decide
whether referral to a specialist is needed. In addition, specialists
themselves might use the test to help select advanced diagnostic studies
for particular patients. FDA will be asking the panel\'s opinion and
recommendations on whether the studies under review support such a
claim. If so, what labeling caveats, if any, would be appropriate? If
not, what further studies would be needed?

In summary, FDA will be requesting the panel\'s input to determine
whether the settings and studies reported in the sponsor\'s PMA
submission are sufficient to support use of the urine NTP test as an
adjunct to clinical testing, or to prompt diagnostic or management
changes. FDA will also be addressing issues pertinent to use of the NTP
results to exclude patients from the two specific categories of disease
targeted in this submission: definite non-Alzheimer\'s disease and
probable Alzheimer\'s disease, given the diagnostic continuum of
affected patients. We will address an issue of intra-patient variability
in NTP results over time, and we will also pose questions concerning
adequate sampling of the intended use population.

It is worthwhile to consider the challenges confronting any in vitro
test aimed at diagnosing AD. The field has near consensus on the
reliability of histological criteria for diagnosis of AD, and results
from histology are treated as a gold standard against which other
testing modalities can be compared. However, the tissue needed to make
such comparisons is rarely available early in the course of AD. Even
postmortem studies of tissue from advanced cases require substantial
time and effort to acquire a large number of cases. But without
histology, there is substantial risk for confusion of AD with other
dementing disorders, or for failure to recognize AD in the presence of
other disorders.

In practice, the NIH criteria for probable AD and possible AD, and the
AAN criteria for MCI, help to systemize the workup of patients
presenting with complaints consistent with AD. However, it is not
realistic to treat the categories defined by these criteria as complete
diagnoses in their own right. This is in part self-evident from the NIH
terminology, which defines categories only according to the likelihood
of AD. The difficulties are given sharper focus by studies that compare
results of category assignment by NIH criteria with histological results
for patients known to be demented at death. Though about 90 percent of
patients classified as probable AD showed its histological signs, only
about 75 percent of possible AD patients had positive histology. For
patients classified as non-AD, about one-third nevertheless had
histological diagnosis of AD. The puzzle of MCI further complicates
matters because patients fitting this class in which overt dementias is
absent by definition, can indeed show histological signs of AD, and they
go on to clinical diagnosis of AD at a substantial rate. It appears that
each category mapped by the NIH and AAN criteria contains patients in a
variety of states, some with Alzheimer\'s disease at variously advanced
stages, some with AD coexisting with another dementing disorder, and
some without AD at all.

Despite their deficiencies, the clinical criteria have been used
effectively in cohort studies, and they have been used as the best
available endpoint for important therapeutic studies. As insights from
the pathophysiology of AD accumulate, and with the ever-increasing
ability to define and measure molecular features, emphasis has shifted
to the use of biochemical markers, or biomarkers, as our best hope for
diagnosis and perhaps intervention against AD. There is significant
ambiguity as to what constitutes a valid biomarker. Here, we\'re
concerned with diagnostic effectiveness. There is at least one consensus
publication addressing this issue, from a working group convened by the
Ronald and Nancy Reagan Research Institute of the Alzheimer\'s
Association and the National Institute on Aging. Their findings were
that an effective biomarker should detect a fundamental feature of AD
neuropathology, and be validated in neuropathologically confirmed cases,
that it should approach 85 percent sensitivity when compared with
histology, and that it should have a specificity approaching or
exceeding 75 to 85 percent.

OIVD emphasizes the importance of the working performance
characteristics, sensitivity, specificity, positive predictive value,
and negative predictive value more than the pathophysiologic explanatory
power of the biomarker. Still, we retain demonstration of strong
diagnostic performance vetted against the pathologic features of AD as
an essential requirement to establish a diagnostic claim for this
disease. This requirement bears directly on the establishment of safety
and effectiveness for an AD diagnostic test. We recognize that a morning
void urine test for neural thread protein poses no direct risk to the
patient. The remaining important aspect of safety is that reliance on
the test should not put more patients at risk for misdirected management
than benefit from improved management. Making a direct improvement in
the accuracy of AD diagnosis, that is improving the accuracy of
diagnosis through improved sensitivity and specificity of the tests that
underlie them, is a highly desirable outcome. Proof of such performance
might be impractical in many circumstances so long as histological truth
is essential. We note again, however, that establishment of a less
ambitious claim, such as improved efficiency or overall consistency in
application of the current clinical diagnostic criteria might provide a
significant public health benefit. In evaluating such a claim, FDA also
has a keen interest in the reliability with which health care providers
can use the test for the benefit of individual patients.

I\'ll now turn to a brief description of two pre-analytical and
analytical issues that are of concern to FDA from review of the PMA
submission. The first issue concerns the patient dropout rate in the
study due to inability to collect a valid first morning void specimen.
There were 133 patients out of the 366 enrolled who were excluded from
the study for this reason. The protocol\'s procedures for obtaining
urine specimens were suitably detailed, and it appears that multiple
attempts to obtain a valid specimen were made for many of the excluded
patients. Yet, 36 percent of patients could not comply. We cannot know
whether the numerous dropouts imposed a bias either for or against the
agreement of NTP results with the clinical categories. It is plausible
that dropouts were more common with more advanced dementia, and that
advanced dementia might therefore be underrepresented in the submitted
data set, versus the selected intended use population. Altered disease
prevalence would affect the predictive values that are reported by the
sponsor.

The second issue arises from figures on the intra-subject biological
variability of urine NTP results. During our review, we asked the
sponsor to investigate whether the degree of patient hydration affected
urine NTP results. We were concerned that variations in hydration might
produce an extraneous, that is not AD-related, variation in NTP results.
The sponsor replied that hydration issues were of unknown importance,
but that they were adequately and most practically addressed through the
requirement for first morning voided specimens, plus the urine
creatinine check known, or meant, to corroborate first void status. At
the same time, the sponsor provided multiple specimen data for 14
patients, nine of whom had reportable urine NTP results spaced no more
than one month apart. This is a short interval compared to the time
course of AD development. The results for these patients showed
variation averaging 5.3 micrograms per milliliter for the six specimens
in which the change could be fully calculated. The other three patients,
each of whom either overshot 60 micrograms per milliliter or undershot 8
micrograms per milliliter for one specimen, generally showed variations
larger than 5.3 micrograms per milliliter. None of the nine reported
patients had values straddling the 22 micrograms per milliliter cutoff
that divides normal from elevated urine NTP levels. However, several of
the patients had NTP values that were near the cutoff value.

FDA\'s concern is that the degree of intra-patient variability observed
for the small number of patients reported by the sponsor calls into
question the reliability of the urine NTP test for characterization of
individual patients. In this scatter plot furnished by the sponsor,
I\'ve added a bar representing both the intra-run standard deviation of
the assay result for single samples. That\'s 2 to 3 micrograms per
milliliter using in this case 2.5 mics as an estimate. And that\'s the
bar on the left. I\'ve also added a bar representing the average
intra-patient variation using 5 micrograms per milliliter as the
estimate for samples obtained no more than one month apart. For one
quarter, that is 50 out of 200 patients, the urine NTP result reported
for the clinical study was distanced from the cutoff value by no more
than one-half of the average intra-patient variation. We also noted from
the analytical data that the intra-run standard deviations for medium
and low NTP specimens analyzed at the sponsor site were one-half to
one-third of the standard deviations observed at remote sites. The
sponsor\'s intra-run standard deviation was about one-half to
nine-tenths of the remote site\'s SD for high NTP specimens. This raises
an issue of training and experience for new users that might benefit
from attention by the sponsor. No inter-laboratory reproducibility data
have been provided by the sponsor.

We turn now to detailed analysis of the clinical study data provided by
the sponsor with their PMA submission. The study design and data set
were as follows. Nine study centers staffed by specialists in memory
disorders obtained urine specimens and worked up 200 patients according
to NIH and AAN criteria. The FDA expectation and intent according to the
study protocol was that all patients would be undiagnosed and newly
referred for evaluation. During the course of review, it became clear
that patients were enrolled at disparate points in their evaluation and
care. The effect of this patient heterogeneity on the observed
concordances between NTP results and clinical categories remains
undetermined. The same is true for the effect of patient heterogeneity
on characterization of test performance for particular intended use
patients, such as patients first presenting to family practitioners
versus patients much farther along in their diagnostic workup.

This concludes my introductory presentation. We\'ll begin now with Dr.
Kondratovich who will continue with her presentation with the
statistical analysis of the clinical data set.

DR. KONDRATOVICH: Good morning. My name is Marina Kondratovich. I am
statistician from Division of Biostatistics, Center for Devices and
Radiological Health. In my statistical presentation, I will touch some
methodological issues related to diagnostic accuracy of medical test,
report on performance of NTP test only for two categories: probable AD
and definite non-AD, some comment on evaluating test based on chain of
comparisons. Then I will make some statistical interpretation of NTP
test as adjunctive aid and as a stand-alone test. Finally, I make some
comment on selection of cutoff.

Let me consider the basic concept in evaluation of a medical test.
Diagnostic accuracy. What is diagnostic accuracy? Diagnostic accuracy of
a test refers to the ability of a test to identify a target condition,
or another term, condition of interest. Target condition refers to
particular disease, a disease stage, a health status, or to any other
identifiable condition within a patient. Here, target condition is
Alzheimer\'s disease.

In a diagnostic accuracy study, first is the investigation, with results
positive or negative. It\'s applied to represent an example from
intended use population. The obtained results are compared with the
results of the reference gold standard obtained in the same subject. The
reference gold standard is considered to be the best available method
for establishing the presence or absence of the target condition.
Diagnostic accuracy for medical test can be expressed by a
sensitivity-specificity pair, or positive-negative predictive value for
some prevalence.

In this study, the NTP test was compared to the four diagnostic
categories: probable AD, possible AD, mild cognitive impairment, and
definite non-AD, not to the pathological diagnosis. It is well known
that these diagnostic categories have some false positive and false
negative results. Indeed, in paper by Blacker, the following table
provides performance of NIH criteria for Alzheimer\'s disease. I would
like to note, emphasize that these numbers do not present exact
performance of the NINCDS criteria, but give us message that NIH
criteria has some false positive and false negative results. Even for
combined categories probable AD and possible AD, sensitivity is only 81
percent, and specificity 73 percent.

So, the diagnostic categories in the clinical study, probable AD,
possible AD, mild cognitive impairment, definite non-AD, cannot be
considered as the reference gold standard. Because the NTP test was
compared to the four diagnostic categories, not to the reference gold
standard, the diagnostic accuracy of the NTP test was not evaluated in
this study. Therefore, the use of the terms like \"sensitivity,\"
\"specificity\" in this clinical study can be misleading. For this
clinical study, we will use terms like \"positive percent agreement\"
and \"negative percent agreement.\"

The sponsor selected cutoff of 22 units for defining positive NTP
results and negative NTP results. After establishing the cutoff, the
continuous data can be presented by this table with eight numbers. So
this table presents all the data from the clinical study. For every
clinical diagnostic category, what is the percent of NTP positive
results, what is the number of NTP negative results. Performance of the
NTP test is described by the proportion of the NTP positive results
among each clinical diagnostic category. For probable AD, for diagnostic
category probable AD, the percent of the NTP positive result is 89
percent, 51 divided by total number. For possible AD, the percent of the
positive NTP results is 38 percent, 21 divided by the total number of
the subjects in this category. For the category MCI, the percent of the
NTP positive results, 51, even larger than for the possible AD, 22
divided by the total number. And for definite non-AD, the percent of the
positive results, 9 percent, four divided by the total number.

In here in your package you saw the sponsor\'s statistical analysis
which compares NTP values for the patient from the extremes of the NIH
classes, probable AD and definite non-AD, by discarding 50 percent of
intended use population, subjects from possible AD and MCI categories.
It can appear that the percent of the positive NTP results among
probable AD patients, and the percent of negative NTP results among
definite non-AD patients can provide some information about performance
of NTP test with regard to reference gold standard. However, these
estimates are invalid for the following reasons. First, not all probable
AD subjects are subjects with AD-positive pathological diagnosis, and
not all definite non-AD subjects are subjects with negative pathological
diagnosis. Second, probable AD subjects does not present a random sample
of the subjects with AD positive pathological diagnosis, and therefore,
spectrum bias can occur. What does mean spectrum bias? It means that
probable AD patient and definite non-AD patient are more likely to
exclude difficult or complex diagnostic cases for which an unknown
number may have been assigned to possible AD or MCI categories. So
reporting of the NTP test only for two categories, probable AD and
definitely non-AD, may be significantly overstated performance of the
test.

Let me consider another problem. We have reference gold standard G. And
test A was compared to this gold standard, and we now estimate of
diagnostic accuracy of the test A, sensitivity A and specificity A.
Also, we compare test B to the test A, and estimate the measures of
agreement between test A and test B, positive percent agreement and
negative percent agreement. It can appear that the diagnostic accuracy
of the test B accuracy here means relative to the gold standard G can be
sometimes obtained through this chain of comparison.

Let me consider this hypothetical scenario. I would like emphasize that
I use the results from the Blacker paper only to demonstrate the idea.
It\'s not the purpose to feed exactly the data which was in this study
or in the Blacker paper. So, like for example, we have combined category
probable AD and possible AD. And we had 113 subjects. Definite non-AD,
we have 44 subjects. From estimation of positive percent agreement and
negative percent agreement, this is the comparison of the test B. Here
is NTP test B relative to test A. We know that there are number of the
NTP positive subjects 72, and there are number of NTP negative subjects
the same. Because we know negative percent agreement, we know the number
of the NTP positive subjects, and NTP negative subjects for this
category. It is easy to show that based on information about sensitivity
and specificity of the test A \-- here is test A \-- it\'s easy to
obtain that 113 subjects from this category is split in 106 true
AD-positive subjects and 24 true negative subjects. And 44 subjects can
be split in 24 true AD subjects and 20 true AD negative subjects. So,
numbers in the marginal cells, these numbers are known, but there is
uncertainty in the cell values because there are a lot of possible
combinations for these numbers in order to have the same sum in the row
and in the column.

So we can consider, for example, best case scenario and worst case
scenario. We can put numbers, the maximum allowable numbers, in the
correct cells, and obtain sensitivity and specificity, like sensitivity
around 58 percent, specificity 100 percent. Or we can consider worst
case scenario, when we\'re putting the maximum number in their own
cells, out of diagonal. Then sensitivity will be only 50 percent, and
specificity 59 percent. So, even if we know performance of the test A
relative to the gold standard, and performance of the test B relative to
the test A, there a big uncertainty about the performance of test B
relative to the gold standard. So, we really don\'t know what is the
performance of the test B. Here is the test and NTP. Again, I would like
emphasize that this is only example to demonstrate idea, because for
example, we are making assumptions that the performance of NIH criteria
is the same like in the Blacker paper, like in the study which we really
don\'t know. So this is only to demonstrate idea that even if we know
this chain of comparison, it\'s difficult to come back through the chain
of comparison and obtain really diagnostic accuracy of the test B.

Let me consider intended use/indication for use. This is some citation.
\"Results from urine NTP kit are intended for use in conjunction with
current standard diagnostic procedures. Urine NTP measurement can be
used as part of diagnostic risk assessment for presence or absence of
definite non-AD. So, according to indication for use, NTP tests should
be used as adjunctive aid. Here is the table of clinical data. NTP test
as adjunctive aid implies that NTP test can provide additional assurance
that the patient diagnosed to have definite non-AD after undergoing a
standard assessment, does in fact have this diagnosis. The only means of
establishing that is to confirm the diagnosis further by other means.
Note that from this data it is impossible to know whether the patient
with clinical category, for example, definite non-AD and negative NTP
results have a lower probability of definitive AD by histology reference
compared to the patient with clinical category definite non-AD and
positive NTP results. In this study, this information is not available.

Let me consider some example. When a clinical impression is definite
non-AD, how much certainty is added to the diagnosis by negative NTP
results, when the negative NTP results can occur 61 percent of the time
for the patient other than definite non-AD? Should the clinician discard
the clinical diagnosis of definite non-AD if the NTP test is positive?
From the submitted data, it is impossible to evaluate the significance
of this disagreement because there is no comparison to the higher order
standard.

Let me consider another example. When the clinical impression is
probable AD, how much certainty is added by positive NTP results when
clinicians know that the positive NTP results can occur 48 percent of
the time for the subjects with other than probable AD categories? Should
the clinician discard the clinical impression of probable AD if the NTP
test is negative? The significance of this disagreement was not
evaluated, and so information is not available.

Let me consider right now statistical analysis which was presented by
the sponsor, and which you have in your review package. In your review
package, you have two statistical analysis. One statistical analysis was
the group, combined group, probable AD, possible AD, and MCI like one
group, all the subjects considered like one group, versus definite
non-AD. So we can calculate positive percent agreement, and a lot like
sensitivity, it was about 60 percent. And negative percent agreement, a
lot like specificity for definite non-AD. Also, we can calculate
positive and negative predictive value. As was mentioned for calculation
positive and negative predictive value, you can use some kind of Bayes
theorem using prevalence and sensitivity and specificity. But there are
some more easier way to calculate positive and negative predictive
value. By definition, what is the positive predictive value? This is the
probability that the subject belonged to this class, positive class, if
their NTP test is positive. So, we have 98 positive subjects, NTP
results are positive. What is the probability that among these subjects,
really person belongs to this class? You need to divide sum of these
three numbers to 98, and it will be positive predictive value. The same
for the negative predictive value. By definition, definition of the
negative predictive value, this is the probability that the subject
belong to negative class, here\'s our negative class, if the NTP results
are negative. So, 40 divided by 102, because 102, this is the total
number of negative subjects, and 40 subjects really belong to this
negative class.

Prevalence also can be calculated from this table. Prevalence is, for
example, for this class, prevalence for probable AD, possible AD, and
MCI. You need to add these three numbers, and then in order to calculate
percent, divide it by 200. Then it will be 78 percent. Another type of
statistical analysis which you have in your review package was how NTP
tests can distinguish between probable AD, and another group. Group is
like possible AD, MCI, and definite non-AD. For demonstrating
effectiveness of the NTP test, characteristics of NTP performance which
are analog to positive and negative predictive value were compared by
the sponsor to the corresponding prevalence. In this exercise, NTP test
was treated as a stand-alone test. Indeed, if we have in this study that
the prevalence of this class, possible, probable AD, and MCI 78 percent,
prevalence of the definite non-AD 22 percent. Suppose that one decided
to call a patient positive. If I tossed a coin, lands head. And
negative, if I tossed a coin, lands tail. For this test \-- so all this
subject right now has toss of the coin positive. It\'s easy to see that
what is the percent of this class among all these subjects. It\'s easy
to see they\'re the same, 78 percent. Similar, for the subjects which
are negative by the toss of the coin, what is the percent of the
definite non-AD for the subjects which are negative by the toss of the
coin? These all subjects which are negative by the toss of the coin. And
among them percent will be the same like prevalence, 22 percent. So, the
NTP test in sponsor analysis. They named this with NTP test was compared
with the performance of random test, which was named without NTP test.
Random test, it means like toss of the coin, toss of the die. So there
are completely uninformative test. In the sponsor\'s statistical
analysis, NTP test was treated as a stand-alone test in contrast to
adjunctive use, which was proposed by the sponsor in the intended
use/indications for use.

So, let me consider the performance characteristics of the NTP test for
distinction between class probable AD, possible AD, MCI versus definite
non-AD. For NTP test positive, probability that patient belonged to this
class was 95.6 percent, with low bound of 95 percent confidence
interval, 90 percent. For the random test, driven by prevalence, if the
random test is positive then this probability is equal prevalence. So
difference is 17.6 percent, with low bound of 95 percent confidence
interval 12 percent. Ninety minus this. For NTP negative test results,
probability that a patient belonged to definite non-AD was 39.2 percent,
with the low bound of 95 percent confidence interval 30.3 percent. If
the random test is negative, then this is the prevalence, 22 percent.
The difference was 39.2 percent minus 22, 17.2 percent, with the low
bound of 95 percent confidence interval around 8 percent. In sponsor
presentation, you saw relative differences. Relative differences mean
that 17.6 percent were divided by the prevalence, and then you obtain 23
percent. Or you saw relative difference 78 percent, which means that
this difference was considered like what is the percent of this percent
from 22 percent. Then relative difference is 78 percent. In my
presentation, I will use absolute difference, because relative
difference can be some kind of \-- have some ambiguous meaning.

So, let me consider statistical interpretation of the NTP results based
on the sponsor\'s statistical analysis. And I would like again emphasize
that this is the consideration of the NTP test like a stand-alone test.
So, for the NTP results positive, probability that the patient belongs
to the class probable AD, possible AD, and MCI, equals 95.9 percent. So
all this numbers should be added and divided by 98. So it\'s like
absence of definite non-AD. Rule out of definite non-AD. Because with
probability around 96 percent, the patient belonged to the class
probable AD, possible AD, or MCI. There are needs for further diagnostic
workup. Let us consider the NTP negative results. For NTP negative
results, probability of the class possible AD, MCI, and definite non-AD,
equals 94.1 percent. For this, you need to consider added \-- you need
to add all these numbers, divide by 102. So it\'s like absence of
probable AD. I would like to emphasize that absence of probable AD does
not mean presence definite non-AD. Absence of probable AD means presence
of all this class, possible AD, MCI, definite non-AD. Because with
probability at 94 percent the patient belonged to this combined class
where possible AD or MCI are not excluded, the clinical decision is
further diagnostic workup. So, for both outcomes of the NTP test, NTP
positive, NTP negative, the medical decisions are the same. Further
diagnostic workup.

Let me consider also confidence interval for these probabilities,
because confidence interval is very important piece of information for
generalization of the results of the study to the intended use
population. In this study, probability of this class was 95.9 percent,
with low bound of 95 percent confidence interval 90 percent. It means
that if the diagnosis definite non-AD will be ruled out based on NTP
positive results, the incorrect decision will be made up to 10 percent
of the time, 100 minus 90. In this study, probability of the class
possible AD, MCI, definite non-AD, was 94 percent, but 95 percent
confidence interval low bound was 87.8 percent. It means that if
diagnosis probable AD will be ruled out based on the negative NTP
results, the incorrect decision will be made up to 12.2 percent of the
time, 100 minus this percent. Again, I would like to emphasize that for
the negative NTP results, absence of probable AD does not mean presence
of definite non-AD, because probability of definite non-AD if the
subject is negative only 39 percent, 40 divided by 102. Like for
example, probability of possible AD is around 34 percent, even the
subject belongs to all this class. Also, I would like to mention that
the absence of definite non-AD does not mean presence of probable AD.
Absence of definite non-AD means only presence from all this class.

Finally, let me make some \-- a few comments on selection of cutoff. For
obtaining the cutoff will relatively high negative percent agreement, an
analog of specificity, 44 subjects with definite non-AD diagnosis were
used. This is too small a sample to assure a representative sample of
all subjects with definite non-AD. This may lead to biased estimates of
performance. More details about this problem you will see in clinical
presentation by Dr. Ranjit Mani.

The cutoff of 22 units was drawn post hoc from the study itself based on
some criteria of optimality. The sponsor checked cutoff values from 20
units to 30 units. So the current data set was used to find the optimal
cutoff, and then the same data set was used to estimate the performance
of NTP test for this optimal cutoff. It is well known problem of the
training and past in fact. The cutoff of 22 units was not validated on
independent data set. So estimate of performance of NTP test are
overstated to unknown degree. Thank you very much. Clinical issue will
be presented by Dr. Ranjit Mani.

DR. TAYLOR: Dr. Becker? The FDA presentation is scheduled to finish at
12:00. Is that okay?

DR. BECKER: Fine.

DR. MANI: Good morning. My name is Ranjit Mani. I\'m a neurologist and a
medical reviewer in the Division of Neuropharmacological Drug Products
at the Center for Drug Evaluation and Research.

What I would like to try and accomplish in about the next 15 minutes is
to address two questions. The major focus of my presentation will be on
whether the urine NTP test is of clinical value. I will then very
briefly touch upon the question of whether the assignment of study
subjects to the four protocol-designated categories was appropriate. I
will take the liberty of addressing the study data from two
perspectives. The first is that of a medical reviewer at the FDA who has
worked in the Alzheimer\'s disease field for the last eight years,
mainly on clinical drug development, but also to an extent in evaluating
diagnostic tests for that condition. The second is that of a clinical
neurologist who has taken care of patients with dementia for almost
three decades, and continues to do so.

Let us start by looking at this table which summarizes the results of
the key study conducted by the sponsor, and which you have seen before.
If one assumes that the conduct of the study was sound, and the methods
of analysis appropriate, several conclusions are possible from the
results in the table. The vast majority of, but not all subjects in the
probable Alzheimer\'s disease category, had a urine NTP level greater
than 22 micrograms per mL. The vast majority, but not all, vast majority
of but not all subjects in the definite non-Alzheimer\'s disease
category had a urine NTP level equal to or less than 22 micrograms per
mL. However, significant proportions of patients in the possible
Alzheimer\'s disease and mild cognitive impairment categories had urine
NTP levels on both sides of the cutoff, indicating that the test may
have little value in delineating each of those groups separately from
each of the other three groups.

Now, based on the summary data presented in the table, the study results
do not run counter to the sponsor\'s contention contained in the most
recent submission that the clinical study results clearly demonstrate
the ability of NTP measurement to discriminate between probable AD and
definite non-AD, using the device\'s cutoff of 22 micrograms per mL.
However, if one then views the sponsor\'s scatter plot, which you have
already seen repeatedly, and which shows the individual urine NTP levels
in each treatment group, an additional concern arises. A substantial
proportion of the individual values in each treatment group is clustered
relatively close to the cutoff of 22 micrograms per mL, with a range
that is within perhaps 10 points of the cutoff on either side. As Dr.
Becker had indicated earlier, the urine NTP test may have an inherent
biological intra-patient variability extending to 7 or more micrograms
per mL that may largely encompass the clustered scores that I\'ve just
alluded to. Thus the discriminating power of the urine NTP test at a
cutoff of 22 micrograms per mL may be even less sharp than has been
suggested by the first table that I showed you.

If, however, you agree based on the table that I showed you earlier that
the urine NTP test can to a large extent discriminate between those with
probable Alzheimer\'s disease and definite non-Alzheimer\'s disease,
then the question arises as to whether such a test has diagnostic value
in clinical practice. And to explore this question further, it may be
useful yet again to try and understand better what these categories
mean.

First, let\'s address the entity of probable Alzheimer\'s disease. The
NINCDS-ADRDA criteria continue to be perhaps the most widely used
diagnostic criteria for Alzheimer\'s disease. These criteria have the
ability to delineate what is arguably the purest form of Alzheimer\'s
disease that can be diagnosed without obtaining histopathological
confirmation, and the criteria include core elements, supporting
elements, features that are consistent with the diagnosis, and features
that make the diagnosis unlikely, or uncertain. But based on the
criteria that I just showed you, there are three elements to the
diagnosis of probable Alzheimer\'s disease, three key elements: one, the
presence of dementia; two, evidence that cognition has progressively
worsened; and three, the exclusion of brain and systemic diseases other
than Alzheimer\'s disease that could explain the cognitive changes. And
therefore the steps involved in making the diagnosis of probable
Alzheimer\'s disease are generally as follows. Step 1 consists of
confirming the presence of dementia and of progressive worsening of
cognition, and Step 2, excluding other causes of dementia by blood
tests, brain imaging, and other appropriate procedures. And for all
intents and purposes, probable Alzheimer\'s disease is still a diagnosis
of exclusion.

There are several important considerations when one looks at the
relationship of probable Alzheimer\'s disease to possible Alzheimer\'s
disease and mild cognitive impairment. These entities may not be
pathologically distinct. The core pathological elements of Alzheimer\'s
disease are present in a high proportion of those diagnosed with
possible Alzheimer\'s disease, and probably in a high proportion of
those diagnosed to have mild cognitive impairment using the criteria
stipulated in this study. And the majority of those with mild cognitive
impairment so defined may progress to overt Alzheimer\'s disease over a
number of years.

The stepwise assessments used in making a diagnosis of possible
Alzheimer\'s disease and mild cognitive impairment is generally similar
to that used in making a diagnosis of probable Alzheimer\'s disease. And
indeed the treatment of probable Alzheimer\'s disease, possible
Alzheimer\'s disease, and mild cognitive impairment may be similar, now
or at some point in the future. So again, there isn\'t a sharp
distinction between these entities.

Now, let us look at what actual conditions the definite non-Alzheimer\'s
disease category included. The individual diagnosis for each subject in
this broad category was entered in that subject\'s case report form. And
this table is based on those entries. And what this table, which is on
two slides, indicates is that a small majority of individuals in this
category was considered to be normal, and that the remaining individual
entities were each quite uncommon. In fact, if one groups all so-called
psychiatric entities together, there is a total of only 11 such subjects
in this study. Thus, in conclusion, the definite non-Alzheimer\'s
disease category does not represent a single clinical entity, a valid
diagnostic term, or a term that most clinicians would be familiar with.
It is an artificial construct created solely for the purposes of this
study. That category represents a diverse group of separate conditions,
the majority of which are individually only minimally represented in the
study cohort. Many of these conditions are unrelated to each other. In
clinical practice, it is these individual conditions, like
age-associated memory impairment, or depression, or anxiety, that are
usually diagnosed, not definite non-Alzheimer\'s disease. A clinician
would most likely want to make a distinction between Alzheimer\'s
disease and the individual entities in this group, but not between
Alzheimer\'s disease and the broad category of definite non-Alzheimer\'s
disease. And lastly, how much confidence would a clinician have in
making a distinction between probable Alzheimer\'s disease on the one
hand, and age-associated memory impairment, or any psychiatric disorder
on the other, based on the results of a study which had only three
subjects with age-associated memory impairment, and 11 subjects
considered to have any psychiatric disorder.

Now, suppose we still agreed that the study results do help in
discriminating between the probable Alzheimer\'s disease and the
definite non-Alzheimer\'s disease categories. A further question is
whether it is actually common in clinical practice to have difficulty
making a distinction between individuals who conform to the profile for
both these entities. And further, once a diagnosis of probable
Alzheimer\'s disease has been made, does it not by definition indicate
that most, if not all, the entities in the definite non-Alzheimer\'s
disease category should have been excluded, assuming that the criteria
were correctly applied? Both the published literature and personal
experience suggest that once a diagnosis of probable Alzheimer\'s
disease has been made, pathological entities that may still not be
excluded include those shown on this slide, among others. This list is
not all-inclusive, and these conditions include fronto-temporal
dementia, dementia with Lewy bodies, vascular dementia, and normal
pressure hydrocephalus. Some of the entities in this list may indeed
represent mixed forms of dementia, and entities that are controversial.
Importantly, the study results contain no data at all which indicate
that the urine NTP test can help in making these distinctions.

Let us now shift to how the sponsor envisages that the urine NTP test
can be used in practice. And I will be showing you a succession of
statements taken from the most recent submission. Based on these
statements, the test design was anticipated to have potential value in
evaluating patients with cognitive symptoms and signs, including those
suspected of having Alzheimer\'s disease, confirming the presence or
absence of the definite non-Alzheimer\'s disease category, and
distinguishing that category from probable and possible Alzheimer\'s
disease, as well as mild cognitive impairment, helping the medical
professional who makes the initial evaluation, for example, a primary
care physician, decide about the need for proceeding further to
additional diagnostic testing or specialist referral. In other words, a
test that is used early in the diagnostic process. The test is intended
to be used in conjunction with standard diagnostic procedures, and not
as a stand-alone test. Now, let us look at a couple of hypothetical
scenarios in which the test may potentially be applied. These scenarios
have been alluded to earlier, and criticized. There are obviously a
number of other scenarios which could be explored, but I have every
reason to believe that the scenarios that I\'m about to describe are
quite common in clinical practice.

The first scenario is that of a middle-aged man or woman. And my concept
of the term \"middle-aged\" is somewhat different from that of Dr.
Bloch, colored somewhat by my own age. This is an individual who is
about 55 years old, which I think most of you would agree is middle-aged
rather than elderly. Anyway, the first scenario is that of a middle-aged
man or woman who complains of poor memory to a primary care physician.
The history has been unhelpful in making a diagnosis, there is no clear
abnormality on physical and neurological examination in a brief
assessment of the patient\'s mental status. The primary care physician
says the assessment inconclusive. Possible diagnoses that the primary
care physician wishes to consider include early Alzheimer\'s disease or
other type of dementia, age-related symptoms, depression, anxiety, a
busy schedule, etcetera. The urine NTP concentration is equal to or less
than 22 micrograms per mL. Let\'s take 16 micrograms per mL for
simplicity\'s sake. Based on the results of the study, the possibilities
include definite non-Alzheimer\'s disease, possible Alzheimer\'s
disease, and mild cognitive impairment. Probable Alzheimer\'s disease is
unlikely, and the question arises as to whether the urine NTP test will
truly help in deciding whether to proceed to further diagnostic
evaluation, including referral and more testing, in this scenario. Could
a clinician really forgo further testing based on these results? The
same scatter plot that has been shown to you before may help further in
addressing this dilemma with this particular patient\'s results falling
roughly there.

The second scenario is identical to the first until the urine NTP test
is done. The urine NTP concentration is less than 22 micrograms per mL,
let us say 28 micrograms per mL. Based on the results of the study, the
possibilities include probable Alzheimer\'s disease, possible
Alzheimer\'s disease, and mild cognitive impairment. The definite
non-Alzheimer\'s disease appears unlikely. The question therefore again
arises as to whether this urine NTP test would help in deciding whether
to proceed to further diagnostic evaluation, specialist referral,
etcetera. The decision may be somewhat easier than in the first
scenario, again based on the study results. But more importantly how
confident can the primary care physician be that most of the individual
entities in the definite non-Alzheimer\'s disease category have been
excluded when most of these entities are minimally represented? And the
scatter plot, again, shows you roughly where this patient may end up,
somewhere here.

Let\'s now briefly talk about the sponsor\'s view of the limitations of
the urine NTP test. Based on this statement taken from the briefing
document, the sponsor appears to believe that the test is not of value
in diagnosing what are termed rare diseases, mixed pathology states, or
other incompletely understood complex or controversial entities. This
view of the limitations of the test leads to further questions. First,
for instance, how does a medical professional such as a primary care
physician who requests the urine NTP test reliably determine in advance
that the patient has a diagnosis for which the test would not be
appropriate. Secondly, how useful is a diagnostic test that is only
applicable in those instances where a diagnosis is already easy to make,
in other words, in purer forms of the disorder. And it is worth noting
that mixed pathological states and incompletely understood or
controversial entities are not uncommon in a population with dementia or
impaired cognition.

Lastly, I will briefly address the procedures used to assign study
subjects to the four diagnostic categories. It remains somewhat
troubling that many key study assessments that form the basis for
assigning subjects to the respective categories were not performed
concurrent with the study. Some assessments were done as much as three
years prior to study entry, whereas others were done after the study was
completed, and in fact after this application was first formally
submitted. Further, a number of subjects entering the study were not
newly diagnosed, raising a question as to whether the study results are
as a whole applicable to newly diagnosed subjects. In addition, the
methods used by the investigators to make individual diagnoses for
subjects in the definite non-Alzheimer\'s disease category are
unexplained, and we have residual concerns about the adequacy of the
evaluations, and the uniformity of diagnostic methods.

So, in summary, this agency continues to have significant concerns about
the results of the sponsor\'s study. One, were study subjects
credentialed appropriately, and two, is the urine NTP test of clinical
value. Thank you very much.

DR. TAYLOR: You have about five minutes, Dr. Becker.

DR. BECKER: I\'ll conclude today\'s FDA presentations with a summary and
restatement of key points. The urine NTP test is intended for use as an
adjunctive test, adding to the information obtained from other tests
that underlie the NIH and AAN criteria for AD and MCI. In particular,
the sponsor combines the patients who do not fit the definite non-AD
criteria, and claims to distinguish them from definite non-AD patients
with 91 percent specificity. Dr. Kondratovich has demonstrated that a 91
percent negative agreement between NTP results and the NINCDS
classification does not imply 91 percent diagnostic specificity. Indeed,
we do not know the specificity or the sensitivity of the NTP test used
alone, or in combination with clinical criteria for distinguishing
patients who truly have AD from those who do not. The combination might
perform substantially worse than, the same as, or better than the
clinical criteria used alone. We cannot know what the true answer is
without comparing results from the clinical criteria and from the urine
NTP test to a higher standard.

The sponsor asserts that the urine NTP test improves the positive
predictive value and the negative predictive value of patient
classifications compared to the prior probability, the PPV and NPV
characteristics. We note that the prior probability performance accounts
for only the natural distribution of patients across the four classes.
That is, the sponsor\'s comparison treats the urine NTP test as a
stand-alone test, and indeed, as a stand-alone test that is examined for
its ability to emulate the imperfect NIH and AAN criteria, but not
histologic reference criteria. It is a comparison in which the
diagnostician\'s skills in applying the clinical criteria are factored
out of the process. On the contrary, the diagnostician, whether trained
in primary care or a specialty surely brings skills to the process. The
diagnostic efforts of the physician, whether he\'s a primary care or a
specialist physician, are not worthless. We need to know how well the
NTP test complements those skills. FDA seeks the panel\'s opinion as to
how well the data submitted by the sponsor answered this critical
question.

The sponsor highlights comparisons for which we seek the panel\'s
opinion concerning clinical significance. These include distinguishing
definite non-AD from not definite non-AD, and probable AD from not
probable AD. Scenarios have been described already, but this area is
worth another visit. Imagine that a skilled evaluator, using the NIH and
AAN criteria, favors definite non-AD for a patient, and then obtains a
urine NTP test that is negative. Should he conclude that the likelihood
of definite non-AD is now increased? That is, are there test performance
data to support such a view? Furthermore, the clinician knows that a
negative NTP result is certainly consistent with MCI and with possible
AD, two classes that include a substantial number of patients with AD
pathology. Should he alter the course of the patient\'s workup in any
way, given this distribution? Imagine another physician, solidly
convinced of definite non-AD for her patient, who nevertheless sends a
routine urine NTP test, and gets a positive result. Should she consider
this to be a save? Has she avoided a terrible mistake? This would
perhaps be an easy scenario if the physician already had doubts about
the truth of a definite non-AD hunch, since there may be enough
divergence of urine NTP results among MCI patients of justify going
ahead with a workup, whatever the NTP result, when MCI is in the
picture. But this physician was solidly convinced that her patient is
definite non-AD until the urine NTP test came back. Should she now line
up a referral at a regional AD research center? Or should she stand on
her clinical skills and dismiss that pesky lab result? Is the lab result
a signal? Is it a red herring? Does it have any known significance at
all? The answer is we don\'t know.

I\'ll say a few more words about within-patient variation of test
results. We found that 25 percent of the test results can be bracketed
within an interval centered on the cutoff value, and representing a
conservative estimate of the average within-patient test variation. We
recognize that only a small number of patients were multiply tested by
the sponsor. Does the panel believe that the sponsor should pay careful
attention to eliminating or compensating for short-term within-patient
variation of test results?

Lastly, the last topic concerns whether intended uses that do not
require histological validation can be framed for the urine NTP test,
and other AD tests on the horizon. We believe the answer is yes, and
that these uses share some aspects of intended uses that were brought
forward for the PMA under consideration. There might be room, given well
validated IV tests, to improve medical practice, even with the imperfect
clinical diagnostic criteria now in use. One opportunity, as noted by
the sponsor, is in more rapid and appropriate referral of patients from
primary care facilities. Another might be in helping to refine the
appropriate selection of advanced tests by experts. Establishing such
intended uses will require carefully designed studies with well defined
hypotheses and well defined success criteria. We seek the panel\'s
opinion concerning the feasibility of such studies. Thank you.

DR. TAYLOR: Thank you. In view of time constraints, and the FDA has used
up their time commitment, we will break a little early for lunch. We
will give the latitude of a whole extra 15 minutes for the lunch break.
So we will reconvene at 1:00, at which point in time the panel should be
prepared to discuss these issues, and at that point, may refer questions
not only to the FDA, but also to the sponsor. So at this point could we
break? I would remind the panel that these issues are not to be
discussed over the lunch break. Thank you.

(Whereupon, the foregoing matter went off the record at 12:03 p.m. and
went back on the record at 1:04 p.m.).

DR. TAYLOR: Okay. At this point we\'re going to recommence the panel
discussion, and I\'d like to call the meeting back to order, and would
remind public observers of the meeting that while this portion of the
meeting is open to the public, public attendees may not participate
unless specifically requested to do so by the chair.

We did finish the morning session without an opportunity to specifically
question the FDA and their particular presenters as members of the
panel, so I would now invite the panel if they have specific questions
relating to the presentations in the FDA segment to address those
questions now. This is Dr. Duffell.

DR. DUFFELL: Bill Duffell, industry rep. Question is for FDA. I noticed
in the panel material that the product is already in use for
CLIA-approved labs. And I just thought maybe someone from the agency
could kind of explain the significance of our decision today concerning
this product for PMA approval versus its current availability in labs.

DR. TAYLOR: Is that something you can address, Dr. Gutman?

DR. GUTMAN: Yes, that would be appropriate for me to comment on. There
actually are two mechanisms for laboratory tests to enter the U.S.
marketplace. One mechanism is for a sponsor to make a commercial kit or
system, and then to sell it at multiple sites. And in order for that
marketing practice to occur, there are requirements for FDA premarket
review, and there are requirements for companies to follow quality
system regs and reporting requirements.

There is, however, an alternative mechanism to enter the marketplace.
Individual labs do have the opportunity to create what are called
in-house or home-brewed tests, or laboratory testing services. There is
actually regulation for those. That is under CLIA. It\'s a very
different regulatory construct than FDA. That would be an operation at a
single site so that you couldn\'t export the test to multiple sites,
although you would be allowed to obtain samples from multiple sites. So
samples can flow to the lab. The CLIA certification can be direct
through CLIA or through one of the dean status inspection groups like
the College of American Pathologists that operates on CLIA\'s behalf.
And there are differences in that CLIA is looking at analytical
performance and the quality of the lab system, and as you would gather
from FDA\'s review, we\'re looking at analytical performance and
clinical performance. CLIA tends to have a more systemic approach, and
FDA takes a more device-specific approach. So there are differences. The
company, as I understand it, and they can comment if I\'ve got this
wrong, is a CLIA certified lab and so it is permitted to market at this
current time their high complexity CLIA lab. The FDA approval would
allow them to export that product to other labs for use at other sites.

DR. TAYLOR: Is that helpful, Dr. Duffell? Any comment from the sponsor?
Okay. Any other questions regarding the presentation this morning? Panel
members?

DR. GOLLIN: I have a question. Do you have a question?

DR. LICHTOR: Oh yes, actually I do have a question.

DR. TAYLOR: Addressed to?

DR. LICHTOR: To the sponsors.

DR. TAYLOR: Okay. I\'ll deal with the FDA questions first, and then
we\'ll come back to the sponsor questions. Any other questions for the
FDA? I would like to remind the panel that we\'re now going to have a
discussion concerning the data, the presentation that we\'ve heard from
both the sponsor, and from the FDA, and the information that we received
in our packets relating to this meeting.

Any member of the panel can address questions then from this point for
about the next hour or as long as it takes to the sponsor, or to the
FDA. When we\'ve had this general discussion, there are some particular
FDA-related questions that have been addressed to the sponsor, and we
will then address those as a panel one by one. There will then be a
second opportunity for the public to ask questions, a second open public
hearing, and then we will finish with summations from the FDA and from
the sponsor. The panel will then conclude their deliberations by voting
on the recommendation that the panel wishes to make to the FDA
concerning this PMA. So members of the panel, do you have any comments
or questions for either the sponsor now or for the FDA? I know you do,
Dr. Lichtor.

DR. LICHTOR: Okay, I\'m Terry Lichtor and I\'m a neurosurgeon, but I was
curious if the sponsors have any data regarding what stage of
Alzheimer\'s disease the NTP becomes positive? Is it something that is
early on, or something \-- a late sort of conversion, and in particular,
has any work been done in animal models such as like transgenic mice.
And the main reason why I ask that is because, having done some work
with them, they get human basic Alzheimer\'s disease at a very precise
time, so you could sort of ask the question when in that time course
does it become positive.

DR. AVERBACK: This is Paul Averback. Those are both very good questions,
and I could answer them in 97 hours, or I\'ll try to do it in under a
minute. Your second question is particularly fascinating because there
is a genetic transfer model for NTP in the mouse. You won\'t find it in
the peer review, but it is in the patent literature, and it\'s a
fascinating findings because these mice get amyloid and phosphorylated
tau accumulations, and they lose a lot of cells, and they act funny. And
we\'re extremely excited about this, because it\'s a wonderful model for
looking for therapeutics.

As far as evolution over time, multiple time-point samples is
problematic. There does seem to be a trend over time, but it\'s not \--
we don\'t have enough data to be definitive on that. But it does remind
me that I should answer something that was stated this morning about
these variabilities of multiple time-point samples. And the agency put
up a slide of our multiple time-point samples and pointed out some
coefficients, the variation, etcetera. What they didn\'t point out, and
I think is extremely exciting, is that out of these 14 cases, and they
had tests at one month, three months, and up to two years, not a single
case went from positive to negative, or from negative to positive. So on
a science test, this is phenomenal. And if you look at the tests we all
use, like the article in the New England Journal of Medicine last year
about PSA. I know it\'s not the greatest test, but PSA, 50 percent of
them flip-flop after three months. So to talk about standard deviations
is one thing, but biological, none of these cases have changed over.
There was one case in the table that actually went from normal to
elevated, and in fact this patient had gone from clinically normal to
become AD.

DR. TAYLOR: Does that answer your question, Dr. Lichtor? Dr. Nath?

DR. NATH: I have a couple of questions.

DR. TAYLOR: Okay, state your name again, please, for the record?

DR. NATH: Avi Nath. And one is that I noticed that the concentrations of
NTP in the urine were in microgram quantities, and while the data for
one of your publications on cerebral spinal fluid is in nanograms per
mL. And so I was wondering why does it get so concentrated in the urine
if this is a brain-derived protein, or is it coming from other organ
systems? And is there a correlation between CSF blood and the urine
levels in single individuals?

DR. AVERBACK: Also a very good question. The nanograms per mL was based
on a sandwich ELISA that used monoclonal antibodies. The current assay
is a different format, and it is much more sensitive. And this is not
unusual. As better tools are developed, we find that there\'s more
signal.

DR. NATH: So would you revise the CSF then to say if you were to use a
different assay system, would it be micrograms instead of nanograms?

DR. AVERBACK: No. The CSF data was done with previous generation tests.

DR. NATH: No, the question was then why is the concentration so low in
the CSF compared to urine. And does the high concentration in the urine
reflect that maybe the protein is coming from non-CNS organs. Maybe
it\'s coming from some other place.

DR. AVERBACK: No, excuse me. The standard that was used to quantify it
in the older work was based on recombinant protein estimates of
quantity. Whereas we have a different assay now that uses a synthetic
standard and has \-- it\'s a totally different system, so it detects
more. I\'m not saying that the signal is necessarily different. We
don\'t use this format on CSF.

DR. NATH: If it\'s a brain-derived protein, and it goes into the CSF,
you say it gets diluted there. If it goes into the plasma from the
brain, from CSF to plasma, then it would get further diluted, right?

DR. AVERBACK: Not necessarily. A lot of analytes concentrate in urine.
There are many analytes \--

DR. NATH: That\'s the question. So you think it\'s getting concentrated,
and it is brain-derived, it\'s not coming from some other organ.

DR. AVERBACK: There\'s no evidence that it\'s coming from any other
organ. There was a lot of work done on that.

DR. TAYLOR: Dr. Averback, if you could remain, I have a couple of
questions that are a little bit on the same theme. This is Dr. Taylor.
The biological variability data that the FDA showed, the 14 patients.
There was a little bit of variation, and it was two days to one month
was that interval. Do you have any data showing repeating the assay on
the same patient within a few days as to whether there\'s any short-term
variation?

DR. AVERBACK: Well, we don\'t have within-day because we used first
warning. And we\'ve done some preliminary work with consecutive days.
But it wasn\'t done as a specific study. These are real examples that we
have.

DR. TAYLOR: Okay, so let me extend the question from there to analytical
variability. From reading the study, all of the assays were referred to
the central lab, which I assume is the same lab that\'s done the 1,500
specimens under CLIA specification. Is that correct?

DR. AVERBACK: Yes.

DR. TAYLOR: And so all the data is in one lab. I\'m not sure, are there
data as to reliability, or reproducibility of performance of this assay
in other labs, or in other hands?

DR. AVERBACK: Yes, there is. In our briefing document there will be a
summary there of the precision study that was done at four sites.

DR. TAYLOR: Okay. The FDA gave a table saying that there was an \-- in
trial run variation of two to three micrograms in other hands for NTP
measurements using different assays, I guess. And within your hands, in
your CLIA lab, the variation, or the SD was one microgram. Does that
reflect the data?

DR. AVERBACK: I\'d have to ask my \-- is that correct?

DR. LEVY: Yes, it was correct. My name is Dr. Levy. It was correct.

DR. TAYLOR: Okay. So my question then extends to the labeling that you
have for your test. It\'s an ELISA test based upon an alkaline
phosphatase color intensity, optical density measurement, right?

DR. AVERBACK: Yes.

DR. TAYLOR: And so you\'re running controls, and you\'re running
standards. From looking at your labeling, there\'s a little bit latitude
allowed in terms of optical density measurement for the standard or the
control to qualify as a valid control or standard. And that\'s fine,
because that\'s the way optical density works. But that\'s going to
affect your standard curve. And what I really want to know is if you run
the same specimen these, four, five times, then, one, what sort of
variation do you see in the standards when you run it five times, and
then what sort of variation do you see in the actual result if you run
it four or five times.

DR. AVERBACK: Yes, we have done these studies. It\'s extremely low
variation. I can\'t quote the exact number, but I can run upstairs and
get it for you.

DR. TAYLOR: Is that where the one microgram SD number comes from?

DR. LEVY: The one microgram \-- comes from running twenty times the same
specimen for five days in terms of \--

DR. TAYLOR: Okay.

DR. LEVY: So you have many data points.

DR. TAYLOR: Okay, good, that\'s the sort of answer I was looking for.
Thank you.

DR. LEVY: Yes. And that was giving you the total \-- variation.

DR. TAYLOR: Fine. So the 22 microgram cutoff level, the concern that
that still raises that I think you should have an opportunity to
address, when you look at your scatter gram plot of where the values
fall in relationship to the 22 number, if it\'s a one microgram
variation and it goes from 22 to 23, or from 22 to 21, that actually
makes a fairly major change in the numbers that are called positive or
negative with regard to the threshold. And I\'m a little concerned, and
I\'d like to give you chance to address how that\'s dealt with, or what
data you have concerning that. For example, the changes, and I apologize
that I\'ve done this off the top of my head so it\'s not \-- I don\'t
claim any statistical validity to this, and I hope no one gets up and
has a go at me for it. But if you change this, if you, for example, if
it just goes up one microgram, and the cutoff then is 23 instead of 22,
you in fact change the number of probable cases from positive \-- from
51 down to 44. That\'s in the probable AD category. And likewise, if you
take the converse of that and drop the number down to 21 as being the
positive, then your definite non-ADs change from 40 to about 30. And
that of course changes the specificity, the sensitivity, the predictive
value, and everything else. So I\'d just like to have you respond to
that, and how you think that that can be dealt with.

DR. AVERBACK: I think that\'s a very legitimate and good question. We
have several answers to that. ROC curves compare sensitivity and
specificity, and the area under the curve no matter how you look at this
is extremely high. I won\'t run through too many slides of that, but in
our submission we took cutoffs everywhere from 20, 22, 25, 30. No matter
where you put the cutoff, you\'re still going to get the same
neighborhood of results. And in the CLIA lab, our cutoff has been in the
same zone for several years. And I can sense that there might be some
insinuation that if you just kind of move these dots a little bit this
way or that way, the relationship would go away, but no matter where you
draw the line there, you still see the same relationship, within orders
of magnitude that is to say. So we have at least one slide. We\'ll call
it up shortly.

DR. TAYLOR: Sure, please.

DR. AVERBACK: I apologize for the delay. Here\'s the \-- this is the
scatter plot I was referring to. So here\'s the cutoff at 25. And it
really doesn\'t seriously impact the relationships we\'ve been
describing.

DR. TAYLOR: Well, it actually does move a lot of probable AD cases
though below the line, that were above the line before.

DR. AVERBACK: To some extent. I mean, there\'s no denying that there are
cases that cluster, like in any scatter plot, but again, I just say the
ROC curve is so right angled that it\'s \-- you\'re getting a gain in
the specificity. Because there\'s only \-- before there were four points
above the cutoff on the definite non-AD, now there\'s three. That\'s a
gain of 25 percent. So you\'d have to do a lot of dots on there on the
left to make 25 percent.

DR. TAYLOR: Now, I understand you would, but on the left, that\'s the
probable AD column. You\'ve gone from six to 20 below the line.

DR. AVERBACK: Six to 20?

DR. TAYLOR: Well, from numbers of six that were below the line when it
was 22, to maybe 20 dots below the line now it\'s 25. On the left-hand
column.

DR. AVERBACK: Well, I mean those are values near the cutoff.

DR. TAYLOR: Yes.

DR. AVERBACK: This is not a stand-alone test. We do not say to make a
decision based on that cutoff. We\'re showing that it has useful
information because it closely agrees with diagnosis. But it\'s not a
cutoff that you use to say ?I\'m going to start a drug\' or ?I\'m going
to do some surgery\' or anything like that.

DR. TAYLOR: Point taken, that\'s why I asked the question as to what \--
how accurate that one microgram variation was. And I received a
satisfactory answer to that, so thank you. Anyone else have questions?
Yes, Dr. Blumenstein.

DR. BLUMENSTEIN: What was the planned size of the study that has been
presented to us today?

DR. AVERBACK: The plan was to have 350 patients who would be initially
eligible, and we expected to get to 200. And the study was closed when
we got to 200 that fulfilled inclusion criteria. And \-- go ahead.

DR. BLUMENSTEIN: I have a protocol here, but I don\'t find anything
about that.

DR. AVERBACK: It\'s in the pre-IDE document.

DR. BLUMENSTEIN: Is there also a statistical analysis plan that was
created at that time?

DR. AVERBACK: Yes.

DR. BLUMENSTEIN: Do you have other ongoing clinical studies at this
moment?

DR. AVERBACK: For this marker?

DR. BLUMENSTEIN: Yes.

DR. AVERBACK: Other ongoing studies. Not of this variety.

DR. BLUMENSTEIN: Which variety?

DR. AVERBACK: Not of a prospective, multi-center, multi-year category.

DR. BLUMENSTEIN: Do you have an autopsy study ongoing?

DR. AVERBACK: We try to follow up every case that we can that \-- every
case that comes to the reference lab is followed up. We do follow-up
periodically with every single case. So we have these 1,500 approximate
cases. Anytime we can do follow-up we do. We contact the doctors as
often as we can.

DR. BLUMENSTEIN: Do you have any results from that?

DR. AVERBACK: Yes. We published one study of that sort a few years ago.
And it had excellent agreement.

DR. BLUMENSTEIN: With autopsy diagnosis of Alzheimer\'s?

DR. AVERBACK: No, with follow-up. Follow-up. Autopsy for these cases,
it\'s 10 to 20 years. Because these are newly presenting cases in the
realistic scenario. These are not institutionalized. It\'s real
patients. Most of these cases were ambulatory.

DR. BLUMENSTEIN: Have you pursued any patients who might be closer to
death in testing and so on?

DR. AVERBACK: Yes, our earlier studies were on different types of
populations, institutionalized ones. We have lots of data from
late-stage Alzheimer\'s.

DR. BLUMENSTEIN: Thank you.

DR. AVERBACK: If I may, on the same topic, because it brings up a
question that we didn\'t get a chance to respond to this morning, and I
wouldn\'t want to let this issue just pass. There was some criticism, or
shall we say maybe query about why we only had 200, why were there 166
people that didn\'t qualify. And this is a very legitimate question, and
a very good question. Why is that, because that does superficially seem
to be quite a large dropout, doesn\'t it? But I know that some of the
panel members who work with demented patients will know that in clinical
trials with demented patients, it\'s not easy to get a first morning
urine sample. And in fact it\'s a lot harder than it might look. These
are people who are not perfectly in control of their lives, and they\'re
forgetful, and for many reasons as is well known to people in the field,
it\'s hard to get good compliance from them. So 166 dropouts, while it
may seem a little funny, is absolutely typical for a study like this.

DR. BLUMENSTEIN: I\'d like to ask a follow-up to that. That implies that
maybe the dropout is greater in some categories than others?

DR. AVERBACK: Do you have a slide for that Jack, on the dropout cases?
It will take awhile to pull it up. There didn\'t seem to be any
differences in those populations with the available data. We did analyze
them.

DR. NATH: While he\'s pulling up the slide, along the same lines, I mean
your definite non-AD patients or almost half of them were normals. So
did you have problems in normals also getting the morning urine sample?

DR. AVERBACK: No, the dropouts weren\'t \-- they were the more demented.

DR. NATH: They were only in the ?.

DR. AVERBACK: I wouldn\'t say only. I\'d have to look. But for the most
part. And it was more predominant in females, as you would expect also.

DR. TAYLOR: Okay, the chart\'s up now.

DR. AVERBACK: No, that\'s not the one.

DR. TAYLOR: No?

DR. AVERBACK: Okay, no. Sorry, we don\'t have the slide.

DR. TAYLOR: Okay. Dr. Gollin has a question.

DR. GOLLIN: Yes. It\'s on the same subject. So you say in the clinical
trial that they should not void for six hours before the early morning
urine for the test. But this doesn\'t seem to be stated in the labeling.
And so I was wondering about that.

And second, in your clinical trial, as you said, about a third of the
specimens were excluded because of an unacceptable urine specimen. And
clearly, as people get older, they have to go to the bathroom during the
night. And so how feasible will this test be if patients have to submit
three or four specimens before they can be tested, or if some patients
just cannot comply?

DR. AVERBACK: Those are both good points. It\'s a fact of life. You\'re
absolutely right. I can\'t argue with you on that. I would add one
comment to that, and this was data that was filed with FDA in I think
2001. There is a difference between people in the trial, and people in
the community who actually want the test. In our own reference lab, with
people who want to have the results and do the test, our own statistics
were that we eventually could get a sample in over 90 percent of people
when they were motivated. In the trial, it was not the same motivation.

DR. GOLLIN: Could I ask another question, please?

DR. TAYLOR: Go ahead.

DR. GOLLIN: Okay, I have another question. You say that there\'s no
downside to the test. Does not positive result on the test raise concern
or perhaps label somebody as probable AD? And might a false positive be
deleterious to a non-AD individual? I know it\'s an adjunctive test, but
still, might this label someone? In the real world. Not in a control
trial.

DR. AVERBACK: Very good question, and also, we prefer to say conjunctive
test. I know \"adjunctive\" has been floating around, but it\'s \-- if
you go, I mean I worked in the emergency room for 30 years. I\'ve seen
people come in who swallow bottles of pills, and swallow bottles of
antifreeze, and they do funny things. The label says don\'t do that, and
they do it. If a doctor is irresponsible, and doesn\'t follow the
labeling, there\'s only so much we can do. But we are very motivated to
make sure that whatever labeling is as tight as possible. And the
language that we always like best includes very standard statements that
it\'s always the doctor\'s decision based on all the clinical
information. So you\'ve pointed out a phenomenon that\'s unavoidable for
any product if it\'s misused.

DR. TAYLOR: Are there further questions? Dr. Parisi, Dr. Nath.

DR. PARISI: I was curious if you could tell us a little bit more about
this protein. You know, it sounds like it\'s related to neurons
obviously. It\'s deposited in the neuronal cell body, and in the
threads. And it seems to be, certainly the early literature suggests
that it\'s higher in CSF \-- in presumably Alzheimer\'s patients. But
could you tell us a little bit about the processing of the protein? Is
that known, or the sequencing? Is the sequence of what\'s in the urine
identical to what you\'ve isolated later from the brain? Have those kind
of studies been done?

DR. AVERBACK: Yes. More good questions. The urine protein has been
identified immunologically to be identical, at least in immunological
terms, with the brain studies using the same monoclonal antibodies on
urine blots and urine gels and this sort of things. In terms of the
sequence, the putative sequence is published in the Journal of Clinical
Investigation. It\'s in the briefing document. And a lot of work has
been done on different epitopes and peritopes, and with analysis using
subsequences. And a lot is known. But not, to answer I think your second
or your third question there, the exact intracellular pathway is not
known. But a lot of information is known. It seems to be very intimately
tied into the insulin-signaling pathway, and you can take the NTP gene
and put it into neuronal cells and culture. And a huge amount of work
has been done on that. And the apoptosis related markers all shoot up.
The neurons sprout, and I mentioned the genetic transfer experiments.
And it seems to be related to apoptotic pathways with insulin receptors,
and there is a relation to oxidative damage as well.

DR. TAYLOR: Dr. Nath?

DR. NATH: Yes, so I have two questions. One is a biochemical question,
and then a clinical one. So if you could just clarify for me the
biochemical nature of this protein with regards to two things. One is,
so you said you immunologically characterized it, but have you ever
sequenced that 41 Kilodalton protein just off of a gel through internal
sequencing, or peptic digest to see if that truly is the same protein
that you have the CDNA sequence on?

DR. AVERBACK: Have we sequenced the actual protein, isolated and
purified from urine?

DR. NATH: Yes.

DR. AVERBACK: No.

DR. NATH: The 41 Kilodalton protein. From anywhere I guess.

DR. AVERBACK: No. The work has been done on the messenger RNA, and then
the CDNA, and then the recombinant protein. And then there have been
probes made to each of these. And then different protocols have been
done to make fractions that are done on gels like you say, and labeled
in different ways.

DR. NATH: Okay. Then a related question was, and if you could clarify
for me, I was just trying to figure out, I don\'t follow this literature
that closely, but from your paper in JNEN which was 1996, there were
several different forms of this protein that you characterized. I think
four different forms. And then here it says that the 21 Kilodalton NTP
species is of particular interest because it is over-expressed and
accumulated in brains with Alzheimer\'s disease. But then subsequent
publications all relate to the 41 Kilodalton protein. So could you
explain those differences to me?

DR. AVERBACK: Yes. First of all, as much as I\'d like to claim
authorship of that paper, I can\'t. So when you say it\'s our paper,
these are researchers at Harvard. And they\'re extremely careful. They
have usually about a five-year lag from when they do the work to when
they submit it for publication, which sometimes frustrates us, but it
also reassures us. At the time, they had information based on gels where
there were different bands. And it appears that the 21 kD is just part
of the larger molecule. The larger molecule is based on the actual MRNA
derived from the actual brain, whereas the earlier work, the \'96 work
that you\'re quoting was using antibodies as reagents.

DR. NATH: So is that a cleavage product of the 41 Kilodalton?

DR. AVERBACK: Believed to be, yes.

DR. NATH: I see.

DR. AVERBACK: At one time it was thought to be a dimer, but cleavage is
a better way to say it.

DR. NATH: And then the clinical question I had was that you had MRI
scans on some of these patients, maybe not all, and certainly some of
those cases that were presented earlier it did appear like there was
some kind of correlation between the urine testing and the MRI findings
for atrophy. I was wondering if you have analyzed this clinical trial
for whatever scans you have available to see if there is any correlation
between MRI findings and the levels of NTP?

DR. AVERBACK: Well, the MRI findings in this trial have been a long and
winding road. We\'ve looked at them quite extensively. The problem is
that they were read independently by different radiologists at different
sites, and that\'s \-- I mean, studies often allow for that, and
sometimes they don\'t. It depends how rigorous the study is for the MRI.
We didn\'t seem to see the best of agreements, and I\'m not criticizing
MRI. Far be it from me to do that. As you know, structural imaging in AD
diagnosis supposedly, according to convention, is to identify other
lesions, such as subdural, or tumor. And the relations, I\'m sure you
know as well as anybody. If you look through the literature, the
correlations between them in all different types of parameters, be it
neuropathology, or be it clinical features, there is a wide swing in it.
But to answer your question, yes we\'ve looked at them. It\'s not really
that good. We did find other subsets of that that are of interest, but I
don\'t want to go too far into that now.

DR. PARISI: There actually are \--

DR. TAYLOR: This is Dr. Parisi.

DR. PARISI: Parisi. There are several studies that show relatively
selective loss of hippocampal volume. And that\'s been shown in some
studies actually to correlate quite well. I was curious, did you find
infarcts? I mean, this is an elderly population. I was surprised at one
of the comments in your report that said there was nothing added by the
MR scans. And at least our experience is that these are oftentimes mixed
pathologies, and small infarcts are very, very common, or severe white
matter disease, for example, is a very prevalent finding in these
elderly patients. Just curious about your experience.

DR. AVERBACK: Yes, I agree with you. In fact, I used to work with Leslie
Iverson who was in the OPTIMA Group, who were the first to actually do
the serial hippocampal measurements at Oxford with David Smith. We have
in our possible AD group, and it\'s not a large enough group to be
dogmatic about it, so we haven\'t made it part of our formal
presentation, but in the possible AD group, if you dichotomize them
according to NTP elevated or NTP normal, on a 2 x 2, versus vascular
lesions reported by the radiologist or no vascular lesions reported,
there\'s quite a good relationship. The NTP negative possible ADs have a
lot more vascular changes. That\'s one thing that we found. It\'s
retrospective, it wasn\'t prospective, and I wouldn\'t proffer it as
reality, but it\'s extremely intriguing.

DR. TAYLOR: Okay. Dr. Blumenstein, Dr. Lopez, any other questions at
this point?

DR. LOPEZ: Yes, a question for Dr. Kondratovich.

DR. TAYLOR: Dr. Lopez.

DR. LOPEZ: If you can go back to explain why this study design does not
support the claim that this is an adjunctive test.

DR. KONDRATOVICH: Because we need to show that there are additional
information which are related to the test which already performed, NIH
criteria. You apply another test, and there are additional information
in this test. So you need to have some kind of like high order standard
in order to understand do you really add more information, because if
there are disagreement, then there is not any resolving of this
disagreement, because we have only NIH criteria and NTP test. And also
some examples I give. So like adjunctive test. If you already know NIH
criteria of categorization, and then you add NTP test, you cannot
evaluate performance of that combination because by definition this
combination should increase, for example, sensitivity, and there are no
big loss in specificity \-- or that improvement in specificity, there
are no big loss in sensitivity. But in order to do this, we need to have
high order references, high order standard. And this data is not
available.

DR. TAYLOR: Yes, please. Would you like to respond? Absolutely. Please,
again give your name.

DR. BLOCH: I\'m Dan Bloch, and I\'d like to respond. Keep my thoughts
straight here. First, it\'s a misconception that this is an adjunctive
test in the sense that there\'s a step-up procedure here where there\'s
a hierarchy of things that are done, first, the classical workup, and
then only after that is NTP applied. That\'s not the case. It\'s an aid
at the same time with everything else that\'s being done. Remember, the
claim here is in the primary care setting. The specialist hasn\'t come
into play yet. This is an aid among other things that are done
concurrently. That\'s one thing.

A second thing is if it were, and it\'s not, but there are examples,
many of them medicine, where the true positives are a two-stage process,
where you first apply something, and then you see if in addition an
independent thing is also positive. Then if the two are positive, this
is super super diagnostic plus. And you have four possibilities, both of
the methods are plus, one\'s plus, one\'s minus, the other way one
minus, one plus, and both are negative, with both negative being
super-negative. Those would be the proper statistics in the scenario
that you just heard from the FDA statistician. We did not \-- this is
clearly not that kind of a statistical workup. Our statistics were
totally inappropriate for the kind of uses that she\'s described. So
again, I just want to make it really clear that in our intended use,
this is an aid, and it\'s not intended to be used only after another
diagnosis is made.

DR. TAYLOR: Okay, thank you. Dr. Becker, did you wish to comment?

DR. BECKER: My name\'s Bob Becker. The term \"adjunctive\" does appear
in parts of the labeling, although we can go back and forth as to
exactly whether that\'s the only way in which the test would be used.
The central feature is that new information is to be contributed. And
there needs to be a manner by which the presence of that new information
can be ascertained. The only way that we are aware of by which that can
be accomplished is by having an external standard of some kind that this
information brings you closer to than does the workup without the
information that the test putatively provides.

DR. TAYLOR: Thank you. You may respond again.

DR. BLOCH: You know, what additional information is \--

DR. TAYLOR: Name again for the record.

DR. BLOCH: I\'m sorry, my name is Dan Bloch again. I\'m the consulting
statistician for Nymox from Stanford.

Again, the question is, as I understand it from the FDA, and the way
they\'re posing it is saying you must have an external standard, or some
other kind of standard to judge this. Because what is the added gain
that you get from this. And I would remind you that, and you know this,
is that without NTP, in the primary care setting, the primary care
physician will be correct 15 to 25 percent of the time. That\'s their
sensitivity. With NTP positive, their sensitivity will be increased to
60 percent. Now, those are just numbers, those are statistics, but they
have meaning. And this is actually part of the data. To have a different
gold standard, a higher standard based on autopsy is clearly not \-- I
mean, I don\'t know how to answer that. The higher standard, if it\'s
going to be based on pathology means you have to kill early onset
patients. Or you follow them for 30 years. That\'s clearly not \-- if
you asked for that you will never have anybody \-- you will never get
the diagnostic set for early Alzheimer\'s, if it has to be based on
pathology. So I don\'t understand that posture.

DR. TAYLOR: Did you have a question, Dr. Parisi?

DR. PARISI: This is Joe Parisi. I beg to differ with that. Many patients
die in MCI and early AD. I mean, we have a large base of pathologic
specimens from those patients.

DR. BLOCH: In our sample of 200 patients, two have died, and have been
autopsied. Both were NTP positive, and both had definite AD. So, from
the autopsy experience that we actually do have from those that were
followed, we have 100 percent accuracy with the NTP.

DR. LOPEZ: I have one last question.

DR. TAYLOR: Dr. Lopez.

DR. LOPEZ: If you compare the possibles with the non-AD, what\'s the
sensitivity and the specificity?

DR. BLOCH: I did not. This is background. The consulting statistician to
Nymox was John Kennedy, a Ph.D. statistician, well known, and was in
practice for himself. He died of a heart attack earlier this year. Three
or four months ago Nymox asked if I could consult for them. I have not
performed any of the analysis, with one exception, and that was at the
FDA\'s request. We performed a bootstrap analysis to validate that the
cutoff of 22 did not introduce bias. And the bias corrected an
accelerated estimate, and I think statisticians here would understand
this, showed that the bias of using the cutoff from the sample that we
derived it from was about 1 percent for all performance characteristics.
In other words, there was no bias that was introduced. I\'m saying this
because, again, in the earlier presentation, it sounded as if we just
simply derived the value from the data that was obtained, and then we
optimized things. But the FDA actually asked us directly to do a
bootstrap analysis, to do a bias correction, which we did do, and it
showed no bias. That\'s the whole story.

DR. TAYLOR: Any other questions from the panel? Mrs. Butcher has a
question. Okay, please respond and then we\'ll come to Mrs. Butcher.
Please. Again give your name.

DR. KONDRATOVICH: I would like to make comment about bootstrap analysis.
We ask sponsor maybe sponsor can apply bootstrap analysis in order to
correct biases which usually can be seen if you use the same training
set for, like testing set. A bootstrap analysis conducted by the sponsor
was absolutely irrelevant. It was more for evaluation of confidence
interval for proportion, which can be obtained by standard software like
StatExact. So bootstrap does not have any relationship with really some
kind of statistical procedures like with one method or bootstrap 0.632
plus. But I don\'t like to put some technical details. And also, all
this bootstrap approaches, it\'s not completely recognized in
statistical community. Usually, independent data set required to
validate cutoff. So sponsor bootstrap was absolutely different entity
about the confidence interval for the usual binomial proportion, how to
calculate confidence intervals for positive and negative predictive
value.

DR. TAYLOR: Thank you. Mrs. Butcher had a question.

MS. BUTCHER: Thank you. I guess my concern, or what comes to my mind as
a consumer is since the FDA has been integrally involved with this study
from the beginning, and now we\'re at the end, and we\'re asking do we
\-- does this study add additional information, could that not have been
presented in the beginning of the study, and had the extra standard
applied in the beginning of the study, or the design made around having
the higher standard, or a different standard. And as a consumer, I come
to the table and say does it help. Does it serve a purpose. And it
appears from listening that a primary care physician would have a
patient present, do this test, and then it would help in that scenario.
And if that\'s the early diagnosis, or the early look that we\'re having
at the AD, then it appears to help. So my question is if the FDA, or
since the FDA has been involved from the beginning, and now we\'re
looking at a requirement for an extra standard, or does this test add
additional information, how could that not have been put into the mix in
the very, very beginning?

DR. TAYLOR: I assume you\'re addressing that question to the FDA?

MS. BUTCHER: Yes, I am.

DR. TAYLOR: So I think Dr. Gutman you are on the hot seat.

DR. GUTMAN: It\'s okay. The company\'s correct, there were very complex
negotiations. They were nuanced. There was some congruence between what
they wanted and what we wanted. There have been changes in the intended
use that have complicated the use of the gold standard. We do think for
this particular claim that we\'ve arrived at at the end it exactly
captures, and your challenge is to decide how it captures, or whether it
captures, it captures Dr. Becker\'s concern about whether for the claim
on the table you have enough insight based on the study that was done to
convince that there is this incremental value. The claim is a little bit
different than the claim that we started with. The clinical studies are
not actually congruent from the starting point in the original pre-IDE,
so there was some drift, and some changes, and some changes in data
collection, some changes in intended use that I think have made this a
\-- let\'s say a colorful journey.

DR. TAYLOR: Does that answer your question, Mrs. Butcher?

MS. BUTCHER: Yes. I would like to follow up with another question for
the sponsor.

DR. TAYLOR: Please follow up.

MS. BUTCHER: And that is dealing with the diversity of the sample, and
the people that were involved in the study, very small numbers of other
than white people, very small numbers of African-Americans, Native
Indians. Has there been any distinction in response for the diverse
population?

DR. TAYLOR: This would be for someone from Nymox.

MS. BUTCHER: Yes.

DR. TAYLOR: I think you did show one slide earlier this morning.

MS. BUTCHER: They did show one slide, and that\'s the one that I was
referring to.

DR. AVERBACK: We were constrained by the trial design that required it
to be consecutive unselected patients as they presented. So we couldn\'t
do any cherry-picking of patients. So it is a representative sample of
the different clinics that were involved. The exact numbers \--

MS. BUTCHER: That was the slide.

DR. AVERBACK: I mean, if you look at the \-- if you add together all the
non-whites, it\'s not that far off from the overall population.

MS. BUTCHER: My question was was there any difference in the response to
the test at all.

DR. AVERBACK: No, we didn\'t see any difference.

DR. TAYLOR: Dr. Gollin has a question for whom?

DR. GOLLIN: For Dr. Averback. It\'s a question from both of us, I think.
And because he just said he was going to ask the same question, or a
similar one.

DR. TAYLOR: \"He\" is Dr. Lichtor for the record.

DR. GOLLIN: Dr. Lichtor. I\'m Dr. Gollin. Would Huntington disease
patients, or other neurodegenerative disorder patients be defined as
non-AD? I mean, ones without AD. Okay, so say Huntington\'s patients,
okay. We\'ll make a very specific category for which testing is
available. Have you tested Huntington\'s, or other neurodegeneration
patients to be sure that their NTP value is less than 22 micrograms per
mL?

DR. AVERBACK: Yes. This is \-- we discussed this this morning as well.

DR. GOLLIN: I didn\'t feel like I got a good enough answer. I\'m sorry.

DR. AVERBACK: No, that\'s fine, I\'m just recognizing it. It\'s not to
say that it\'s not a bad question. It\'s a good question, because in the
interval I actually looked in the briefing document, and it\'s actually
right in the briefing document. So if you look in that JCI paper, in one
of the tables there you will see there was a cohort of Parkinson
patients, and multiple sclerosis patients in the sandwich assay that was
in use at the time for NTP. So there was quite a lot of effort to make
sure it wasn\'t a non-specific neuro finding.

But again, I have to emphasize that our intended use for this is for the
primary care physician in the realistic context to help them evaluate
Alzheimer\'s. Someone who has a clear-cut stroke, and who\'s demented,
just is not that much of a diagnostic dilemma. And to be a definite
vascular dementia. And a Huntington\'s, depending on who the clinician
is, may not be somebody who would fall into the capture of the intended
use population.

DR. TAYLOR: Does that satisfy the dual questioners?

DR. GOLLIN: Yes.

DR. TAYLOR: Okay.

DR. AVERBACK: In fact, here\'s a quote from Dr. Parisi, which basically
I think says it better than I said it. \"Patients with stroke who become
demented may be less likely to be evaluated in dementia clinics, and
less likely to be given the diagnostic label of dementia. This may
explain why vascular dementia is less common in referral-based series
compared with population-based series.\"

DR. TAYLOR: Would you like to argue with that, Dr. Parisi?

(Laughter)

DR. TAYLOR: Good. If there are no further general questions, at this
point in the procedures we really need to move to the specific questions
that the FDA has raised, and provide an opportunity for the panel to
address each of those issues or questions. I understand that there are
four questions, Dr. Becker, is that correct? And we have an hour allowed
for this. So I would propose that we try to move through these about 15
minutes per question, although I recognize that the questions do have
overlap and are somewhat intertwined, and it might not be as simple as
that sounds. So I think we could perhaps proceed by putting up the
questions, and I would point out that copies of the questions are in the
folders and were available on the sign-up table outside of the room. So
is this the first one, Dr. Becker? Okay, then I\'d like to really ask
the panel to begin discussion, and is there anyone on the panel that
feels they\'d like to start? Dr. Blumenstein.

DR. BLUMENSTEIN: I\'ve been sitting here struggling with this. And I\'m
a fan of the show Twilight Zone, those of you who are old enough to
remember that show, or if you have access to the SciFi channel now. I
feel like when I hear the sponsor talk I\'ve entered into the Twilight
Zone, whereas when I hear the FDA talk things are all right. With the
sponsor, I don\'t see that the study design matches the indication, and
there has been changes in the study design, and it\'s quite confusing,
and so forth. I also find that the analysis does not match the study
design. And I want to now kind of explain. The FDA has already presented
a lot of the reasons why I feel that way, and I don\'t want to be
redundant and go back into that. But it comes down to that I don\'t see
a hypothesis. I don\'t see any way to assess a specific diagnostic
setting. I see this as being throw a net out there, get some data, and
then see what the data say about the performance of this device.

The question was brought up by Dr. Butcher over there about whether this
actually adds value and so forth. Well, on the surface it appears that
way, but I don\'t believe the analyses. I don\'t believe that the
numbers that are represented are actually what they say they are. And
that has to do with the fact that these \-- the kind of thing that the
FDA has already said, that it\'s inappropriate to talk about sensitivity
and specificity, predictive value of a positive test, predictive value
of a negative test, and those sorts of quantities that are traditionally
used to evaluate diagnostic tests. It\'s inappropriate to use those
numbers in this setting. And now that can be a little bit controversial,
because it has to do with whether you feel that there\'s a gold
standard. And sometimes gold standards have some imperfections in them.
But in this case the gold standard is false gold.

There\'s a great deal of squishiness in the categorization, the
partitioning of the patients into the diagnostic categories. The ROC
curves that are presented, where one category, the most extreme
categories are presented to me are just totally nonsense. And yet you
see a very high area under the curve, and that\'s represented as being
something meaningful. It doesn\'t mean anything. It\'s based on, first
of all, sensitivity and specificity, which don\'t mean anything, and so
on.

What it really comes down to is that whether you talk about this as
adjunctive, or conjunctive, or whatever language you want to use, this
test tells you something. And if it told you something about whether
there was a pathologic condition in the brain, then it seems like to me
it would be of extreme value. But we don\'t know what it tells us. We
know it tells us that there is some kind of relationship to these four
diagnostic categories. There seems to be kind of a trend there. And
admittedly that trend exists. But when I try to figure out, well, how is
that going to be used in a diagnosis, if I believe that \-- if I take
the word \"sensitivity\" and I take the number that\'s represented as
being an estimate of sensitivity, I think wow, that seems pretty good.
But then I have to stop and think, well what does that number actually
mean? First of all, it\'s not a sensitivity. And so as a result of all
that, I\'ve come to the point where I can\'t feel that this test
actually measures something that is clinically meaningful.

DR. TAYLOR: Other panel members? No further comment?

DR. LOPEZ: I always have the question about who are the \--

DR. TAYLOR: This is Dr. Lopez.

DR. LOPEZ: Who are these possible AD cases, possible Alzheimer\'s
disease cases. Because you follow the criteria, these are supposed to be
people with Alzheimer\'s disease plus some other condition. And the NTP
was able to identify half of those cases. We follow the definition
proposed by the NINCDS criteria that these are cases with multiple
comorbidities, this is the population that is usually seen by PCPs. This
is the person that goes to a PCP every two months, or every month, to be
assessed, and that\'s the person who will complain of having a memory
problem. It could be for Alzheimer\'s disease, or it could be for
something else. So, in terms of getting a benefit, if half of that
population is going to be negative, but may have Alzheimer\'s disease.
So I don\'t know how the consumer is going to benefit at that point. So
I think that this group, this possible AD group needs a better
definition.

DR. TAYLOR: Anyone else on the panel with Discussion Point Number 1?

DR. NATH: I have very little to add, but was just going to state that I
share the same concern as Dr. Lopez. And additionally, if the intended
use of this test is to separate probable from non-Alzheimer\'s patients,
then the concern really is the non-Alzheimer\'s group because more than
half of them are normals, and the rest of them were diagnoses with just
sample sizes of one, two, or three. So it becomes a really, as the FDA
pointed out earlier, was an artificial control. And having distinct \--
enough number of populations with each of those distinct diagnoses would
really be helpful to know if you can really separate one from the other
or not.

DR. TAYLOR: Dr. Duffell?

DR. DUFFELL: I guess I\'m struggling with some of the comments I\'ve
just heard, because sounds like we\'re trying to say it\'s black or
white so to speak. And if I understood the sponsor correctly, they are
just saying it\'s just another piece of data in the bag, so to speak,
the medical bag, to make that diagnosis. It\'s really not drawing a line
to be on one side or the other. So it\'s not conclusive, it\'s just a
little bit more information. And yet, what I\'ve seen presented seems to
suggest to me that there is a higher probability with this test, it\'s
not absolute, but a higher probability that you will come to a right
overall conclusion. So I don\'t know, maybe I misunderstood your last
remarks, or some of the others, but you know, it\'s just going through
my mind. I just wanted to share it with the rest of the panel. So you
know, just keeping it in mind. Because I do see that there is value to
this test. It may not be absolute, it may not draw a line in the sign,
but it\'s just another piece of data in the clinic to make a decision of
how we follow and treat this patient moving forward.

DR. TAYLOR: Anyone want to comment on that? Dr. Blumenstein.

DR. BLUMENSTEIN: Well, and I agree that there\'s a probability of a
positive test giving a higher \-- I mean, more likely to be probable AD.
But it\'s not a sensitivity. Can\'t be labeled as such. And it would be
misleading to label it as such. And then \-- comes the issue then of how
it is that one behaves given that all you have is a probability that
it\'s probable AD. And so that\'s really what it comes down to.

DR. DUFFELL: May I follow up?

DR. TAYLOR: Yes, please. This is Dr. Duffell again.

DR. DUFFELL: Okay. That helps me. I appreciate that clarification,
because I think if it\'s kind of a labeling issue, then that\'s
something where the company needs to work with the FDA to make sure that
there is adequate disclosure in the contents of the labeling about what
type of an interpretation one can make. So.

DR. TAYLOR: I see no further comments from the panel on this. Oh, I\'m
sorry, I didn\'t see your hand behind the microphone. This is Mrs.
Butcher.

MS. BUTCHER: Yes. And I guess I\'m looking again at the populations. Are
there important populations that require more study to establish
effectiveness for the urine NTP test within them? And the answer is we
don\'t know. If they\'re all coming out the same, then we don\'t know if
there are other populations that we need to address.

DR. TAYLOR: Correct, with the numbers available we don\'t know the
answer to that. Correct.

MS. BUTCHER: That\'s right. So we just don\'t know. We can\'t answer
that.

DR. TAYLOR: Yes. At this point I\'m going to ask Dr. Gutman if he feels
that the panel have given any sort of adequacy of an answer?

DR. GUTMAN: Yes, I think it\'s been very helpful.

DR. TAYLOR: Then could we move to Question Number 2? And I\'d like to
ask Dr. Becker to display that on the screen such that everyone can
readily see it. Okay, this is Question Number 2. Do we have anyone on
the panel that wishes to initiate the discussion? Dr. Duffell.

DR. DUFFELL: Yes, I think this question actually speaks to the point I
was trying to make earlier. You know, what I\'m highlighting in my mind
is the word \"certainty\" and \"exclusion.\" That\'s black and white
again, and I don\'t think that\'s what the sponsor put forth.

DR. TAYLOR: Okay, you\'d like to find a word other than certainty, would
you?

DR. DUFFELL: I\'d like the statisticians to remark on probability. I
mean, that\'s probably what we\'re talking about. But again, I think
that\'s probably something for the company to work out with FDA from a
labeling standpoint.

DR. TAYLOR: So that\'s three probables right there. So maybe that\'s
really where we are. I agree, and as we pointed out at the beginning,
these questions are obviously interwoven, and answering, or asking, or
discussing one is obviously spilled into the other. And this in fact has
partly been discussed with the previous question. Does it raise any
other issues for the panel? Dr. Nath?

DR. NATH: Well, I guess the issue it raises for the company was that \--
what they had brought up earlier was that they\'re not really trying to
increase the certainty of the diagnosis of Alzheimer\'s beyond what the
clinical criteria are suggesting, at least who have been examined by a
specialist. So, the question really is, is this a fair question to ask.

DR. TAYLOR: Yes. That\'s the fair question. Nothing more from the panel
on this question? Dr. Gutman, has that been adequate?

DR. GUTMAN: Well, I think what, you know, perhaps this question wasn\'t
phrased as precisely or crisply as we might have done a better job.
Because I think the issue, at least the issue that resonates throughout
FDA, and that we\'re asking for in-point is, is the certainty added by
this diagnosis one that will actually demonstrate effectiveness. And our
concern that was very much on the table is will this test actually
change diagnostic decision-making in a positive way. So is there enough
certainty being put on the table that more intelligent decision-making
at the expert level or at the primary care level will actually occur? I
mean, the bottom line is does it make a difference.

DR. TAYLOR: Okay. So, let\'s quickly try to rephrase that. Does the test
add sufficient clinical value that it would make a difference to patient
care at the intended site of use. So if that\'s now the question, then
Dr. Blumenstein has an answer.

DR. BLUMENSTEIN: Not an answer. I don\'t think that\'s been studied, and
I think the way that that could be studied is that if you did a
randomized trial, and used the test in one group, and didn\'t use the
test in the other group.

DR. TAYLOR: Expand on that, could you?

DR. BLUMENSTEIN: You would obviously have to have some measure of
outcome that would talk about, let\'s see, how does it add certainty to
the diagnosis, or something along those lines. Some outcome measure. But
you would then study what happens within each group of patients, and see
if it, quote, \"improved things\" according to the selected outcome
measure, whatever that would be.

DR. TAYLOR: Are you feeling helped, Dr. Gutman?

DR. GUTMAN: Well, I find that beguiling. I\'m not sure \-- is that the
only choice? Are there other choices?

DR. BLUMENSTEIN: You\'re the one that asked the question.

DR. GUTMAN: Well, that\'s one answer, so yes, I mean I respect that
answer, sure.

DR. TAYLOR: Dr. Lopez next, and then \--

DR. LOPEZ: Well, I think there are two type of groups here. One is the
expert. I mean, that won\'t change much. I mean, the expert will be able
to make the diagnosis without any problems. The expert does not need the
test. The question is whether the PCP working in the middle of
Pennsylvania, seeing 90 patients per day can get help of this test. And
probably yes. But it has to be demonstrated. It is positive. If the test
is positive. Because you always have the biomarker temptation. Say I\'m
doing a urine test, it was negative. You may not have Alzheimer\'s
disease. So you always, you have this conflict of I hate to come back to
the word adjunctive test, and a biomarker. And that\'s the risk that you
have in that physician, working alone, very busy, that really needs
help.

DR. GUTMAN: Okay, but I think the question we\'d like, and you don\'t
have to answer it this round. You can answer it the next round, or you
can answer it when you finally vote, because both Drs. Kondratovich and
Dr. Mani put it on the table is, is the signal strong enough that it
will allow you to make clinically meaningful, based on the data at hand,
will it do what everyone wants it to do, which is help make better
decisions at \-\-- well, at the primary care level.

DR. NATH: So, I agree that \--

DR. TAYLOR: Dr. Nath, and then Mrs. Butcher.

DR. NATH: Sorry. So I agree that the concerns are the same as we
discussed with the previous question, but I don\'t have a problem with a
test being done at a primary care clinic, and then being confirmed by a
specialist. And for example, the thing that comes to my mind is an ANA
test for lupus. I mean, most often we\'ll do a screening test, and we
know we get a lot of false positives. And then we just send them to the
rheumatologist, who will most often tell us your patient does not have
lupus. And so what is important about this test is the degree of false
positivity and false negativity that we get with this test. And
unfortunately we just don\'t have enough data to make those kind of
conclusions at the present time.

DR. TAYLOR: Okay. Mrs. Butcher, you\'ve been wishing to ask a question?

MS. BUTCHER: Well, as a consumer I was going down the same path, and my
whole thought about it is when I go to a doctor as a consumer, he\'s
only going to have so many minutes for me. And if he has this tool in
his toolkit, and can pop it out, and this doesn\'t mean that he will
leave his clinical analysis and all of his experience behind. He takes
that into the room with him as well. But this is just another tool to
help him to do better what he needs to do. So I look at it really as
just an additional tool in the toolkit of a primary care physician to
move people in the path to get what they need. And the help, if it\'s
available, should be given. Because they\'re on the front line.

DR. TAYLOR: Okay. I think Dr. Gulley has a question.

DR. GULLEY: Yes. So, as a \--

DR. TAYLOR: This is Dr. Gulley.

DR. GULLEY: Yes, Dr. Gulley. As a primary care physician, they may see a
positive test and then be able to refer them on, and expect that many of
those patients would have either probable, possible, or MCI. However, if
they had a negative test, that really does not add, in my mind, any
significant utility. It does not mean that there\'s an exclusion of one
of those categories.

DR. TAYLOR: So would you like to see that addressed as a labeling issue?

DR. GULLEY: That is one option.

DR. TAYLOR: Dr. Blumenstein?

DR. BLUMENSTEIN: Well, one of the things that a randomized trial \-- I
hate to sound like an advocate of a randomized trial because that seems
like a dirty word these days, but I am. But one of the things that might
happen in the study where you would look at how this test was actually
used by primary care physicians is that you might find that they become
over-reliant on it, and don\'t do the other things that they\'re
supposed to be doing, and then finding the negative test, and so forth.
So that\'s why it has to be, you know, an outcome that\'s comprehensive
and actually sees what happens to the disposition of all patients
randomized.

DR. TAYLOR: That\'s an interesting point, but on a philosophical issue,
you know, you\'d rule out half of medicine if you took that attitude
because tests are there and people do get reliant upon them. Good or
bad, that\'s just the way it is. Dr. Gutman? Joe?

DR. PARISI: I thought the \-- this is Parisi talking again. I thought
the cases that Dr. Mani used illustrated very nicely that a positive
result or a negative result still left you in the same quandary. So I\'m
not sure how it really helps. And I think it might be more upsetting to
a patient to be labeled as potentially having something where they may
not have it, and more upsetting to their family. So I think this is a
very, this is a very crucial decision, and I\'m not sure we have enough
information to really make that \-- be able to say that we have \-- that
we can say with some certainty that it has meaning or doesn\'t have
meaning.

DR. TAYLOR: So if we asked the question differently, and say it was a
positive test may mean something, but a negative test doesn\'t.

DR. PARISI: Perhaps. Have to think about that.

DR. TAYLOR: Dr. Gulley.

DR. GULLEY: Yes, James Gulley. I think that in either case for the
primary care physician, a positive test would result in a referral, but
a negative test should perhaps in a referral too because \-- so you\'re
left in the same quandary, because the number of patients with the
negative test that have other diseases going on that would be outside of
the perhaps scope or practice of the family care doctor are \--
compromise a large portion of that population.

DR. TAYLOR: I think I saw another hand. Yes, Dr. Duffell.

DR. DUFFELL: Yes, I was just going to comment because we\'ve said it
twice. I know you\'ve said it once, and you just said it about labeling
the patient. I don\'t think that\'s what we\'re talking about doing with
this test of labeling, because again, that gets to the objection I had
before about certainty and all that. It\'s just another piece of data.
It may ultimately lead to a label, but that would be decided by the
specialist in that case, referred on from the primary care.

DR. PARISI: I guess one other comment I would have is that ideally a
biomarker should be able to detect something that you can confirm
pathologically, if you want to make it a marker for disease. I\'m not
sure we\'ve done that with this agent.

DR. TAYLOR: Okay. Dr. Gutman, have we done Question 2?

DR. GUTMAN: Yes, I think you\'ve had a lively discussion on the essence
of what this question was intended to evoke.

DR. TAYLOR: Dr. Becker, could we move to Question 3? I\'ll give everyone
a moment to read it. Again, this seems to overlap with some of the
discussion we\'ve had, but Joe, it really relates to your point in a
sense. You have any comment? This is Dr. Parisi.

DR. PARISI: Well, again, I think the data we\'ve seen for the diagnosis
of definite non-AD versus one of the other three, there certainly seems
to be a trend in those two groups. But I\'m not sure you could use it
for a diagnosis, for exclusion. I don\'t think we have that much
information.

DR. TAYLOR: Dr. Nath?

DR. NATH: I agree. The concerns are still the same. I mean, if you are
going to differentiate probable Alzheimer\'s from non-Alzheimer\'s then
you\'ve got to characterize the non-Alzheimer\'s group a lot better than
what we have currently in this trial.

DR. TAYLOR: Anyone else?

DR. GULLEY: I would say that \--

DR. TAYLOR: This is Dr. Gulley.

DR. GULLEY: Yes. I would say that a positive test only means that
definite non-AD is likely excluded, and that doesn\'t appear to be
terribly clinically meaningful in the primary care practice setting. And
a negative test only means that it is unlikely that the patient has
probable Alzheimer\'s disease, but may still have mixed disease. And so
a negative test appeared to have little clinical utility.

DR. TAYLOR: Again, the discussion does really overlap the previous two
questions. So are there any other new thoughts, or new discussion issues
from the panel? That seems not to have been wonderfully helpful, Dr.
Gutman.

DR. GUTMAN: No, that\'s fine.

DR. TAYLOR: Could we go to Number 4 then, Dr. Becker? This question
again has overlap, but it does raise the specific issue of whether the
setting in which this test is used is defined, and I know that\'s been
alluded to by both the sponsor and the FDA, and been touched on by the
panel. Is there further discussion about whether the setting can be
defined?

DR. NATH: I guess the setting \-- one thing we know for sure \--

DR. TAYLOR: Dr. Nath is speaking.

DR. NATH: So, one thing we know for sure is that it\'s not helpful in a
specialist clinic, and it may be, the intended use is really in a
primary care physician\'s clinic. And we\'re assuming that, you know,
they\'re not going to be able to do a Mini-Mental Status evaluation, and
a decent neurological evaluation. So the \-- and the concerns with being
able to use the test adequately in that setting, the primary care
setting, overlaps with the previous questions, with the previous
comments made on the previous questions I think. So the concerns still
remain the same in the primary care setting, but I think it can be
clearly said that if it\'s going to be of any benefit for future use, it
would only be in a primary care setting.

DR. TAYLOR: Dr. Duffell?

DR. DUFFELL: Yes, I\'d just like to echo your remark. I think the
usefulness is in the primary care because the treatment decisions won\'t
be made at this level. That\'ll be made by the specialist level, is at
least how I would interpret a response to this.

DR. TAYLOR: So, yes go ahead. Dr. Lopez, and then Dr. Nath.

DR. LOPEZ: In general, PCPs prescribe medication, and they \-- usually
when somebody complains of having memory problems they get a
prescription for a cholinesterase inhibitor. So they initiate treatment.
So my question is if the clinical symptomatology indicates Alzheimer\'s
disease, and the test is negative, are they going to change the
prescription. In an expert clinic, probably not. In a PCP, it may. You
have somebody who is complaining I have to fill out three prescriptions
for high blood pressure, one for diabetes, and one for Alzheimer\'s
disease. So probably at the moment of prescribing medication, the PCP is
going to say, well, since this test is negative, I\'m going to cut down
the cholinesterase inhibitor. So it can go either way. So that\'s why
you have to be very careful with that. But in general, PCPs initiate
treatment.

DR. NATH: So I\'m just trying to put my \-- Avi Nath again. So I was
just trying to put myself in the shoes of a primary care physician, and
I realized my practice is anything but, is that if you were a primary
care physician, and you see a patient who complains of memory
dysfunction, and the test comes back negative. So what will you do? If
you don\'t have a conclusive diagnosis for him, you\'re going to refer
him to some specialist, anyhow, whether it be a psychologist or a
neurologist, to try and figure that out. If the test is positive, then
he\'s going to refer the patient anyhow. So my guess is that what it\'s
going to determine at the primary care physician, correct me if I\'m
wrong, is not what the test shows, but rather what the patient complains
of. And if what the patient complains of is memory dysfunction, and he
can\'t really figure that out, he\'s going to send the patient off
irrespective of what the test shows.

DR. TAYLOR: Did I see someone else on the panel? Dr. Gulley.

DR. GULLEY: Just one brief follow-up to that. Yes, James Gulley. Unless
the primary care physician chooses to treat the patient for Alzheimer\'s
if he had a positive test, as was mentioned previously. He may choose to
initiate treatment for Alzheimer\'s disease, and may not.

DR. NATH: Well, the treatment of Alzheimer\'s is not just, you know,
giving them some Aricept. I mean, there is lots of things that have to
be done for treating the patient properly. And which involves social
work. I mean, lots of things that go along with it. So the care, I
don\'t think that the primary care physician is going to be able to
handle these kinds of patients very well. He\'s going to need help from
some specialist clinic to help him.

DR. TAYLOR: Does the panel feel there\'s a difference in a sense as to
how the primary care physician would handle patients that are probable
AD versus the other two categories that have a lot of positives in them?
Because that\'s really what we\'re talking about, right? With possible
AD and MCI, we\'ve got, you know, not quite a 50/50 split of positives
and negatives. With probable AD it\'s pretty good, it\'s 51 to 6 out of
57. So can the primary care physician make that discrimination as to
which patients get referred and which ones don\'t? And does this test
help? That\'s really the question, right?

DR. NATH: Yes, I mean that is the question, and what I was trying to
struggle with is that is he really going to base his decision on the
test, or base his decision on the complaint of the patient. Because if
the patient complains of a memory dysfunction, and even if the test is
negative, he\'s still faced with trying to tell the patient, either he
says, well you know, you\'re just faking it, go home. The patient is not
going to be satisfied. He\'s going to go end up in a specialist clinic
anyway. Right? He\'s going to get a second opinion. Or he says, okay, I
can\'t figure it out, I\'m going to send you to somebody else. And he\'s
going to seek help from a specialist. Maybe I\'m wrong, but that\'s the
way it appears to me.

DR. TAYLOR: Yes, Dr. Lichtor has a comment.

DR. LICHTOR: Well, since you bring that up, all the \-- although I
don\'t do primary care, but all the primary care physicians I know, when
they have patients with memory problems, they refer them all to
neurology, and they don\'t really treat them anyway. So, that makes this
point a non issue to me. I mean, I think all the patients are going to
get referred to neurology anyway. So, I don\'t see how it\'s really
going to help them, because they\'re going to go, as you say, based on
their clinical diagnosis, not whether the test is positive or negative.
I don\'t know any primary care physicians who try and manage these
patients.

DR. TAYLOR: This is Dr. Lopez.

DR. LOPEZ: If you are in a city where you have a big university hospital
where there are many specialists in town, probably they are going to be
referred to a specialist. The problem is when you\'re in those small
towns where you don\'t have access to a specialist, or the specialist is
two hours away from the clinic, or three hours from the PCP office, or
six months, the appointment\'s in six months. So, that\'s why the PCP is
important. It\'s more in the rural areas than in the city areas.

DR. GUTMAN: There\'s just one additional nuance \--

DR. TAYLOR: This is Dr. Gutman.

DR. GUTMAN: \-- that might have been missed here because it wasn\'t as
clearly phrased as we might have done, which is that the notion of
individual management versus group is sitting here because the groups do
seem to segregate in a certain way, and there is some concern about the
variation around the cut point. I don\'t know if anyone would dare to
express an opinion on whether that\'s overwrought, or well taken, or
something in between. But that was an inherent at least subtext of this
question.

DR. TAYLOR: Well, I think we had a little discussion earlier with the
sponsor regarding, first of all, why the cut point was 22, and second,
given that it\'s 22, what the analytical precision of the test is, and
whether it can hit 22 every time on the patient. And some variable data
was provided by the sponsor, and for all I know you have that data in
your voluminous files. I didn\'t see it.

DR. GUTMAN: We tried to share everything relevant with you.

DR. TAYLOR: So, it seems to me as though the analytical accuracy of the
test is perhaps okay, although a one microgram variation does push
patience either way, and in some ways it would be good to see a greater
number of patients, and see if they continue to segregate. They have
done another 1,500 patients, and it would seem to me that in terms of
just comparing analytical value, there might be some utility in looking
at how reproducible it is to re-run some of those 1,500 to aggregate a
larger number. I mean, we just saw 14 patients that were repeated here.
They might have a larger number where the clinical outcomes not the
question here for clinical comparison, it\'s the analytical comparison.
So it doesn\'t really matter which group they\'re in, it\'s just whether
the analytical comparison works. There might be some value to that. And
it would seem to me, too, that it would be good to have an evaluation of
the reliability of the test in other labs. And again, I\'ve been told
that that exists, but that the variation is even greater there. It may
be, although I\'m not sure from the data that I\'ve seen whether I\'m
interpreting that correctly, and perhaps I could ask the sponsor that
question. If it is looked at in different labs, are you seeing different
variation? And maybe you could address that when you sum up at the end.
Does that help, Steve? Okay. I ask you now then, Dr. Gutman, have we
addressed all four items, or are there still residual issues?

DR. GUTMAN: No, I think you\'ve done fine.

DR. TAYLOR: Okay. Yes, I\'m sorry, I didn\'t see you Dr. Duffell.

DR. DUFFELL: It\'s just an afterthought on your comment. Those other
results that the sponsor has I\'m sure weren\'t collected under the
setting of a clinical trial. So you\'ve probably got consent issues I
would imagine as to whether or not you could go back to some of these
patients and use earlier results and things of that sort. I don\'t know
if that really would be something that they could do or not.

DR. TAYLOR: Well, I\'m not sure whether you want to use earlier results.
I\'m just wondering whether they\'ve got bank specimens. I know that you
throw away any frozen urine, but on the other hand, once you\'ve
processed the urine, you can freeze it and do repeat testing if I
understand it correctly. I mean, the controls are frozen and thawed.

DR. DUFFELL: I mean, I don\'t even know what FDA would think about going
retrospectively like that to that kind of data or not. But anyway, I
just thought I\'d bring it up, because it may not be as easy as, you
know, to the lay person it sounds like, oh, well you\'ve got all those
samples, let\'s just go grab them and try this. It may not be quite that
straightforward is all.

DR. TAYLOR: Well, nothing\'s ever that straightforward, and I wouldn\'t
presume to speak for the FDA. I\'m not sure any individual can, but Dr.
Gutman\'s as near as we can get to it today. So you should perhaps
address that question to Dr. Gutman.

DR. GUTMAN: You should recommend good science and we\'ll try and work
with the company on whatever the recommendations are.

DR. TAYLOR: Thank you. Okay, at this point then I \-- I\'m sorry, Joe.

DR. PARISI: One more concern that we\'ve talked about a bit, but in the
data that we were provided, patients that had sequential exams, Patient
7 is very interesting. A 77-year-old lady, she started off in 20.7 at
initial. One year later it was 10.1. So she dropped by a factor of half.
At two years she\'s 11, so she\'s hovering around 10, and then she\'s up
to 19 again at another two-year point. I\'m not sure what the interval
between those two-year points was, but that seems like an enormous
swing, to my mind. And you know, if you catch her early on when she\'s
20.7 and she\'s a little cognitively impaired, even though it\'s below
the threshold, you might be worried about some kind of cognitive
problem. On the other hand, if you catch her a year later when she\'s
10.1, you probably wouldn\'t have any concern at all. So I just want to
emphasize, you know I think this variability is a problem.

DR. TAYLOR: Yes, I mean this is really rather alluding to, and we did
have a brief discussion with Dr. Averback earlier about that. And he
made the point that in the 14 patients none had switched, and that\'s
absolutely true. But the issue is whether there\'s a big enough number
there, and whether they systematically looked at whether patients do
switch, and whether if you run the same patient on five consecutive
days, although I agree that\'s going to be really hard to do in many of
these patients. But what sort of variation do you get in the test. And
then if you run exactly the same split specimen on five consecutive
days, we\'ve heard an answer to that, and that\'s reassuring. But I
think that is a little bit of a concern considering how close the
clusters are to the cutoff point on either side, both above and below.
You\'re sitting in the laboratory, and then having a clinician call and
say what does this mean, you say well, there\'s the reference standard,
and then they quote statistics to you, and then you\'re lost, you know?

I think it\'s been a reasonable open discussion. We maybe have touched
on most of the issues here. Anything we\'ve missed as a group? So the
form here then at this point is that we are now at \-- okay, we\'re now
at 2:40. We normally would have a 15-minute break, and so we will do
that, at which point we will return at let\'s say 3:00. And we would
then have the second public session, at which point the public can
speak, and we then go on to have a summation from the FDA, and then a
final summation from the sponsor. So let us reassemble in 20 minutes.
Thank you.

(Whereupon, the foregoing matter went off the record at 2:40 p.m. and
went back on the record at 3:00 p.m.).

DR. TAYLOR: Okay. We have reached the point where we hold the second
open public session. I\'d wish to ask now whether there are any
individuals who wish to address the panel. If so, would you please raise
your hand and identify yourself at this time? Seeing no one, I wish now
to ask the panel if there are any other questions they wish to address
before we proceed to the final summations, either to the sponsor or to
the FDA. Are there any final questions?

Okay, seeing none, before we move to the panel\'s recommendation and the
panel\'s vote, are there any further comments or clarifications from the
FDA?

DR. GUTMAN: No, we think you\'ve covered all of the points we wanted you
to.

DR. TAYLOR: Then we can move to ask the sponsor whether they have any
final issues or clarifications that they would like to present to the
panel. A summary, yes. Please. There\'s normally about 15 minutes
allocated to this, Dr. Averback.

DR. AVERBACK: Okay.

DR. TAYLOR: That\'s okay?

DR. AVERBACK: We\'ll try to be as brief as we can. Again, want to thank
the panel for listening to our presentation today, and asking some very
good questions, and very constructive comments. There are a number of
issues that we would like to address directly that we would like to now
respond to.

Our thesis is that this measurement is absolutely safe. There\'s no
downside in our view. It can\'t hurt anybody. There\'s no definitive
action taken from it that can lead to danger, and there\'s no bodily
risk, and it adds useful information. A lot of the debate that we
listened to in the last half hour struck us as debate about the practice
of medicine. And different doctors have different patient populations.
In fact, according to the literature, 70 percent, or 65 percent of
Alzheimer\'s cases are managed and treated by primary care physicians.
And they do not refer every case. We\'ve seen a heterogeneity in your
comments, which is very typical of the practice of medicine, and it\'s
part of the problems that we\'re addressing here today. And we think
that this device may actually help to answer a lot of those basic
questions about the heterogeneity of practice. I know I\'m at one
extreme, a neuropathologist, and at the other end, an ER doc. I see the
two wide extremes. Some people think that\'s a little too extreme, but
there\'s a lot of swath in between. And we think this device will be
helpful that way. And we\'re not claiming that it\'ll make decisions.

And a lot of the discussion we heard, it was disappointing to us because
there was discussion of actions being taken with the device. I\'ll get a
positive, I\'ll do this. I\'ll get a negative, I\'ll do this. We would
like to stress to you that overall, and I\'m speaking statistically,
these people can be referred or not referred, they can come back for
follow-up or not come back for follow-up, or come back earlier, or come
back later. They can have other tests done. They can have \-- it\'s
infinite the number of choices in the practice of medicine. Any active
doctor knows this. So we are not saying that you get a result and you
stereotypically do this or do that. And the discussion seemed to go that
way, and I would just like to again say we\'re only trying to say that
it adds useful information in the toolbox, and that that will overall be
helpful.

A couple of specific points we would like to touch on. The comment about
the outcomes trial from Dr. Blumenstein. Just in defense of our little
company, this trial was a blinded trial. So in order to establish the
veracity of this, it had to be blinded. The doctors in this trial
couldn\'t use the results to show different outcomes. This is blinded.
And I\'m told, I\'m not an expert in this, but I\'m told by experts that
the standard of approval is will the device influence diagnostic
decision-making. And that\'s the standard of approval. Will it add some
useful information, in other words. We are not saying that it replaces a
doctor, or that it leads to concrete decisions.

And I think all of the issues that were raised are pertinent and good,
and you know, we would obviously be willing to work with FDA to tighten
up the labeling as the case may be, or do postmarketing surveillance to
try to answer any and all of the issues that have been raised. Thank you
very much.

DR. TAYLOR: Thank you. At this point the panel is now ready to vote the
recommendation to the FDA for this PMA. I would remind the panel that
the industry representative and consumer representative do not vote, and
that as chair, I vote only should there be a tie. I\'m going to ask Ms.
Rufina Carlos, the Executive Secretary, to now read the panel
recommendations options for premarket approval applications. Ms. Carlos?

MS. CARLOS: The Medical Device Amendments to the federal Food, Drug, and
Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows
the Food and Drug Administration to obtain a recommendation from an
expert advisory panel on designated medical device premarket approval
applications (PMAs) that are filed with the agency. The PMA must stand
on its own merits, and your recommendation must be supported by safety
and effectiveness data in the application, or by applicable publicly
available information. Safety and effectiveness are defined as: safety,
according to 21 C.F.R. 860.7(d)(1), there is reasonable assurance that
the device is safe when it can be determined based upon valid scientific
evidence that the probable benefits to health from use of the device for
its intended uses and conditions of use when accompanied by adequate
directions and warning against unsafe use outweigh any probable risks.
Effectiveness, 21 C.F.R. 860.7(e)(1), there is reasonable assurance that
the device is effective when it can be determined based upon valid
scientific evidence that in a significant portion of the target
population, the use of the device for its intended uses and conditions
of use when accompanied by adequate directions for use and warnings
against unsafe use will provide clinically significant results. And
valid scientific evidence, 21 C.F.R. 860.7(c)(2), valid scientific
evidence is evidence from well controlled investigations, partially
controlled studies, studies and objective trials without matched
controls, well documented case histories conducted by qualified experts,
and reports of significant experience with marketed device from which it
can fairly and responsibly be concluded by qualified experts that there
is reasonable assurance that the safety and effectiveness of a device
under its conditions of use. Isolated case reports, random experience,
reports lacking sufficient details to permit scientific evaluation, and
unsubstantiated opinions are not regarded as valid scientific evidence
to show safety or effectiveness.

Your recommendation options for the vote are as follows. Approvable, if
there are no conditions attached. Approvable with conditions. The panel
may recommend that the PMA be found approvable subject to specified
conditions, such as physician or patient education, labeling changes, or
further analysis of existing data. Prior to voting, all of the
conditions should be discussed by the panel. Not approvable. The panel
may recommend that the PMA is not approvable if the data do not provide
a reasonable assurance that the device is safe, or the data do not
provide reasonable assurance that the device is effective under the
conditions of use prescribed, recommended, or suggested in the proposed
labeling. If the vote is for not approvable, the panel should indicate
what steps the sponsor may take to make the device approvable. Dr.
Taylor?

DR. TAYLOR: Are there any questions from the panel to Ms. Carlos
regarding these voting options before I ask for a main motion? Are there
any questions? In that case, is there anyone on the panel who wishes to
make a motion? Dr. Blumenstein.

DR. BLUMENSTEIN: I move not approvable.

DR. TAYLOR: Is there a second for the motion? Dr. Parisi. The motion is
open for discussion. Any discussion from the panel? Last call, is there
any discussion from the panel? In that instance, I will then ask the
panel to vote, reminding the panel that the procedure will be to raise
your hand, and that following the vote I shall ask each member of the
panel briefly to state their reason for voting the way in which they
did. The motion then is for non-approvable. All those in favor, please
raise their hand. So I\'ll read the names for the record. It\'s Dr.
Parisi, Dr. Nath, Dr. Blumenstein, Dr. Gulley, and Dr. Gollin. Thank
you. Those against? Dr. Lichtor, and Dr. Lopez have voted against. That
leaves, I believe, no abstentions. Correct. I will now ask each member
of the panel to briefly state their reason for voting the way that they
did. We\'ll begin with Dr. Parisi and move around the table.

DR. PARISI: Thank you. I think the issue is whether or not NTP really
serves as a reliable biomarker of disease. And I think the conditions
for identification of a biomarker, its ability to detect a feature of
the Alzheimer\'s neuropathology, and I don\'t think that\'s been
addressed or demonstrated. It needs to be validated and
neuropathologically confirmed AD cases, and that hasn\'t happened. It
needs very high sensitivity and specificity, and we\'ve heard a lot of
data to that point. Some of the data are conflicting, but \-- so I
don\'t think we have enough information to really come to a conclusion
about the specificity or the sensitivity of the \-- of NTP.

Ideally, a marker ought to be biologically \-- have some kind of
biological relationship to disease pathogenesis, and I\'m not sure
we\'ve seen \-- I don\'t think we\'ve had data to support that point
either. There was a consensus conference at NIA that Dr. Becker
mentioned briefly, a consensus report of the working group on molecular
and biochemical markers of Alzheimer\'s disease from the Ronald Reagan
Research Institute and the NIA working group that was published. And I
think a lot of the issues that we\'ve discussed today actually come out
in this paper. One of the recommendations of that paper was actually
that the marker, the putative marker be confirmed by at least two
independent studies conducted by qualified investigators with results
published in peer review journals. And I guess I would encourage the
sponsors of NTP to possibly pursue that venue of validation.

DR. TAYLOR: Thank you. Again, I\'ll ask the panel to make any comments
that are in addition to or differ from those made by a former member. So
Dr. Nath, could you comment next?

DR. NATH: So while I agree with the comments made, there\'s no doubt
that the test itself is very safe. And I don\'t think I would argue
against that. The questions were regarding the efficacy, and I wasn\'t
entirely convinced that the current clinical study is adequate in order
to really justify it. I felt that the sample sizes were too small,
conclusive diagnosis could not be made in between the groups, and no
longitudinal data was available from the patient samples themselves. And
in the few examples provided, it seemed like the cutoff really is too
close for differentiating the non-Alzheimer\'s from the Alzheimer\'s
patients. And in the few examples of longitudinal data, the fluctuation
is also of concern. So these pieces of information influence my
decision.

DR. TAYLOR: Dr. Blumenstein?

DR. BLUMENSTEIN: It may seem odd for me to say this, but I\'m reminded
of the difficulty I had when I was asked to be on the panel for the
silicon gel breast implant. The issue to me is characterization of
efficacy and safety. First of all, I don\'t know that I agree that the
device \-- the diagnostic is perfectly safe, because I think that it
will change people\'s lives to see a result in a clinical setting.

The characterization of the performance of the device is not, as I\'ve
tried to discuss before, is not adequate. The wrong kind of language is
used, the wrong kind of comparator was used, and all sorts of problems
like that. I don\'t, and I\'m not saying that the device isn\'t
effective in the sense that it does seem to correlate with something
that seems to be related to a diagnostic behavior. But it does not \-- I
don\'t think it could be characterized as it has currently been studied
or represented in a manner in which I feel comfortable with the
labeling.

DR. TAYLOR: Dr. Lopez?

DR. LOPEZ: Okay. One thing that I, as a neurologist, and as somebody who
works in the field of dementia, I believe that anything that increases
awareness of the disease is positive and is important. So I think that
would be very important to have something in the community, and the PCPs
to have a tool that can increase their awareness of the disease. The
problem that I have with the study is that it\'s not \-- I\'m not
convinced that it works in Alzheimer\'s disease. I would be convinced
that it works in Alzheimer\'s disease if the probables and possibles
were similar. And I would go back to the charts, and I would review all
those possible AD cases. It may be the case that you have here cases
where they don\'t have Alzheimer\'s disease, or they have other
dementias. And see if that can improve the sensitivity in that group.
And that would be probably one step towards the approval.

DR. TAYLOR: Dr. Gulley?

DR. GULLEY: Yes. So, I\'d like to echo the remarks of Dr. Nath and
previous members. I don\'t think that effectiveness was demonstrated. I
think that perhaps safety can be assumed with this. However, based on
presented data we are unable to assess whether there are false
positives, the true number of false positives or false negatives, and
therefore you cannot define the patient\'s at risk to look at the
risk/benefit ratio.

As far as the effectiveness, in addition to the previously mentioned
comments, there appear to be good correlations with two of the disease
categories, probable Alzheimer\'s disease and definite non-Alzheimer\'s
disease. However, there didn\'t appear to be good correlation with the
possible Alzheimer\'s disease or MCI, and certainly there was no
correlation with the neuropathologic gold standard. Furthermore, there
are some concerns with the patient variability in the testing, as well
as the use of the training set and the testing set as the same group.

DR. TAYLOR: Okay. Dr. Lichtor?

DR. LICHTOR: Okay. As a neurosurgeon who manages these patients to a
certain extent, to me there\'s really two major issues. A, it\'s not
really an identifying patients with Alzheimer\'s disease. It\'s more B,
which is the help and management of patients with dementia who do not
have Alzheimer\'s disease. And that\'s more of what I see. But I feel
that this test does add some information, and only time will tell
whether or not this will pan out to be helpful.

I think the downside of the test is really nothing, so although \-- so
there\'s really no risk that I see. I think many tests in medicine are
not 90 percent reliable, or 98 percent reliable. I mean, we wish that
were, but whether you realize it or not, a lot of times we make surgical
decisions saying maybe there\'s only a 70 or 80 percent chance our
surgery is going to help. And just be honest with the patients and tell
them that. And I think it seems like you\'re being up front about what
the efficacy, or at least the reliability of this test is.

I also say that although you say that the test is really geared for
primary care people, and it may help them some, but I think also many of
my neurology experts are frequently not sure of the diagnosis in these
patients. And I think this test may provide some additional information,
but obviously we don\'t have enough data to tell. But I think only time
will tell if this test will help in management of these patients, but I
think there\'s a possibility that it would, and as long as there\'s a
possibility that it would I don\'t see any reason why it can\'t be added
to the number of other tests that we order for these patients.

DR. TAYLOR: Dr. Gollin?

DR. GOLLIN: I have a number of concerns about the effectiveness of the
test. I don\'t feel that we\'ve been given reasonable assurance that the
device is effective under the conditions of use that have been
prescribed, recommended, or even suggested in the labeling. First, in
terms of whether adequate specimens can be collected on the pre-analytic
side, I\'m concerned that the test can\'t be used in many of the
patients who may really need it, because they may not be able to give
specimens.

I have concerns, number two, whether the analyte is constant from sample
to sample, and from laboratory to laboratory, and so on. I\'m concerned
about study design, and whether we can interpret the results that we
have, and to me the numbers still are small. I don\'t have sufficient
data to be convinced that a patient with a negative result will be
helped by the test, and even whether a patient with a positive result
will be helped by being treated by a primary care physician rather than
referred to a neurologist which might otherwise happen. And so for all
these reasons, I don\'t think the test is useful in refining the process
of physician decision-making in terms of the diagnostic workup for
Alzheimer\'s.

DR. TAYLOR: Thank you. I would like to summarize then the voting outcome
for the recommendation. The motion on the table was for non-approval.
Voting in favor of the motion were Dr. Gollin, Dr. Gulley, Dr. Parisi,
Dr. Nath, and Dr. Blumenstein. Voting against the motion were Dr.
Lichtor and Dr. Lopez. And you\'ve heard each of the panel members give
a brief explanation for the reason they voted, and the motion therefore
is passed of a recommendation for non-approval.

As a final issue, I\'d like to ask each panel member if they have any
comment or recommendation for the sponsor as to what they believe may
make the test approvable in the future. And in this instance, I\'d like
Mrs. Butcher to open the comments.

MS. BUTCHER: Again, I think the numbers may help, if there were larger
numbers in the study. And secondly, to work closer with the FDA so that
you\'re not at the end of the process saying that there\'s not a fit.
And perhaps to design the whole study so that it marches hand in hand,
and when you get to the end, you come out with a result that you\'re
both \-- that the FDA and the sponsor is aware of and ready to go
forward with.

DR. TAYLOR: Dr. Duffell?

DR. DUFFELL: I\'ll pass, but I would like to make a closing remark when
we\'re done with comments on approvability.

DR. TAYLOR: Do it now.

DR. DUFFELL: Okay. I think it\'s, you know, I wanted to make remarks to
both FDA as well as the sponsor. I mean, this is a long, exhausting
process of many years. They bring them to this table, as well as a lot
of hours by FDA in analyzing and working with the sponsor over the
years. I think what we\'ve seen here today is an ongoing thing that I
see where there\'s always room when you\'re dealing with science and
medical data for reasonable men and women to differ on a conclusion.
Obviously the sponsor felt as though they had an approvable product, and
FDA clearly had some questions about that. I think what is most
important at this particular juncture, and I\'m sure FDA will work with
the sponsor in doing this, but just to make it clear is I think, being
on the receiving end of this before, is to get the comments quickly back
to them so that they can work constructively together to try to either
resolve questions that can be answered within the existing data set, or
be about evaluating whether or not new studies are needed to satisfy
information that we didn\'t have today. So I would urge FDA to work with
them, and likewise the sponsor to work constructively with FDA in
getting those things under way.

DR. TAYLOR: Thank you. Dr. Gollin?

DR. GOLLIN: I didn\'t feel like the data convinced me. Therefore, I
would urge the sponsor and the FDA to work together to get data, or
interpret \-- or analyze the data such that the panel can be convinced
that the test is an effective test.

DR. TAYLOR: Dr. Lichtor, do you have any suggestions as to what might be
done?

DR. LICHTOR: Well, just a few brief suggestions. And one, I guess
everyone else said, I\'d like to see bigger numbers. But two, I think if
you can show how management of patients is changed by this study. For
example, do you have patients that, say, further tests which may be
expensive weren\'t ordered because of the results of this study. Or
could this study somehow expedite the management of these patients with
dementia who \-- where the diagnosis is not clear. I think that\'s the
more challenging group.

DR. TAYLOR: Dr. Gulley?

DR. GULLEY: There may be several different options here. One perhaps
would be repeating a test using neuropath as a gold standard. However,
realizing that that is a long process, perhaps a test in the primary
care setting, if this is the intended \-- because the neuropath gold
standard would be needed to show if the test were to be better than the
currently accepted NIH criteria, then perhaps you could do the test in
the primary care setting to see if that helped aid in the diagnosis, or
referral pattern, or changes in management as was previously mentioned
by Dr. Lichtor, but decreased the number of expensive tests needed to
get the diagnosis. I don\'t know the exact endpoints of that trial, but
that could be done in discussion with the FDA.

DR. TAYLOR: Dr. Lopez?

DR. LOPEZ: Well, I\'m just going to repeat what they said before, except
I believe that the test should show that it can identify people with
Alzheimer\'s disease in general. Probable and possible. And in this
case, it may require to go back to the possible AD and review the
charts. It is \-- maybe you have there some people with other dementias.

I\'m still, I\'m not sure if the MCI group helps here. It may, it may
not help. We don\'t have \-- the criteria for MCI are constantly
changing. And the criteria for MCI is going in a direction which is very
different to the one proposed by the American Academy of Neurology. So I
don\'t know if it helps here.

The other thing that would help is if you can show that you can identify
people at different stages, in mild, moderate, and severe. And you can
do the \-- you have the Mini-Mental State Examination score here. You
can use people \-- you can dichotomize the score in plus/minus 20. So
those with the scores higher of 20 would be mild, scores less than 20
would be moderate and severe. And you can show that this test can
identify people in early stages, and in the moderate and severe stages.
People in the \-- you don\'t need the test in people in the moderate and
severe stages. You don\'t need to do the test. They have the dementia,
it\'s pretty much advanced, the diagnosis is there. The target group is
a group with mild dementia. Because you don\'t know in which way that
group will go. And if the diagnosis will be different down the road, it
will change the diagnosis.

So I think that there are two issues here. One is what I would like to
see, is that the test works in Alzheimer\'s disease in general, probable
and possible, and that the test is sensitive to detect Alzheimer\'s
disease in mild stages. It may be that what you are picking up here is
just a more advanced process. And it may be that the test is sensitive
only to Alzheimer\'s disease in moderate to severe stages. But it would
be important to know that you can pick it up through the whole natural
history of the disease. But \-- and I\'m not sure if including cases
with MCI is useful.

DR. TAYLOR: Dr. Blumenstein?

DR. BLUMENSTEIN: I\'d like to echo what Dr. Lopez said, especially the
issues about longitudinal studies, and studies that would give you some
idea of the time course. Treatment monitoring also comes to mind. I\'m
not sure how many potential treatments are being evaluated, but that
would be an excellent place to get repeated test data. And I would have
felt a lot more comfortable had this test \-- the data that we have been
presented to us as more like a biomarker, and if we had seen things like
associations with the components used to make the diagnosis in addition
to the overall partitioning of the patients into those squishy
categories.

DR. NATH: I also feel that a longitudinal study would resolve a lot of
the questions that were raised by a number of individuals on the panel,
because it would not only validate the test for reliability and
variability over a period of time, and collection, and all those other
kinds of things, but it would also help resolve the diagnoses of these
patients over a period of time, because the patients in the possible
category will declare their diagnoses if you follow them for a finite
period of time. And all those \-- even if you did not have autopsy data
on those patients, you have a better certainty of what the diagnosis
really is.

I would also strongly suggest, as I have done previously, is that
consider using other groups of neurological diagnoses in sufficient
numbers to give us a feel for whether this really is something specific
for Alzheimer\'s, or would it be just as specific for any
neurodegenerative disease.

And if a longitudinal study is going to be designed, then some idea of
correlation with severity of the disease is important. And as Dr. Lopez
said, that recognizing the mild patients is probably going to be
clinically the most relevant. But if you\'re going to do correlation
with severity, and I know it costs \-- these studies can be quite
prohibitive, but if possible, a standardized protocol for doing MRI
testing might actually be very beneficial because that will resolve the
issue of vascular dementia versus, you know, other forms of dementia,
and front-temporal dementia. But it will also give you the ability to
quantitatively actually measure atrophy, whole brain atrophy, or
hippocampal atrophy, and really show that, yes, the protein levels
correlate with some objective measure besides the clinical evaluation.
Because we know that you can have a lot of plaques and tangles in the
brain and still do really well on the MMSE if you\'re very highly
educated. You know, so there are limitations to the clinical exam, and
I\'m hoping that the MRI might add another dimension to it.

DR. TAYLOR: Dr. Parisi?

DR. PARISI: I think we\'re all struck with the potential very exciting
observation that NTP may have a real role in an understanding of
pathogenesis of Alzheimer\'s, or may have a role in the disease itself.
But the validity of the assay, it needs to be established against
carefully studied cohorts of ideally longitudinally followed patients
and controls. Patients with dementia, including other non-Alzheimer\'s
type dementias.

One thought that comes to mind is that the NIA sponsors many
Alzheimer\'s disease centers around the country, and they all have large
cohorts of patients, and perhaps partnering with some of these may in
fact enhance your ability to do some of these studies.

DR. TAYLOR: Thank you. I think that summarizes the panel comments. As
chair, sitting watching the proceedings, I would agree with many of the
thoughts of other members of the panel. I think there\'s partly an issue
of claims versus labeling, and obviously the claims then reflect the
stringency with which the FDA look at the data and measure the data. So
it would seem to me there might be a basis for the sponsor Nymox to sit
down with the FDA and see if they can negotiate a set of claims and a
set of labeling requirements that allow the design of a study that\'s
actually feasible. Clearly it\'s not feasible to do a study where the
outcome is the current gold standard, which is histopathologic
diagnosis. That\'s not going to work. So you\'re left with these
surrogate standards for diagnosis that themselves are hardly gold
standard. They are sort of something below bronze. And it does make it
very difficult to design a study when the thing you\'re measuring
against is itself not really quantifiable. And that\'s the challenge I
think you have. It\'s almost as though you\'re looking for \-- in
another environment, if the test were classified as a 1 or 2, as
substantial equivalence to something. And I don\'t know whether you can
evolve in that direction with the FDA. I think we all feel more data is
required, both horizontal in terms of numbers of patients, and
longitudinal. I personally found the prospect of the test very exciting,
and it would truly be disappointing for all of us if there is not
something here that can be useful.

With that, I believe that the panel comments are closed, and there\'s a
final housekeeping issue from Rufina who\'s going to remind us, I think,
to destroy all of this material.

MS. CARLOS: Before we adjourn for the day, I would like to remind the
panel members that they are required to return or destroy all of the
confidential materials they were sent pertaining to this meeting.
Materials you have with you may be left at your table, and any others
may be sent back to me at the FDA or shredded as soon as possible.

DR. TAYLOR: At this point then, since there is no further business, I
would like to adjourn this meeting of the Immunology Device Panel. I
thank you all for your attendance, and for your courtesy during the
course of the meeting. Thank you.

(Whereupon, the foregoing matter was concluded at 3:40 p.m.).