DEPARTMENT OF HEALTH AND HUMAN SERVICES

    FOOD AND DRUG ADMINISTRATION

    CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

**`BLOOD PRODUCTS ADVISORY COMMITTEE`**

**`64TH MEETING`**

**`VOLUME II`**

    Friday, September 17, 1999

    8:00 a.m.

    Bethesda Ramada Inn

    8400 Wisconsin Avenue

    Bethesda, Maryland

PARTICIPANTS

Blaine F. Hollinger, M.D., Chairperson

Linda A. Smallwood, Ph.D., Executive Secretary

MEMBERS

John M. Boyle, Ph.D.

Corey S. Dubin

Norig Ellison, M.D.

Richard J. Kagan, M.D.

Jeanne V. Linden, m.D.

Gail B. Macik, M.D.

Mark A. Mitchell, M.D.

Kenrad E. Nelson, M.D.

David F. Stroncek, M.D.

Joel I. Verter, Ph.D.

NON‑VOTING CONSUMER REPRESENTATIVE

Katherine E. Knowles

NON‑VOTING INDUSTRY REPRESENTATIVE

Donald H. Buchholz, M.D.

TEMPORARY VOTING MEMBERS

Mary E. Chamberland, M.D.

Michael G. Fitzpatrick, Ph.D.

Paul R. McCurdy, M.D.

Carmelita J. Tuazon, M.D.

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Opening Remarks 3

**IV.** **Medical Device Panel Reclassification**

**of HIV Drug Sensitivity Assays**

Introduction and Background:

Andrew Dayton, M.D., Ph.D. 6

Overview of Device Reclassification:

Leonard Wilson 9

Presentation:

Douglas Mayers, M.D. 58

CDER Perspective:

Jeff Murray, M.D., MPH 101

Open Public Hearing

Curtis Scribner, Visible Genetics 141

Michael Ussery, Innogenetics 146

Tony Lam, Applied Biosystems 151

Brendan Lardner, VIRCO 155

Charge to the Committee:

Linda A. Smallwood, Ph.D. 164

Committee Discussion and Recommendations 168

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**Introductory Remarks**

DR. SMALLWOOD: Good morning and welcome to the second day of the 64th
meeting of the Blood Products Advisory Committee. I am Linda Smallwood,
the Executive Secretary. Yesterday, I read the conflict of interest
statement. It also applies to today\'s meeting.

This morning, the Blood Products Advisory Committee will be sitting as a
medical‑device panel. You will hear presentations that will describe the
role of a medical‑device panel. For this purpose, we have asked
consultants to join us today in this deliberation who will be sitting as
temporary voting members.

I will introduce those consultants to you. They are Dr. Carmelita
Tuazon. Would you please raise your hand, Dr. Tuazon. Dr. Paul
Edelstein. And Dr. Roy Gulick. We understand that, because of the
weather, that some individuals have had difficulty in getting here. We
are assuming that they will be coming since we have not heard that they
are not.

We also were to have join us, as a guest of the committee, Dr. D\'Aquila
who advised me that he was unable to attend today.

The Chairman of our committee is Dr. Blaine Hollinger. Dr. Hollinger,
would you raise your hand, please. For those of you who were not here
yesterday, I will just quickly run through the committee and give myself
a memory check here.

Dr. Gail Macik, Dr. Richard Kagan, Dr. Mary Chamberland, Dr. John Boyle,
Dr. Norig Ellison, Dr. Michael Fitzpatrick, Ms. Katherine Knowles, Dr.
Donald Buchholz, Dr. Joel Verter, Dr. Mark Mitchell, Dr. Jeanne Linden,
Dr. Paul McCurdy. We also have Mr. Corey Dubin. I don\'t see him here
this morning but I assume he will appear.

Are there any declarations that would need to be made before we proceed
with this meeting concerning any conflict of interest or any perception
thereof?

Hearing none, then we will follow the agenda as closely as we can. We
have a lot today. We will try to meet the time frame that has been
established if everyone will cooperate accordingly.

At this time, I will turn our meeting over to our Chairperson, Dr.
Blaine Hollinger.

DR. HOLLINGER: Thank you, Linda. We will stick within our time frame,
hopefully, today. This is, I think, an important meeting today as we sit
as a medical‑device panel for reclassification of HIV drug sensitivity
assays. This is, of course, an important issue, also.

I think it is going to be an interesting morning. I hope you have all
looked at these forms. Mary Chamberland said that she has been in
government a long time and she said it took her six hours to fill it
out. OMB says one to two hours, but‑‑I told someone that that means that
we all get a royalty of about 5 percent on anything that is produced.

So, we are going to start this morning with an introduction and
background. Andy Dayton is going to start us off today and then we will
go to an overview of the device reclassification. Then we will have a
presentation of the problems and issues associated with this.

**Medical Device Panel Reclassification**

**of HIV Drug Sensitivity Assays**

DR. DAYTON: Good morning.

\[Slide.\]

Today, you are going to be asked for your recommendations as to whether
or not HIV drug resistance genotype assays should be reclassified as
class II medical devices rather than class III medical devices.

This is a timely issue because downclassification would foster rapid and
simplified regulation of numerous, currently diverse, HIV genotype
assays and this would facilitate antiviral drug studies and, ultimately,
accelerate physician access to information useful in the management of
individual HIV‑infected patients.

I am going to give a very short presentation of the regulatory
considerations. My presentation, in general, will give you a general
overview of basic regulatory and technical issues involved today.
Following my short presentation, Len Wilson will present a more detailed
and comprehensive review of the regulatory issues.

\[Slide.\]

After that, I will give a brief overview of the scientific and clinical
issues and then Jeff Murray and Doug Mayers will present more‑detailed
summaries of the relevant clinical and scientific literature. After the
presentations on regulatory and technical issues, there will be an open
public session and then a session for committee discussion following
which you will be asked to make a recommendation on the classification.

I want to emphasize at this time, as you have already been told, you are
sitting as a classification panel. We are not requesting you to vote on
approving or clearing or licensing any product. We are asking you to
decide at what level we should regulate HIV drug resistance genotype
assays. What I mean by this will be explained during the course of this
session and I believe you have also had an introduction yesterday as to
the various classifications available.

\[Slide.\]

Currently, there are no FDA‑approved or cleared assays for the assays
for the determination of HIV drug resistance. Given this, HIV drug
genotype drug resistance assays, by default, are class III medical
devices requiring premarket approval.

An option exists, however, to classify such devices into class II, or
510(k), when general controls and special controls exist to insure the
safety and effectiveness of the device. It is FDA\'s view that adequate
special controls can be provided by adherence to a guidance document
containing recommendations for study designs, reagent characterization
and performance characteristics‑‑for instance, reportable range,
sensitivity, precision, specificity, stability, et cetera‑‑and by
completion of postmarketing surveillance studies designed to evaluate
the correlation between predicted and observed viral phenotypes in a
clinical setting.

\[Slide.\]

These are the questions that we are going to asking you at the end of
the presentation and, of course, you are welcome to alter them as you
see fit. Does the committee support the reclassification of HIV drug
resistance assays from class III medical devices to class II medical
devices? If the answer to No. 1 is yes, what additional special controls
or requirements, if any, does the committee recommend?

If the answer to No. 1 is no, what additional specific criteria does the
committee recommend to allow future reclassification as class II
devices?

\[Slide.\]

The science involved can be quite complex and, certainly, much desired
information is incomplete. However, we urge you to remember that the key
issue is not whether or not all the scientific information is complex or
whether all the scientific questions have been answered. The key issue
is whether or not you believe we can identify special controls which
will guarantee reasonable efficacy without requiring the completion of
full‑blown, traditional clinical trials before marketing.

In the next presentation, Len Wilson will focus on this issue from a
regulatory perspective.

Len?

**Overview of Device Regulation**

MR. WILSON: My presentation today is to take the committee through the
regulatory pathway to classify medical devices. Why do we do this?
Because the law says we must classify medical devices. So we go through
this exercise periodically as new products come up or we want to change
the regulatory classification of existing products.

In the past five or so years that I have been engaging in reclassifying
devices, this committee has voted on a number of them, sometimes
classifying up from a I to a II, sometimes classifying down from a II to
a I, et cetera. So there are no surprises in this process.

With that, what I would like to do is have the first slide and
essentially start out.

\[Slide.\]

What we are trying to reclassify here an HIV mutation test. An essential
proposal is that the HIV mutation test can have a reasonable assurance
of safety and effectiveness when regulated as a class II medical device.
Class II medical devices, as I will discuss later, have some
requirements associated with them. One of the requirements is having a
special control.

The proposal here today is that the FDA would develop a guidance
document for the content of the 510(k) filing, the class II
medical‑device filing, which we would review and we would clear if the
manufacturer provided sufficient information to assure the safety and
effectiveness of the device.

And then there is an additional special control that we are proposing,
postmarketing surveillance. This would be used, as Dr. Dayton described,
to do some follow up. I want to emphasize that the postmarketing
surveillance component of a special control here is not intended to be
the basis for the approval of the product, approval or clearance of the
product.

The postmarketing surveillance is intended to answer some unanswered
questions or some prospective concerns.

\[Slide.\]

What I will be talking about are, basically, three topics. Is the
product a medical device? If so, who regulates it within the Food and
Drug Administration? And, into which regulatory class should it be
assigned?

\[Slide.\]

Is the product a medical device? According to the law, if a product is
labeled, promoted or used in a manner that meets the following
definition in Section 201(h) of the FD&C Act, it will be regulated by
FDA as a medical device subject to premarketing and postmarketing
controls.

\[Slide.\]

A device, by definition, is an instrument, apparatus, implement,
machine, contrivance, implant, in vitro reagent or other similar or
related article including a component part or accessory which is‑‑

\[Slide.\]

‑‑recognized in the official National Formulary or U.S. Pharmacopeia or
any supplement to them, intended for use in the diagnosis of disease or
other conditions, or in the cure, mitigation, treatment or prevention of
disease in man or animals or‑‑

\[Slide.\]

‑‑intended to affect the structure or any function of the body of man or
other animals and which does not achieve any of its primary intended
purposes through chemical action within or on the body of man or other
animals and which is not dependent on being metabolized for the
achievement of any of its primary intended purposes.

\[Slide.\]

So now we have established that this type of a product would be a
medical device. The next question is how would it be regulated by the
FDA, either by the Center for Biologics or the Center for Devices, the
Center for Biologics Evaluation and Research, the Center for Devices and
Radiologic Health.

The Center for Devices and Radiologic Health regulates most of the
medical devices that are in commercial distribution in the United
States. In 1991, there was an intercenter agreement which was issues
between the two centers. In general, CBER has the lead for regulating
medical devices used or indicated for the collection, processing,
storage or administration of blood products, blood components or other
analogous products.

So, for example, this empowers the Center for Biologics to regulate
those test kits which are used to screen blood donors.

\[Slide.\]

But it also states that CBER also regulates in vitro tests including
diagnostic tests and any other medical devices intended for use in
dealing with retroviral products. So this particular product that we are
talking about today is a retroviral product, so the Center for Biologics
has jurisdiction.

\[Slide.\]

I wanted to underscore, also, even though we have jurisdiction over this
product, we use the same sets of regulatory requirements that are
dictated by the Food, Drug and Cosmetic Act which the Center for Devices
uses. So we are using the same sets of rules, here.

\[Slide.\]

Devices are classifying as required by law into one or more of three
categories, or classes, depending on the regulatory controls needed to
provide reasonable assurance of safety and effectiveness. This would be
class I, class II or class III.

\[Slide.\]

A device is automatically, by law, in class III if it was not on the
market before May 28, 1976. This was the date at which the Medical
Device Amendments to the Food, Drug and Cosmetic Act were passed
establishing medical‑device law and regulations. Or if no predicate
device exists; in other words, FDA has not cleared a 510(k) for the same
device. So a predicate would mean, in this particular situation, has the
Food and Drug Administration cleared an HIV mutation test or
viral‑resistance test before. Is there something that we can compare
against?

And the answer is no. So, by default, as we move down, it would be in
class III in the absence of formal classification. However, there is an
option where the FDA can classify products into some other
medical‑device classification.

\[Slide.\]

So the steps, in general, to classify a medical device are found in the
regulations, 21 CFR 800 through 899. It can be initiated by FDA or a
sponsor. In this particular instance, FDA is bringing it to the
committee. A sponsor would mean someone who was petitioning the FDA who
would be trying to get a test kit approved or cleared. They can petition
the FDA and say, \"Gee; I would like to have this regulated as
such‑and‑such as class.\" And then we would go through this same type of
a cycle except it is coming externally.

We would obtain a recommendation from an advisory committee, this
committee. Based on that recommendation, we would publish, in the
Federal Register, for comment, the outcome of the committee\'s
deliberations and vote and then get some comments, make potentially some
changes, and then publish a final rule.

Once that final rule is published, into the CFR would appear, once the
administrative processes are completed, a section that would be
entitled, for example, HIV Mutation Test. It would have a number and
then any sponsor who comes to the Food and Drug Administration to get a
test approved or cleared, they could cite that as a predicate and they
could file, in our proposal, a class II‑‑it would be regulated as a
class II and they can file a 510(k).

\[Slide.\]

In the regulations, the committee should consider, in determining safety
and effectiveness‑‑and this is something that you may want to tag on the
slides that I gave you‑‑you should consider the persons for whose use
the device is intended, its conditions for us, probable benefit to
health weighed against risk of us, and the reliability of the device.

\[Slide.\]

Which regulatory classification are we attempting to vote on here? Well,
all medical devices, as stated earlier, are classified into three
classes. Class I, general controls are sufficient to assure the safety
and effectiveness of the device. Class II, general controls are
insufficient to insure safety and effectiveness of the device so special
controls are added on top of the general controls in order to insure
safety and effectiveness of the device.

Class III devices are those where general controls and special controls
are insufficient to insure the safety and effectiveness of the device
and premarket approval is required. That would be a PMA, a class III. In
general, a premarket approval application, which I will touch on later,
essentially, there would be clinical trials associated with it because
the answers for the safety and effectiveness of device could not be
assured by general controls and special controls.

I will walk through what these controls are.

\[Slide.\]

What are general controls? General controls, which apply to all medical
devices, are registration of the manufacturing facilities. We need to
know, at FDA, where the product is being manufacturing. The manufacturer
is required to have a medical device listing, what products are being
manufactured there.

These two bits of information are used so that FDA knows where to
inspect on its periodic inspections. These products are routinely
inspected on a periodic basis for their compliance with good
manufacturing practices or what we now call QSRs.

There was a revision to the good manufacturing practices. Good
manufacturing practices are those sets of rules by which manufacturers
produce products in a clean environment, have quality control, et
cetera, et cetera. Again, these are listed in 21 CFR 800.

Recently, within the last two years, the good manufacturing practices
section has been revised and upgraded. They are now termed QSR, quality
system regulations. The important point here to consider is that they
have been strengthened considerably. However, in classÊI products,
design controls, which I will explain in a moment, are not required, in
general.

Class I general controls also include labeling requirements to make sure
that there are adequate instructions for use, et cetera. For a class I,
a submission of a premarket notification also known as a 510(k) is
required. It is also important to note that certain general controls can
be exempted, also. That could be done by the Food and Drug
Administration as well as by a committee vote.

For example, some products we may exempt the need to file a 510(k). This
committee voted on such a situation several years ago where we dropped
the requirement for a 510(k) for copper sulfate for use in determining
hemoglobin in blood donors.

\[Slide.\]

Some more general controls; record keeping and requirement for repair,
replacement and refund when defects are found.

\[Slide.\]

Some examples of class I devices; heat‑sealing devices to crimp blood
collection tubing; alanine aminotransferase tests. This is a
clinical‑chemistry test and you can see the it has an asterisk. This, in
fact, has been exempted from filing a 510(k). So all the other general
controls apply, but they are not required to file a 510(k) to get
premarket clearance. An ammonia test system; iron‑binding‑capacity test
systems.

The 21 CFR 862 is that section which is listed in the regulations and I
will show you an example of what you would have in this particular
situation for HIV mutation tests as we move towards it.

\[Slide.\]

Class II; general controls are insufficient so, therefore, you would
need special controls. Now, special controls consist of, for example, a
guidance document. And I have bolded that because that is what FDA is
proposing. A guidance document would basically have the content of the
510(k) submission spelled out. There would be some clinical data if
indicated. There would be contraindications, warnings, adverse effects,
et cetera.

Now, I want to draw attention to the committee that, in August of 1989,
FDA issued what we called then a points‑to‑consider document. But it is
essentially a guideline for manufacturers as to what to submit for a
product‑license application for a blood screen. This is, conceptually,
what we are looking to produce here for this particular product. Dr.
Dayton will go into that in more detail.

Another special control can be a performance standard. Are there
voluntary standards or international standards that can be applied to
this type of product. What FDA would do, then, is we would recognize it
by rulemaking, notice, comment and rule, and that would be the special
control for that particular device if voted on by the committee.

\[Slide.\]

There could be special labeling, some restrictions, some additional
information that would be imbedded into the labeling that wouldn\'t
normally occur in a medical device because there is some greater concern
that has to be mitigated.

Patient registries; sometimes, patient registries are necessary to track
particular devices, how they are used, because there could be a problem
with them that we would have to get back and notify the patient. Again,
I am bolding here postmarking surveillance to answer unanswered
questions once the product does get into the marketplace.

It is important to note, going back to the GMP part, the QSR, design
controls are required for class II medical devices. Now, what are design
controls? The short answer is that design controls are part of the
manufacturing process where each product has a set of controls placed on
top of it where design input, design output, verification and validation
of all the manufacturing processes are tightly controlled.

This is a new concept because FDA has determined, over the last decade,
that failures of medical devices consists basically of two types. They
weren\'t manufactured according to the instructions. The other type is
they were manufactured according to the instructions but there was a
design flaw and the product didn\'t work.

The objective here of design controls is to insure that the design of
the product has been adequately challenged and it insures that the
manufacturing process, as well, can be conducted with integrity.

\[Slide.\]

Examples of class II devices; an empty container for the collection and
processing of blood, transfer bags, a quality‑control kit for
blood‑banking reagents. The controls that are used relative to CLIA,
positive and negative controls for HIV tests, hepatitis tests, are
regulated under this regulation. And they are classified as class IIs.

CMV serological reagents; the CMV test kits which are used electively to
screen donors are regulated as class IIs. Lectins and prolectins used in
blood banking are regulated as class IIs. However, we have recently
exempted them from filing 510(k)s because the safety and effectiveness
could still be assured without doing that.

\[Slide.\]

Class III; general controls and special controls are insufficient to
insure the safety of the device, so premarket approval, also known as a
PMA, must be filed. There is an alternative to a PMA called a PDP, a
product‑development protocol, but it gets you to the same place.

The main issue here is that clinical trials are required to insure the
safety and effectiveness of the device.

\[Slide.\]

Some examples of class III devices are HIV home‑collection test systems
which are sold over the counter in pharmacies; HIV tests for prognosis;
and HIV tests for monitoring. These would be the viral‑load types of
tests.

\[Slide.\]

I tried to put together a compare‑and‑contrast chart for class II versus
class III. This is not all‑inclusive, but I think this hits the major
points. Class II, general controls; class III, general controls. Class
II, special controls; class III, special controls, if necessary. Class
II, clinical data not always required. We do have the authority to ask
for clinical data in a class II medical device. It is generally not
done, but we do have the authority. With a class III, clinical data is
always required.

QSR design controls are required in both. We have a postmarketing order
option. In other words, we can say to manufacturers, \"You need to do
some follow up to answer some unanswered questions.\" Both classes are
required to report, under medical‑device reporting, if there is a
failure that could cause serious injury. They have to report that to the
Food and Drug Administration.

A difference with the class II is that there is a 90‑day review cycle.
510(k)s have a 90‑day review cycle. PMAs or class IIIs have a 180‑day
review cycle. The reason for that is that the content of the class III
PMA is generally more detailed so FDA is allowed more time to conduct
the review.

As I stated earlier, class II products have periodic QSR inspections
which are conducted by the field investigators. For a class III device,
there is a difference. There is a preapproval inspection and then
periodic QSR inspections are conducted. So, with the class III, there is
basically a GMP inspection of the plant or QSR inspection of the plant
prior to the approval.

\[Slide.\]

So, which regulatory classification are we looking at here? Well, in the
regulations, Chapter 1, 12 CFR 866, immunology and microbiology devices,
subpart D, serological reagents. The proposal would be that, in Section
866, and a number would be assigned, there would appear an HIV mutation
test.

\[Slide.\]

This is what it would look like, actually, in the regs.
Mutation‑detection reagents; a, identification, HIV mutation‑detection
reagents are devices that consist of ligands use to identify mutations
in the HIV genome in infected individuals. The identification of
mutations aids in the clinical management of HIV‑infected individuals.

We used the term \"ligands\" because we wanted to have flexibility
whereby this could be done by nucleic‑acid testing or, potentially, by
other means, serological and the like. So we would have the regulatory
designation that we would be able to use for some variance on the same
theme.

\[Slide.\]

The next part of the regulation would basically be which classification
is it. It would stated that it is a class II and special controls are
required.

\[Slide.\]

So the FDA proposal is that an HIV mutation test can have a reasonable
assurance of safety and effectiveness when regulated as a class II
medical device and the special controls proposed consist of a guidance
for the content of a 510(k) and postmarketing surveillance.

With that, I would ask Dr. Dayton to resume to spell out the concepts
associated with the guidance document and the postmarketing
surveillance.

DR. DAYTON: Do you want to take some questions now because we are going
to on to the sort of technical and scientific issues.

DR. BUCHHOLZ: I wonder if, for the committee, you could indicate the
actual time for the review as opposed to the statutory or guidance times
for a 510(k), for a PMA and for a supplement to a PMA, say, an average
over the last couple of years, just to give us a feel for how long it
takes if, for example, one wanted to make a change in a product that was
a PMA product, how long it would take to make that change as opposed to
a product that was a 510(k) product.

MR. WILSON: You have asked a number of questions there. I will do my
best and, if I slip on one, please‑‑I don\'t have the actual review
times with me, but let me try to help answer that question. For a
510(k), when the manufacturer supplies that submission, we are obligated
to review it within 90 days.

There is a device action plan that CBER is now fully engaged in and the
effort is to make that date on all medical devices that are filed under
510(k). If the manufacturer does not provide sufficient information to
allow us to make a determination of substantial equivalency to a
predicate, we would write a \"more information\" letter.

Now, it is up to the manufacturer how long the manufacturer responds.
There is a statutory requirement of 30 days an we have the option of
actually withdrawing it if they don\'t respond. I can tell you that many
manufacturers have taken a lot more time than 30 days to respond.

We try to be reasonable and flexible, particularly when products that we
think are a benefit to public health, are valuable to the market. When
the manufacturer does respond to the additional information with the
510(k), the time clock is reset. It is another 90‑day review cycle. Now,
we do our very best to review those products as efficiently as possible,
but we do have the authority to do that.

I think, to try to answer your first question, a fair number, maybe half
or more of the 510(k)s that CBER reviews, take more than one review
cycle to get clearance. So you are talking approximately six months
beyond. The regulatory requirements for making changes in a 510(k) are
somewhat different from those for a class III medical device. And we
spell that out in guidance. CDRH has done a great job of articulating
it.

It leaves the decision to the manufacturer. It is essentially if there
is a new intended use or if there is technicologic change, they are
required to file an additional 510(k). In other words, they would have
to wait to make those changes. So that is the 510(k) side of it.

PMAs, we have a statutory requirement of doing the review within 180
days. Depending on the type of response that we get, we can reset the
clock on a deficiency letter to an additional 180 days. I would say, in
most instances, in CBER‑regulated products, we do not have many products
that we have approved under class III under one review cycle.

Making changes to a PMA product, more stringent rules are required. So,
therefore, a supplement would need to be filed in many instances. The
supplement would have a 180‑day review clock on it.

Did I capture all your concerns?

DR. BUCHHOLZ: Thank you.

DR. HOLLINGER: The real asset here, somewhat, is the assurance of safety
and efficacy between these two classes, II and III. Can you give us some
more information about what you really mean by safety and efficacy, how
these really differ between II and III in terms of classifying
something? Maybe some examples, even.

MR. WILSON: I think the best example would be where we have apheresis
equipment. Apheresis equipment, in fact, has two regulatory levels
associated with it, a II and a III. Class IIs are those which the
technology is by centrifugation. Class IIIs, which are intending to
downclassify to II but, to try to answer your question, is by
filtration. So separation of the blood components are performed by a
different technology.

The centrifugation has less of a concern relative to the product
produced‑‑the platelets, for example‑‑than the filtration. The concern
with the filtration was that there would be membranes that would
potentially capable of activation platelets, so there were additional
issues of safety and effectiveness that would be of scientific concern
so that, at the time when those products were‑‑back, approximately ten
years ago, when they first came to the marketplace, they were class
IIIs.

It was found that, with the data presented to a committee back in the
1980s, that those instruments by centrifugation were found to have
sufficient safety and effectiveness regulated at the class II level.

Recently, some data has been presented to the committee whereby we have
got enough information now. What is enough information? It has been out
on the marketplace for a period of time. We have looked at the MDR
reports, the medical‑device reporting, and found that the problems are
not serious and, therefore, we feel that the lower regulatory controls
would provide us safety and effectiveness.

There are some advantages and disadvantages to which regulatory class a
product is in. There are some requirements that manufacturers have to
follow‑‑annual reports, for example‑‑with a PMA and the like.

Am I helping you here? That would be, for example, where we had safety.
Effectiveness, I am stuck here. If I could try to roll the two of them
together where the platelet is performing, when separated by filtration,
as well as when separated by centrifugation.

As you can imagine, there was a lot of detailed analysis to determine
platelet function and the like. And it was determined that yes, the
platelets were not compromised and the equipment could be felt to be
substantially equivalent.

DR. HOLLINGER: You have placed HIV tests for monitoring and for
prognosis, the NAT test, as a class III device. I think that has
something to do with what we are talking about here. I would like to
know, if you can, in the short term, tell me a little bit about why you
decided that that should be a class III device for both prognosis and
monitoring.

Some of those systems are very much maybe what we are going to be
discussing here today with this test.

MR. WILSON: I can give you the short answer. The short answer is that
when we first were reviewing HIV monitoring, viral‑load type tests, we
did not have anywhere near the kind of information and knowledge base
that we have today for genotype testing. Again, that would be the short
answer.

I think that Dr. Dayton will be providing you those distinctions as he
continues with his talk.

DR. MACIK: You talk about if you are going to make it a class II that
you would look, perhaps, at putting on postmarketing surveillance. What
does that mean an what weight does that carry if you take it out into
the market and you are watching it and something comes up. I did not go
clinical trials as a phase III. You put it out as a phaseÊII.

You are really allowing your postmarketing surveillance to be your
clinical trials. How can you bring it back? How do you get it if we let
it out there ahead of time?

MR. WILSON: Very good question. First of all, the
postmarketing‑surveillance order can have a number of different
requirements, not necessarily those constituting a clinical trial.
Again, the idea here is that the postmarketing surveillance is not
intended to be the basis for approval. That would be backwards; we clear
the product and then we will find out if it works.

No; that is not what we are trying to do here. What we are saying is the
product is clearable with what is provided to us. And then there are
some logical additional unanswered questions that, from a public‑health
point of view, probably should be evaluated. So the postmarketing order
would be structured on that.

Again, Dr. Dayton would be providing you with where we are headed with
that.

Let\'s say something goes terribly wrong. We have several regulatory
options here. One is an inspection of the facility to determine problems
with‑‑complaint handling, to see if there are a number of problems
there. We also have some, by law, ways of dealing with products that are
not performing; they are either adulterated or misbranded.

So there are compliance mechanisms to control that. I think that, if,
over a period of time, it becomes evident that a product has problems
that were not foreseen, it could be brought back to the committee and we
could present a proposal to upclassify it to the III.

Also, as I said earlier, FDA could propose to the committee. Sponsors
could also do the same thing. So there are some regulatory remedies. You
are not in II forever, if you vote for a II. But we are trying to look
at our knowledge base of dealing with guidance documents, dealing with
what we already know about these types of tests and the technology and
we feel, at least at this point, that a class II would give us
reasonable assurance‑‑the law says \"reasonable assurance of safety and
effectiveness.\"

DR. FITZPATRICK: You mentioned that you don\'t have to do full‑blown
clinical trials. So that implies to me that FDA would, then, open the
door for the manufacturer to submit data from clinical use that was not
part of a clinical trial, which they don\'t do in some other instances.
Is that what you are saying?

MR. WILSON: That could be a part of the postmarketing‑surveillance
order. Again, I think Dr. Dayton would be able to frame out where we
are, what we are proposing with that.

MS. KNOWLES: I think that I recall that even FDA recalled a
home‑collection test kit for HIV that was in III at one point in time in
the last two years; isn\'t that correct‑‑because it did not perform?

MR. WILSON: There was a home‑collection test which was classified as III
that there was a problem associated with some labeling and it got
relabeled on the pharmacy shelves and FDA took action, basically,
because there was a violation. That got corrected.

MR. DUBIN: Early on in the year, our organization had met with
Commissioner Henney. One of the things we discussed was postmarketing
surveillance in terms of AIDS drugs because we had concerns. We had all
supported fast track but we thought fast track was getting a little out
of hand.

What was conveyed back to us was a resource issue, that what we were
talking about would involve a lot of FDA resource in terms of both
people power and dollars, and there were some questions. So I think my
question is, in terms of undertaking this and managing it in a
postmarket climate, does FDA have the resources and the people power to
be able to do that and stay on top of it close enough to insure that we
don\'t have some of the problems we are seeing with AIDS drugs.

MR. WILSON: I can\'t always predict the future, but I think that the
tools that we have are structured to enable us to assure these types of
orders and maintain the integrity. For example, for postmarket studies,
it would be a postmarketing order, the obligation of the manufacturer to
do X, Y and Z.

A lot of times, we will have reporting requirements periodically over a
period of time. I can tell you first‑hand, if we don\'t get the report,
we call them up and say, \"Where is the report? You are obligated.\" We
put it in writing. We send it out and, if we don\'t get it, then we have
several other options. Directed inspection; the reviewer can propose,
because the manufacturer has not responded to the Office of Compliance,
we would like to have a directed inspection to the firm. This can be
done on a priority basis depending on the particular product involved or
health issue.

In many instances, and I have triggered them myself, within a week or
two or three or sometimes overnight, we can have inspectors into the
plant. They know what the problem or the concern is and the headquarters
is often on the phone on a daily basis with the inspectors because they
are not the headquarters reviews and they will need a little bit
insight. We have got a very good working relationship in that regard.

Does the help to answer some of the concerns?

MR. DUBIN: Yes.

DR. TUAZON: I know that the genotyping and phenotyping assays are being
used clinically right now. What regulatory measures do we have on those
used at the moment?

MR. WILSON: There are no cleared or approved tests by FDA. The products
I assume you are talking about are those that would be generically
identified as \"home brew?\"

DR. TUAZON: They are really done by the labs do our routine testing for
HIV patients.

MR. WILSON: Right. But the actual reagents, themselves? They build the
test themselves?

DR. TUAZON: These labs that we sent through the medical centers are sent
through diagnostic labs like LabCor or Quest Diagnostics.

MR. WILSON: There is‑‑and this can get a little bit complicated so I am
going to try to give a short answer but there is a regulation called the
ASR Rule, analyzed specific reagents, which has requirements for some
home‑brew types of products. I guess I can say that, with the outcome of
this vote here, that may have some effect on the regulation of those
types of tests.

But the objective of that would be to level the playing field. I think
it is important to bear in mind that‑‑I think all want good‑quality
tests of high integrity that have the reliability, et cetera. Whether it
is a home brew or whether it is regulated by FDA as a normally
distributed commercial product, it should work well.

So we have got two arms for regulation, one for the home brew and the
other for traditionally commercially distributed products.

DR. HOLLINGER: Thank you, Mr. Wilson.

Dr. Tabor?

DR. TABOR: Just in further answer to Mr. Dubin\'s question; provided
there is no negative impact on the public safety, the use of the 510(k)
mechanism is resource saving for FDA because a lot more FDA human
resources have to go into the review of a class III device than a class
II device.

DR. DAYTON: Let me elaborate on some of the questions that Len just
answered and, in particular, let me start with Dr. Hollinger\'s question
about special controls and how you would choose between class II and
class III. Let, of course, gave a very accurate answer but the way I
wanted to elaborate on it was to portray to you how we feel this
decision should be viewed for this particular product today.

Imagine‑‑you don\'t have to imagine. Take a mutation which gives you
well‑documented resistance to a certain drug. Let\'s assume that there
is a long history in the literature studying that mutation. You see it
appear in patients when they are on that drug. If you switch to another
drug, it disappears, they do better, et cetera, et cetera, et cetera.

This would be the kind of data that we would consider adequate to let
this product be regulated under class II. In other words, there is a lot
of data in the literature. It is well‑done. It is well‑known. It is
well‑characterized. And we don\'t see a particular need for clinical
trials, premarket.

Take, by comparison, another mutation. Let\'s say there is one study
which shows that it appears when patients are on a particular drug. We
would want to see more data for that second type of mutation.

The way we would like to handle this is we would like to‑‑the
postmarketing surveillance, essentially, is claim specific. So the way
that we would handle this is we would like to let a product under class
II regulation go to market for the first type of mutation to back a
claim for the first type of mutation.

So, in other words, the assay could claim to pick up that particular
mutation which is well characterized and that would be of benefit to the
patient. If they wanted to have an additional claim for the second type
of mutation, the one which isn\'t so well characterized, they would have
to submit additional data in the postmarket period to get that claim.

We feel that, by splitting it up like that, we can get these products
out there fairly quickly and we can also control them very effectively.
The whole issue of claims is very important because that is what the
postmarketing surveillance will address. Postmarketing surveillance
will, in part, be largely claim‑specific. It will address additional
claims.

In terms of FDA mission, even if there is one mutation out there and it
is clinically relevant and an assay can pick it up and can redirect
therapy, that is benefit. That is clinical benefit.

In the real world, we believe that there are mutations which are fairly
well characterized. There are a lot of mutations which are less well
characterized. In fact, Dr. Mayers and Jeff Murray will be presenting
data to show that, actually, these assays are clinically beneficial. We
believe that the reason for that is because the mutations‑‑there are
mutations that are correctly characterized.

I think that those were the key issues that I wanted to address before I
sort of give the introductory talk to the next two speakers.

\[Slide.\]

The highly‑active antiretroviral therapy has been a tremendously
successful approach for treating HIV infections. Unfortunately, it is
not perfect and it is still plagued by therapeutic failures. Mostly,
therapeutic failure is heralded by falling levels of CD4‑positive
lymphocytes and rising levels of circulating HIV.

However, these two parameters are not always inversely correlated and
they are, at best, indirectly measurement of therapeutic failure.
Consequently, there is an increasing need for more accurate and more
direct measures of therapeutic failure, particularly measures which
identify the mechanism of therapeutic failure.

\[Slide.\]

HIV drug resistance assays promise to fill this need. One of the most
common, but by no means only, causes of treatment failure is the
existence or emergence of virus species resistant to the drugs included
in the regimen. Various categories of assays exist to measure HIV drug
resistance.

As general examples, in one approach, virus is isolated from a patient,
expanded, titered and tested in replication assays in the presence of
antiretroviral drugs. In another approach, the reverse transcriptase
and/or protease regions of the infecting virus are isolated and
subcloned into well‑characterized laboratory strains.

These derivative viruses are then expanded, titered and tested for drug
sensitivity and resistance. Dr. Murray will go into more detail on the
types of assays currently available, but these assays are
time‑consuming, laborious and ill‑suited for use in general clinical
laboratories.

\[Slide.\]

HIV genotype assays have been developed as a relatively simple,
cost‑effective measure for determining the drug resistance sensitivity
profile of HIV in infected patients. These assays can either be based on
direct sequencing technologies or on hybridization technologies. The
information they produce is the nucleic‑acid sequence or genotype at
critical codons of reverse transcriptase and protease which are known to
be critical for determining drug resistance and sensitivity.

In other words, genotype assays determine the viral genotype and use
this information to predict viral phenotype which, for our purposes
today, is the clinical phenotype which, in this case, is the drug
resistance sensitivity profile of the circulating virus or the expected
response of circulating virus to clinical intervention.

\[Slide.\]

The predicted phenotypes are then used to guide treatment choices for
patients identifying to which drugs the predominant viral species is
resistant. This information is used with information about the
patient\'s previous viral regimens and it can be useful in choosing new
regimens in patients experiencing therapeutic failure.

So it is an important point to realize that these are not stand‑alone
assays. These are used in the context of the entire clinical picture of
the patient. In fact, as you will learn later, these assays often will
not detect minor species and there can be minor species of resistant
mutants left over from previous antiretroviral therapy.

\[Slide.\]

The motivation for FDA\'s desire to downclassify these genotypes is that
we feel it would be an overall benefit to the public health.
Downclassification would allow enhanced physician access to these assays
by allowing sponsors to go to market with premarket clinical sensitivity
and specificity data, allowing postmarket clinical‑trial data to further
correlate assay prediction with clinical responses.

This would significantly facilitate clinical trials for new drugs and
therapeutic regimens. As I said, the relevant science can be complex and
incomplete but it is FDA\'s opinion that sufficient information exists
to insure a significant level of efficacy of these assays by formulating
an appropriate set of special controls.

In other words, we feel that, although we are not perfect, there is
enough science out there that we can sit down and say, this is what
needs to be done. We can identify these studies and they will tell us
whether or not these assays are going to be beneficial.

It is also FDA\'s opinion that postmarketing studies can be designed to
further improve the efficacy of these assays as increasing scientific
knowledge is obtained.

\[Slide.\]

We are drafting a guidance document outline requirements anticipated for
regulation of HIV drug resistance assays as class II medical devices.
Obviously, we won\'t go very far with that document. If you decide to
regulate it a class III, we will just recast it as a class III document
and change the ideas.

This document,as it stands now, addresses issues pertaining to assay
precision, reproducibility and accuracy, quality control of reagents,
laboratory testing and pre‑ and postmarket clinical data requirements.
FDA\'s current thinking about the contents of this guidance document is
contained in a September, 1999 concept memo which covers highlights of
the guidance document and which has been included with your pre‑meeting
materials.

What we gave you in the pre‑meeting materials doesn\'t cover all of the
details in the guidance document such as the manufacturing controls. We
tried to limit it to the critical issues which are relevant to your
decision here today.

Over the course of the next few minutes, I will review these highlights
with you.

\[Slide.\]

First, we start with the nonclinical laboratory data and we focus on
validation of phenotypes predicted by genotyping. I will start out by
saying that in this part of the guidance document, we expect to attract
a lot of comment, a lot of discussion. The guidance document will be put
out in draft form for public comment after we have cleared it in‑house
and there will be a lot of scientific input to it at that point.

What we are thinking about now, as an example, is that, in general,
sponsors will be expected to validate claims that certain genotypes
predict certain phenotypes. We expect that validation studies will
include in vitro viral‑replication assays and determination of the
effect of a given genotype on the 50 percent or 90 percent inhibitory
concentrations of the drugs in question.

We are also entertaining the concept that when non‑clinical validation
studies demonstrate an eight‑fold or greater increase in the IC50 or
IC90 associated with a given resistance mutation, validation may or may
not also include certain types of clinical validation studies of
individual mutants.

We also expect that when nonclinical validation studies demonstrate a
less than eight‑fold increase in the IC50 or IC90 levels associated with
the mutation that validation will require clinical validation studies.

\[Slide.\]

We have requirements for analytical sensitivity. We assume that we will
ask sponsors to perform sensitivity, precision and reproducibility
studies on spiked samples and anticipate that sponsors will submit
sensitivity data for all single and multiple mutations for which a claim
is sought. Basically, what we are saying here is if it is there in the
tube, can you measure it? Can you sequence it?

The sensitivity studies should determine and validate both the minimum
viral level and the minimum mutant proportions reliably detected by the
assay. So we want to know can you pick this up if your viral load is
down at 1,000 copies per ml, or does it have to be up at 10,000Êcopies
per ml.

If the resistant mutant is present as 5 percent or 10 percent or 25
percent of the infecting population, can you detect it? We assume, but
it may not necessarily be true that the assays will demonstrate in these
studies sensitivity at viral levels which are clinically relevant.
Certainly, that is our preference.

FDA also anticipates requiring accurate titration of sensitivity through
and below the minimum detectable levels and proportions. Basically, we
want to know how quickly does assay performance deteriorate with
decreasing levels or proportions of the analyte.

\[Slide.\]

Clinical data. A key issue here is going to be validation of the
phenotypes predicted by genotyping because that is the key question. Our
current thinking is that validation studies should, optimally, include
determinations of the existence or appearance of a given phenotype in
patients subject to antiretroviral therapy as well as correlation of the
disappearance of a given mutation with changes in antiretroviral
therapy.

Throughout these studies, FDA will probably want to see data on overall
viral burden, as well. We are considering the possibility that viral
burden may be an adequate indicator of response to therapy for
particular drugs. FDA may variably recommend or require clinical studies
to validate the phenotypes of individual mutations according to the
changes in IC50 and IC90 determined by in vitro viral replication
studies.

Basically, what we are saying is, let\'s see how good your in vitro data
is and then we will decide whether or not we will need additional
studies. Certainly, we will be interested in seeing data in the
literature as well as data done specifically at our request.

\[Slide.\]

For clinical sensitivity, one of the things that has been proposed to be
done is to do sensitivity and reproducibility studies on a panel of
unspiked specimens whose genetic makeup is known. Basically, somebody is
going to have to, presumably, sponsor, or industry, is going to have to
take a bunch of patients, get specimens on them, determine what the
distribution of the viral swarm, or the quasi‑species, is and then show
that they can always pick up the mutations that they are looking for, or
can pick them up with a certain sensitivity. These would be unspiked
samples.

On this particular issue, of course, and, as on all the others, further
discussions will determine whether or not the panel must include
representatives of all genotypes to which a claim is sought.

\[Slide.\]

The FDA is also considering requiring traditional clinical trials in
which assay phenotype predictions based on genotype correlate with
changes in viral burden and/or mutant representation in response to
antiretroviral therapy. FDA may also allow these studies to be
prospective or retrospective on archived specimens.

\[Slide.\]

To facilitate these things coming to market, we are giving serious
consideration to the concept of requiring either the panel‑type clinical
studies or the traditional clinical trials but not both to be submitted
premarket. Now, certainly, a manufacturer could submit both premarket if
they wanted to, but we feel that there is a likelihood that we will be
willing to say, \"Well, look; if you have got the clinical‑trial data,
you can do the panel‑type data postmarket.\" Or, \"If you have the panel
data and you want to go ahead, you can get some of the clinical‑trial
data postmarket.\"

In this case, FDA would anticipate requiring the alternative studies to
be submitted postmarket, as I have just said.

\[Slide.\]

As we have discussed here, we are almost surely relying on extensive
postmarket studies to further support claims made during the approval or
clearance process as well as additional efficacy claims; for instance,
new correlations between phenotype and genotype.

\[Slide.\]

In being asked to classify HIV drug resistance genotype assays as class
II medical devices, you are being technically asked to vote on the
classification and on the adequacy of special controls. This presents a
little bit of a quandary for you because the special controls are
outlined in the guidance document and we have only given you highlights
of that guidance document, and it hasn\'t been finished.

Although the special controls are in a guidance document which is
currently in draft format only, we feel that the information presented
today will convince you that the clinical and scientific data in the
literature are such that our expertise, together with the expertise of
all of the scientists, clinicians and members of the general public who
choose to contribute to the final document will be sufficient to
formulate adequate special controls to insure efficacy and safety.

So, in the upcoming presentations, what you need to look for is does it
look like the field is at a point where the field can sit down and
identify adequate special controls for at least some mutations which
would allow these kits to go to market with such identified special
controls.

With that, we have some presentations. Who is up first? Doug? We have
going to have Doug Mayers talk. We will entertain questions, but one
thing I did want to say in response to Dr. Hollinger\'s question about
class III regulation of viral‑load tests. Len was really quite accurate.
We know a lot more now with these tests that are coming to market, or
are coming up, the genotyping tests than we knew in the early days of
viral‑load testing.

There are going to be a lot of questions. I am certainly happy to
entertain questions now. You are just about to get two talks that go
into the scientific and clinical literature in much more detail than I
have described it. So I am certainly willing to answer questions, but if
you think it might be answered in the next two talks, you are certainly
welcome to wait.

DR. HOLLINGER: It doesn\'t look like the committee thinks they can wait.

DR. VERTER: It\'s a good try, though. In trying to read some of the
documents last night and listening to the two presentations this
morning, I wonder if you could clarify‑‑I am still having trouble
understanding the II/III issue. From what you just described, it seems
to me almost like a very fine line. In fact, it almost came down to the
statement, \"Considering the concept of requiring either the panel‑type
clinical studies or the traditional clinical trials, but not both,\"
whereas, in a III, do you require both and in the II only one? Can you
give me some feel about that?

DR. DAYTON: We are kind of skirting the issue a little bit there. And it
is confusing. I think one key point to make is we can make class II
regulation as stringent as we want it, if we really want to. So we can
make it as stringent as class III, basically.

What was the second part of your question?

DR. VERTER: I was just trying to clarify in my mind, and maybe in some
others, as to where the fine line is. I understood what you just said
and I thank you for that comment.

DR. DAYTON: The real question is, as I said, does it look like we can
identify special controls or studies that are going to make this thing
effective, even partially effective. The critical issue is not so much
whether we require one pre and one post. That is something that we are
thinking of.

The real issue is does the science say, \"Look; the field is far enough
along that some mutations can be fairly well guaranteed to be relevant
in measuring them and, therefore, be effective. That is the key issue.

Have I answered your question? Have I addressed it?

DR. VERTER: You have addressed it.

DR. MITCHELL: Can you tell me what do you mean by panel‑type clinical
studies? Is that presenting panels of known‑‑

DR. DAYTON: It would be‑‑basically, as the proposal stands now, we
somebody would assemble a panel of 50 unspiked patient specimens.
Presumably, they would take each one and they would make multiple clones
from them by standard microbiological techniques, sequence them in the
regions that we are interested in, and come up with a description of the
distribution of quasi‑species in the viral swarm.

So, for instance, if there is a particular mutation you are looking for,
it might be there 10 percent or 1 percent or 25 percent. Then you would
take a panel of these and you would challenge them. You would put them
through your assay as opposed to subcloning and sequencing and
everything. You would put them through your one‑shot assay and you would
see how well you pick up the mutations that are there and at what
concentration.

In a way, it is like the spiked panel studies except that it is
unspiked. It is a more natural environment. And it is a tougher
challenge. Does that explain it?

DR. MITCHELL: Yes. Thank you.

DR. BOYLE: I think I am grappling with the same thing everybody else is,
but let me see if I understand correctly. In a class III, you would
normally require clinical trials before it be approved for use in the
marketplace whereas, in a class II, you might require clinical‑trial
data but it could be done postmarketing?

DR. DAYTON: Well, no. In a class II, we actually could require clinical
trials premarket if we had to. That is an option. But what we would be
doing in a class II situation, in the situation we would like to do, is
looking at clinical data in the literature and be able to say, \"Look;
these mutations here are really quite well established so we are quite
confident that they deserve a claim for that.\"

But there are this whole set of other mutations over here that we know a
lot less about. So, if you want to claim them, you come back postmarket.
You can go to market but you only get a claim for the first set of
mutations and you only get the second set of mutations when you come
back and prove it.

But, again, it could be data in the literature, not necessarily
clinical‑trial data. We could also specify clinical‑trial data in
postmarketing, which we may do.

Len, did you want to comment on that question?

MR. WILSON: Maybe I can help out a little bit. I am going to use an
example of something that already exists, CMV assays, class II medical
device. The intended‑use statement goes on the line of to detect
antibody to CMV in the serum of blood donors, or some such. It doesn\'t
say, for the prevention of CMV transmission. It doesn\'t say that.

If it said for the prevention of CMV transmission, you would have to run
a clinical trial to show that it does that. But since it is limited to
for the detection of CMV antibody‑‑all right; what is the content of the
510(k) class II. Many of the concepts that Dr. Dayton has described are
just, simply, reproduced in the class II.

We have analytical sensitivity data, analytical specificity data.
Because it is used for the blood supply, we run a study that is in blood
donors to check specificity because you can\'t check specificity in a
blood‑donor population any other way than running it. And why would we
do that? Because we don\'t want to have too many units of blood tossed
out because of false positives.

We do have, and I think along the lines of where Dr. Dayton is going,
some known positive samples that we would test‑‑the manufacturers would
use the test to determine whether or not, in fact, they truly detect a
true positive. But it is not in clinical‑trial format in that sense.

So, therefore, that enables FDA to clear the product with claims or
labeling limited to what the thing has been documented to do. So, in
terms of this particular assay, there are a lot more questions and we
know that, because of viral resistance and mutations, things are going
to change and the logical issue is that there are going to be new
mutations and how does this correlate and the like. That could be done
in a postmarketing surveillance type of order.

I hope that helps.

DR. DAYTON: If I can continue on; what I think you will see in the later
presentations is that there are quite good laboratory studies for the
significance of various mutations. There is data for the appearance and
disappearance of these mutations in the literature and there are also
studies coming out showing that use of these types of assays has
clinical benefit.

So, if you put all of that together, that is really telling you a very
strong message; hey, these things work. What we would be saying is,
\"Okay; these things work but we want to see more in the postmarket.\"

Does that answer your question?

DR. BOYLE: Yes.

DR. FITZPATRICK: You said the panels have not been developed yet. When
we began HIV testing, there were difficulties developing reliable panels
in enough source to be provided to all the laboratories doing testing to
get similar results. Is your expectation that this is much easier now?

DR. DAYTON: We are leaving that up to sponsors at the moment. We are
certainly open minded about how to actually approach this. It should be
reasonable for a sponsor to assemble his own panel which might be the
quickest way to do it, but it is quite laborious.

It would be also possible to have a centralized panel set up. Also a
sponsor has the alternative of coming forward with the clinical‑trial
data while he waits‑‑and doing the panel postmarket. We are trying to
make it flexible so that it can go either way.

I think Ed wants to comment on this.

DR. TABOR: I think the discussion is confusing the issue tremendously.

MR. DUBIN: We have done that before.

DR. TABOR: I think part of it is that it is focussing on constructing
panels and focussing on postmarketing surveillance. The issue is between
whether this should be a class III device or a class II device. The
discussion should have nothing to do with blood screening because a test
that is used for blood screening usually is a licensed product for which
a PLA is filed.

What we should be focussing on is is the clinical impact of this assay
so great and, perhaps, so unknown that you need clinical trials and to
file a PMA and have an 180‑day review clock which really translates into
more than a year of review time with resubmissions or is the clinical
significance of this so clear and is the impact on the patients\' health
more an issue of management than of life and death such that the
manufacturer can file a 510(k), have a 90‑day review clock, and have
minimal or no clinical data.

Postmarketing surveillance is another issue, I think, here. It is not
totally divorced from this but you shouldn\'t be focussing on something
that you want clinical data and you are going to wait and get it after
marketing. If you want clinical data, it should be a PMA and a classÊIII
device.

The question here is are the manufacturers going to have to go through a
longer review cycle with more clinical data up front or are they going
to be able to file a 510(k) with only special controls and any clinical
data, really, as icing on the cake.

DR. DAYTON: Let me just elaborate on Ed\'s response. It is absolutely
correct. Again, don\'t feel that you are having to judge a particular
product. You are asked to judge, is the science such that we can judge a
product, or that a product can be judged.

DR. HOLLINGER: I think probably we ought to listen. I think that the
next step should probably be to listen and see what the data is out
there and see what it means. Let\'s have one more and then let\'s go to
some of the data.

MR. DUBIN: I was going kind of towards where you were going, Dr. Tabor.
Here is how we frame the question. I think, from our perspective, the
big plus is if this is going to give clinicians who are actually, at the
grass‑roots level, treating patients and dealing with resistance
problems, then that is going to give the clinicians more freedom and
more ability to move.

I think, from our perspective, that is clearly a good thing because,
certainly, in hemophilia, this is a big problem in the infected
hemophilia community. We are having a lot of problems with the resistant
strains and a lot of our guys are in trouble.

Our only concern, and the way I was trying to frame it, was we have had
concerns about how fast‑track has gone, things that have happened and
have caught our attention and concerned us. But I think, in this
instance, the issue is, and I agree with you, if we can do this in a way
that provides the freedom to the clinicians and the ability to track it,
then it seems like a no‑brainer on one level from our perspective.

DR. STRONCEK: I have a couple of comments. There are a number of HLA
tests where genotyping is used to determine phenotype which are marketed
so I presume they are regulated. Are those regulated as class II‑‑class
II, I would presume.

The other question is are the current NAT tests being done on blood, are
they regulated as class III? Ed seemed to suggest that it is something
different. Then, if that is true, I am really confused.

DR. TABOR: Let me answer your second question. The NAT test to be done
on blood, or for blood screening, they will be required to file a PLA or
BLA for licensure the same as for any of the other required or
recommended tests for screening blood. There was a very big regulatory
issue about two years ago when the manufacturers wanted to just go ahead
and do the testing. And we said, \"No; there are a number of issues that
make this a blood‑screening assay.\"

So those will be PLA tests that are being done under IND now, and they
are totally separate from what we are talking about here.

With regard to the HLA test, I think someone from Devices will have to
answer that. I am not familiar with that.

DR. DAYTON: I don\'t know the answer to that.

MR. WILSON: Those HLA tests which are used that are labeled for the
detection of the antigens are predominantly class I. There are some
which are class II. I am talking about the ones that are non‑diagnostic.

DR. BUCHHOLZ: Just having watched this from an industry perspective for
a number of years, I wonder if I could try simplifying a little bit this
class II and class III.

I think, back in 1976 when this device legislation took place, there was
an effort to kind of establish risk categories associated with a device.
A device, class I, not much risk if something goes wrong; class III, a
lot of risk if something goes wrong.

I think, in some of the original language, there was the concept of
life‑sustaining device for a class III device, like an implanted
pacemaker. I think the thing that is probably confusing the committee is
that there are now some things that are, by fiat, put in class III
because there was no predicate device; by that, there was no device like
what we have today because the problem didn\'t exist.

So those devices end up being bumped in this classÊIII category until
they can get dispersed into, perhaps, a more appropriate category.

Does that help a little bit?

DR. HOLLINGER: Thank you, Don.

Why don\'t we go ahead, Andy.

DR. DAYTON: I guess we are ready for Doug Mayers.

**Presentation**

DR. MAYERS: I want to thank the FDA for making drug resistance
interpretation seem simple.

\[Slide.\]

What I would like to do in the next forty minutes or so is go over the
background of HIV resistance testing, a little bit about the biology of
HIV resistance and then overview the current clinical data both
retrospective and prospective. By nature, this is going to be a survey
and not exhaustive because there are far too many studies today than the
time I have to present them.

I just want to make a caveat that I will occasionally use a company
slide in this talk because I didn\'t have a slide to illustrate the
point, but those slides are made to illustrate a biological point and
not the support any company and, where possible, I have used every
company in the area\'s slides, one of each, so they don\'t feel like
they have been slighted.

\[Slide.\]

It is important to recognize of HIV that the replication of the virus is
very rapid in a patient such that patients make up to a billion
particles each day with a half life of about one day.

\[Slide.\]

The reason this is important from an HIV resistance point of view is
that the virus, as a replication strategy, makes, on average, one error
per each progeny virus. So, if a billion viruses are produced and you
have a 10,000 base virus making, on average, one error, that means you
have 100,000 of every single‑base variant and about ten copies of every
double‑base variant in your patient.

So when you have these discussions of do drug‑resistant viruses exist at
some level, yes, in all of our patients, they exist and they are
spontaneously produced every day in the patient. This is the virus\'
strategy to escape immune pressure and it also uses it to escape drug
pressure.

\[Slide.\]

In 1989, two years after AZT was introduced into clinical practice, Doug
Richmond and Brendan Larder had a paper that came out in Science. What
they showed was that viruses were produced in our patients that were
100‑fold less susceptible to AZT than when they started therapy.

This shows the phenotype assay results from that paper. What you have on
the vertical axis of this is the amount of virus replication relative to
a no‑drug control. On the horizontal axis is drug levels. What you can
see in the upper left‑hand panel, C, is that for the virus in light blue
that the virus is susceptible to AZT and it takes about 0.03 micromolar
of drug to suppress it.

Then, as you watch the viruses over time, you can see that you move out
to the yellow virus which is obtained a number of months later and now
the virus is 100‑fold less susceptible to AZT and it takes about 3
micromolar of drug to suppress it.

We were very lucky with AZT. You have an 100‑fold difference between
sensitive and resistant virus so it is fairly easy to pick out what
resistance was. This is the standard type of phenotypic test that would
be reported out to the clinician.

\[Slide.\]

About six months later, Brendan Larder and Sharon Kemp took paired
isolates from that original study. They took studies from before the
patients had seen drug and a sample of virus when the patient had highly
drug‑resistant virus. With six pairs, they were able to show that there
were four mutations associated with AZT resistance at positions 67, 70,
215 and 219.

Over the years after that, two more mutations were associated with AZT
resistance but most of the story was well explained with six paired
isolates. This would be the resistance‑associated mutations or a
genotypic assay. So you can either grow the virus in the presence of
drug or you can look for mutations associated with resistance.

\[Slide.\]

Once we had these assays available, we were fairly quickly able to show
what was associated with the development of resistance; host factors,
either advance disease or low CD4‑cell counts, virus factors such as
very high levels of HIV RNA in the blood, baseline drug susceptibility
and antiviral drug activities, the virologist\'s paradigm being that if
you don\'t have a drug, you don\'t have drug resistance.

\[Slide.\]

Looking at the emergence of resistance, there are three patterns that we
see in the clinic. There are some drugs in which you see very rapid
emergence of very high‑level resistance. These are drugs such as 3TC and
the non‑nucleoside agents. The reason you see very high‑level resistance
emerge quickly is that a single‑point mutation will produce a hundred‑
to a thousand‑fold resistance to these drugs.

So these viruses preexist in the patient and if you do the calculation,
you expect it would take about fifteen days for them to emerge under
drug pressure. In monotherapy studies, it took about fifteen days for
these drugs to produce high‑level resistance. So these are the drugs in
which it has very clearly been associated with the loss of activity is
associated with single‑point mutation.

The next drugs take a moderate amount of time, usually three months or
more, to get high levels of resistance. And these would be drugs such as
zidovudine, abacavir and the protease inhibitors. The reason these drugs
take a bit longer to get high levels of resistance is you have to have a
number of mutations. So it takes the accumulation of three, four or five
mutations to get high‑level resistance and it takes the virus a period
of time in the presence of drug to get to those high levels. But it is
fairly easy to describe what resistance is in them because they do get
the high levels of resistance.

The last group of drugs, ddI, ddC and d4T are really where much of the
controversy of interpretation of resistance assays comes from. From
these drugs, you never really get very high levels of resistance in the
clinic with the drugs. You get four‑ to five‑fold resistance which is
almost within the assay variability of a phenotypic assay. So there
always a fair amount of debate as to what ddI, ddC or d4T resistance is.
This leads to some of the variability in the reports that the clinicians
receive from the laboratories.

\[Slide.\]

Looking at a crystal structure of the reverse transcriptase, what you
can see is that along a loop between about bases 65 and 75, there is a
whole string of mutations associated with nucleoside resistance with
multiple different agents. And so it wouldn\'t be surprising that
resistance to one drug might be associated with cross‑resistance to
other drugs in the class.

\[Slide.\]

This has clearly been shown. For zidovudine, it produces low levels of
resistant to ddI and ddC as you get high levels of zidovudine
resistance. But, more importantly, it has been shown that once you have
high‑level zidovudine resistance, combinations of AZT‑ddI and AZT‑ddC
did not lead to clinical benefit.

For 3TC, abacavir, ddI and ddC, these drugs all have overlapping
mutations. Clearly, one drug will produce mutations at some level of
decreased susceptibility to the other drugs. And d4T hangs out by itself
because we really, even in 1999, don\'t understand d4T resistance very
well.

\[Slide.\]

An aspect that has been very interesting to virologists but it has
complicated things for the clinician is that the virus can take numerous
routes to get the high levels of resistance. The good news from a
clinical point of view is that the vast majority of isolets do it the
way you would expect. They get AZT resistance. They get 3TC resistance.
They add the classical mutations together to produce a high‑level
resistant virus.

But, in the last year or two, we have discovered that a small number of
patients can go down a different pathway of a 151 mutation and, even
more fascinating, the virus can actually add six bases into that loop I
showed you and produce high‑level resistance by an insertional mutation
which we never expected to see, but it can be easily identified.

\[Slide.\]

From a clinical management point of view, though, the vast majority of
our patients are failing with 215 and 184 with associated other
nucleoside mutations. So, from a clinical point of view, the
overwhelming majority of patients fail with known mutations and known
resistance patterns.

\[Slide.\]

Moving to the non‑nucleoside drugs, the non‑nucleoside drugs have a
totally different pocket from the ones of the nucleosides. The picture
has actually become relative simple in 1999 because of the use of the
non‑nucleosides in combination with either AZT or d4T. The vast majority
of the non‑nucleoside agents right now are failing with a mutation at
position 103, a single‑point mutation called K103N. This mutation,
essentially, inactivates all of the non‑nucleoside drugs.

\[Slide.\]

This just shows, in a number of clinical isolates, that isolates that
only had the 103N mutation with non‑nucleoside resistance had developed
significant decreases in susceptibility to efavirenz, nelvirapine and
delavirdine.

\[Slide.\]

Moving to the protease enzyme, the protease enzyme has sort of a
bewildering assay of mutations that you can see but, in all honestly,
only about five or six of them are really critically important to
high‑level resistance. Those are shown in this model by the red balls.
They are the mutations that tend to occur in the active site of the
enzyme and produce resistance.

There are a number of other mutations that are associated, in this
figure with the yellow or white balls, and these are compensatory
mutations. What you see the virus doing in patients is the virus will
develop a critical‑site mutation, a red‑ball mutation, and get some
level of resistance. But then it doesn\'t grow very well. It doesn\'t
cut proteins as well as a protease so it adds in two or so of the
compensatory mutations. Then it adds back in another resistance mutation
and it works its way through fitness base.

But, for the practicing clinician, what you really need to do is just
count how many critical‑site mutations were there.

\[Slide.\]

This shows the critical‑site mutations for the drugs that are currently
available. For saquinavir, it is 90 and 48. For indinavir, it is 82, 46,
84. Nelfinavir, it has been the D30N, usually L90M, occasionally. And
for amprenavir, it appears to be a 50 mutation.

\[Slide.\]

An issue that has caused real concern of resistance was initially data
from indinavir where they showed that if you had high‑level phenotypic
resistance to indinavir, there was a loss across the class of
resistance. For ritonavir, it is 100 percent. For saquinavir, it is 60
percent. Nelfinavir, it is about 75 percent. And, with the newer data
for amprenavir, it is probably closer to 55 to 60Êpercent of these
isolates would be resistant.

This is one place, as we will see later, where genotyping hasn\'t been
as useful as we might have liked and phenotyping actually has been very
useful to help find which of the lucky patients has sensitivity to one
of the proteases that remains.

\[Slide.\]

For nelfinavir, this appeared to be different and amprenavir it appears
to be different in that initial resistance to one drug does not produce
cross‑resistance to the rest of the class. A concern that has come up
has been that, even though they don\'t have primary mutations that are
cross resistant, they share a lot of the background polymorphisms and
the compensatory mutations and so, are you one mutation short of
disaster.

\[Slide.\]

It appears that may actually be the case for these drugs so that you can
get a good response with the next agent but you have to totally suppress
the virus or you can rapidly see broad class resistance emerge after
that type of protease inhibitor.

This just shows that the addition of a single V82A mutation took a virus
from totally ritonavir‑susceptible to highly ritonavir‑resistant.

\[Slide.\]

The slide illustrates the point that in the management of patients on
protease‑containing regimens that a single‑point mutation will lead to
the initial loss of antiviral activity but if you leave the patient on
the protease inhibitor for any extended period of time, you will see the
sequential additional of multiple mutations.

The reason this is important is that is important is that, in most
instances, there is low‑level resistance associated with single‑point
mutation and not very broad cross resistance. But once you get to five
and six mutations in the virus, you have a virus that is highly likely
to be both highly resistant and relatively broadly cross‑resistant.

\[Slide.\]

This is just some data that came out of a recent meeting in which they
looked at patients who had had several PI regimens. They looked at
ten‑fold decreased susceptibility to any of the available agents and
showed that about three‑quarters of the isolates had decreased
susceptibility to all of the agents by the time they got there.

\[Slide.\]

Switching over to susceptibility testing, the sort of gold standard for
susceptibility testing was an assay developed in 1990 between the ACTC
and the Department of Defense in which we took patient isolates, we grew
them and expanded them, titered them and assayed them for drug
susceptibility on patient‑donor lymphocytes.

\[Slide.\]

This assay allowed us to look at roughly 95Êpercent of the patients and
look at how they were failing on drugs. This just shows the
susceptibility pattern. The green and the yellow are pre‑therapy
isolets‑‑the white and the red are post‑therapy isolets‑‑that were
obtained from that original study the Doug Richmond did back in 1989.

\[Slide.\]

The nice aspect about this assay was we had reasonably good quality
control. You could note susceptibility within about three‑fold. Sort of
a standard of thumb has been that if the decrease in susceptibility is
less than three‑fold for these types of assays, you are not really sure
if it is resistance or just assay variability.

The newer assays may be able to get down to the two‑fold,
two‑and‑a‑half‑fold, but I think the two‑ to three‑fold is about as
close as you can know a phenotype on a virus.

\[Slide.\]

We were able to actually set reasonable cut points for sensitive,
partially resistant and resistant that actually had clinically validated
meaning. The sensitive of less than 0.2 micromolar was based on
patients\' isolates who had never seen drug and the range of
susceptibilities in wild‑type virus. Resistant was associated with loss
of clinical activity and clinical disease progression.

\[Slide.\]

The problem with this assay is illustrated in this chart. Times 0 on the
bottom is the time at which phenotypic resistance emerged in these
patients. This was a study done in about 1993. What we showed was that
patients who always remain sensitive had good stable CD4 counts. The
unfortunate news was that, by the time we saw phenotypic resistance from
a co‑cultured virus from the cells, the patient was already failing by
enough‑‑had had about a 50Êpercent CD4 decline and so the clinicians
didn\'t need our assay to tell them that they were not doing well.

\[Slide.\]

About this same time, data began to emerge from 3TC and also some of the
AZT studies that, if we took the plasma virus and looked at that for
mutations or susceptibility that we could actually detect resistance
very nicely at the beginning of the rise in the viral load as opposed to
the PBMCs where it took a bit longer to show up.

So most of the focus on resistance testing has moved from trying to take
cells in coculturing virus to looking at the virus that is circulating
in the plasma in an individual patient.

\[Slide.\]

Currently, all of the assays available, either genotypic of phenotypic,
basically PCR a segment of the virus that includes the protease gene and
the early 250 to 300 bases of the polymerase gene which is where we have
identified resistance mutations. So, basically, you lift out from the
plasma the protease and part of the RT gene and then, for phenotypic
assays, you clip it into a vector and grow it up. For genotypic assays,
you sequence it.

\[Slide.\]

This just points out that we have to PCR amplify for all the assays we
use on that segment of the genome.

\[Slide.\]

This just shows what a sequence looks like that we are actually doing.
The sequence with the arrow over it shows the detection of the emergence
of a subpopulation of virus. So, basically, you either have a peak by
itself which can be described as a single amino acid or you have a peak
where there is a mixture. Those can be associated with minority
populations of virus.

For all the assays we use for genotyping right now, they all use
population sequencing and we basically can pick up somewhere between 30
and 50 percent minority populations. So these assays clearly do not pick
up minority populations well. We are not picking up 5, 10Êpercent virus.
We are picking what the predominant circulating virus is in all of these
assays.

One of the difficulties with doing these assays is also illustrated by
the arrow in the second row because the mutation they are pointing out
isn\'t associated with resistance.

\[Slide.\]

For the common viruses, we take that same segment of the genome. We PCR
amplify it, put it into a deleted vector, grow it up and then test it
against drugs. The reason that this has been, I think, very useful in
the development of resistance testing is that this allows us to not have
the alterations in the virus associated with growing it up for long
periods of times in cells. It also speeds up the process so, instead of
taking six to eight weeks to get a phenotype back to the clinic, the new
RVA assays can turn a result around in about three weeks back to the
clinic.

So it has been a significant increase in speed and it looks like there
has also been an increase in quality control such that their variability
appears to be less than the variability we had with the PBMC‑based
assays.

\[Slide.\]

This just shows the types of susceptibility curves that they can get.
What you see here is the blue curve on all these figures is a control
virus that they put on the plate, and the yellow curve is the clinical
isolate. As you can see for 3TC, the virus has essentially no
susceptibility to 3TC. As the curves shift toward the right, you are
seeing increasing resistance. So these are the types of assays that the
companies are doing for phenotypic testing right now.

\[Slide.\]

At this point, I would like to switch over to clinical relevance. This
has always been a somewhat contentious topic.

\[Slide.\]

For clinical significance, zidovudine is the only drug for which we have
data for clinical progression and death. I honestly believe that we will
probably never have any other single drug for which we will be able to
show clinical progression and death because of the use of combinations.

But, for AZT, we could clearly show with greater than 1.0 micromolar
resistance at baseline if this was the associated progression and death
in both the ACTG 116B, 117 study and a prospective study in the
Department of Defense with about a two‑and‑a‑half to three‑fold risk of
disease progression. This was independent of the other baseline
parameters available to us at that time.

\[Slide.\]

For the pediatricians, this is a similar study looking at the 215
mutation in plasma virus. What they did was, the yellow dots are the
children who had no disease progression and were doing quite clinically
well. The orange dots are the children who were progressing and having
disease progression.

What you can see is that the children who had no disease progression
also had no evidence of the 215 mutation and the children who were
progressing developed increasing amounts of the 215 mutation in their
plasma virus and it was strongly associated with disease progression in
this cohort.

\[Slide.\]

The companies have been doing a very good job recently with the new
drugs in defining the phenotypes and genotypes associated with loss of
activity of their drugs. This is illustrated in this slide from abacavir
where the company looked at abacavir in its clinical trials and found
out that, if clinical isolates had less than an eight‑fold decrease in
susceptibility from a wild‑type isolate that they could get a good
clinical response and if it was more than eight‑fold above the wild‑type
virus that they were not getting good activity.

They also were able to find the genotypes associated with lack of
activity of abacavir. As you notice, they are the genotypes that are
associated with a multi‑drug‑resistant, multi‑nucleoside‑resistant,
virus.

\[Slide.\]

Similarly, for nelfinavir, they were able to, in expanded access, look
at the major mutations associated with resistance and were able to show
that‑‑they could literally count major mutations and response was
related to how many major mutations were present, or they could look at
phenotypic susceptibility as broken by four‑ to ten‑fold and show,
again, a very nice association with decreased drug susceptibility
phenotypically or presence of resistance mutations predicted who would
respond or not respond to nelfinavir.

\[Slide.\]

Similarly, for ritonavir and saquinavir, they were able to look at
phenotypic and genotypic resistance. What they showed very nicely was
that the predictors of failure were the same as we had seen previously
for zidovudine, CD4 count, disease stage, HIV RNA, but also either
phenotypic resistance or genotypic resistance predicted lack of response
to saquinavir and ritonavir.

\[Slide.\]

Moving into broader‑based clinical studies, Andy Zolopa and the group at
Stanford looked at patients who received ritonavir and saquinavir who
were all PI experienced. They looked at short‑term virologic responses,
and the clinical predictors were the same as we had seen previously.

Of note, drug history, number and prior duration of drugs predicted poor
response and simply counting the major protease mutations, the red‑ball
mutations, I showed you earlier. If you simply counted them, the number
of mutations in the virus predicted response to ritonavir and
saquinavir. The more you had, the worse you did.

\[Slide.\]

Steve Deeks presented data at the same meeting which, I think, gave us a
great deal of insight into what you need to get a good response in an
experienced patient. They took eighteen patients who had received
abacavir, saquinavir, nelfinavir and nelvirapine. These were all four
new drugs these patients had never seen. So they took four drugs that
the patients were naive to. They looked at a phenotypic assay.

\[Slide.\]

What they showed was that seven of the patients had only zero or one
active drug in the regimen by susceptibility testing. In those patients,
none of them got a response. It was only very transient and none of them
went below the limits of detection of the assay.

So this was showing the impact of cross‑resistance in this population.
Eleven patients had two or three active drugs. They all had a sustained
response and eight of ten went undetectable. None of them had all four
drugs in the combination active. What this basically told us was if you
are going to get a good response in a regimen for heavily pre‑exposed
patients, you are going to need to find two or three active drugs to
give that patient.

\[Slide.\]

That is the retrospective data. I am now going to move to the two
prospective trials that have been done on genotyping. The first trial is
the GART trial, GART standing for genotypic antiretroviral resistance
testing. It was a trial done by the CPCRA in patients who had had a good
response to protease‑containing regimen and then lost that response.

The patients had plasma virus, had plasma sent in. The virus was
sequenced. It was reviewed by a panel of three virologists; myself, Tom
Merigan and John Baxter. We gave the clinicians back a report of
susceptibility and we also gave them some recommendations for treatment
at that time.

You have got to remember this trial started in 1996. The community docs
really were not comfortable that they could take the sequence data and
use it in clinical management at that time. So the test was a test of
getting the sequence data with some suggestions versus using your own
clinical judgment in the management of these patients.

It had a short‑term virologic endpoint of 4, 8 and 12 weeks of follow
up. The reason the data was chopped after 12 weeks was that the patients
and their physicians were allowed to switch drug regimens if they
hadn\'t had a good response during that time period. So the test was
only relevant during that short period of time.

\[Slide.\]

Looking at the randomization, patients had about 230 CD4 cells, about
30,000 copies of HIV RNA. The majority of the patients had received
nelfinavir for indinavir which was common to the community at that time.
About half of them were failing on their first
protease‑inhibitor‑containing regimen and the other half were on their
second or third regimen.

\[Slide.\]

Looking at the baseline resistance mutations, as we had shown
previously, in this population, about three‑quarters of them had both RT
and protease mutations. About 20 percent had RT mutations alone. And 5
percent had absolutely no mutations in their virus. It is the impression
of the clinicians and the virologists in the study that that 5 percent
was probably not actually on drug at the time that these susceptibility
tests were done.

Looking at the mutations, we saw, again, 184 and 215 were the
overwhelmingly common human‑failure mutations with only 1 or 3 percent
of patients getting the insertion in the 151 mutation. And we had a
variety of protease‑inhibitor mutations.

\[Slide.\]

The bottom line was that if you use genotyping to assist in the
management of the patient, we could get about a half‑log better
virologic response at the 4‑ and 8‑week time point than we could by
clinical judgment alone. And this was a highly significant p‑value.

\[Slide.\]

This just shows the response over time and shows that, actually, the
best response was, unfortunately, at four weeks and there was some
paling off of response during the 8‑ and 12‑week time period as some
patients got a transient response to drug and then resistance reemerged.

\[Slide.\]

But it should be noted that, at all time points, about twice as many
patients were undetectable using resistance testing as they were if you
just used clinical judgment alone. Even at the 12‑week time point, about
28Êpercent of our patients were undetectable with genotyping and about
15 percent were undetectable with clinical judgment alone.

\[Slide.\]

A point of contention in this study has been that the patients who were
getting the genotyping also received, on average, one more drug than the
patients who were getting phenotyping based potentially on the fact that
their docs could see the resistance data available.

\[Slide.\]

But we have actually gone back and reanalyzed the data. If you look for
patients who got three drugs, four drugs or five drugs, at every number
of drugs, the patients did better if they had genetic data to assist in
the management than if they guessed with clinical judgment alone.

We think this actually explains the results of this trial. The green
curve is the viral‑load response that you see in these patients. The
blue bars show you how many active drugs were present in the no‑GART arm
and the yellow bars show you how many active drugs were present in the
GART arm.

What you can see is that, on average, patients who got the genotypic
testing were able to get one more active drug in their regimen than they
could get by clinical judgment alone. The response the patients got was
clearly associated with the number of active drugs they received. And so
it appears that the genotyping allowed us to find, on average, one more
active drug to give in a salvage regimen than you could give by clinical
judgment alone.

\[Slide.\]

So the conclusion was that GART, with expert advice in patients failing
antiretroviral therapy, was superior to no‑GART as measured by
short‑term viral‑load responses. In a greater viral‑load response,
reduction in GART was attributed to the greater number of active drugs
prescribed.

I\'m sorry I didn\'t bring the slides, but one of the truly impressive
findings for us in the trial has been the robustness of this finding.
This half‑a‑log difference held up over CD4 ranges, over viral‑load
ranges, over resistance profiles, over first failure, second failure,
third failure.

Basically, any cell that had more than eight patients in the cell had a
significant difference with genotyping.

\[Slide.\]

The second prospective study was the VIRADAPT study which was conducted
in France. This was a bit different study in that there were basically a
number of French clinicians at about three French medical centers who
followed a series of patients and did genotpying and then would meet and
discuss the results either with genotyping or without genotyping for the
manufacturer of individual patients.

\[Slide.\]

It is a little bit smaller study. There were 43Êpatients in the control
arm and 65 patients in the genotyping arm.

\[Slide.\]

The patients in the study were a bit more advanced than the GART
patients. They had, on average, a plasma HIV RNA of about 150,000. The
CD4 cells were about 200 to 220, and quite a few of them had actually
had symptomatic HIV disease.

\[Slide.\]

If you look at their prior exposure, they were very heavily exposed.
They had seen, on average, one‑and‑a‑half to two PIs when they came into
the trial. They had had, on average, about four nucleoside agents and,
again, about half of them were first‑time failures and the other half
were second‑ and third‑line‑failure patients.

\[Slide.\]

The results in this trial show that they actually got a sustained
benefit to six months. The difference between this trial and the GART
trial was that if you hadn\'t gotten a good response at three months,
you could retest the patient at three months and go to six months. And
so, in GART, you got one test, we followed you. In this trial, you got a
test every three months.

The data went out to six months in a randomized fashion. As you can see,
there is about a half‑log difference between the two arms out to six
months that persisted. They subsequently extended the analysis out to a
year and they have had a stable reduction in RNA out to a year in these
patients who could get repeated testing.

The trial was no longer randomized after six months because, once the
GART results were released, the French unblinded the trial and took
everyone over to genotypic testing.

\[Slide.\]

Of note, and very similar to the GART results, you can see that roughly
30 percent of patients were undetectable in the GART arm and about 14,
15 percent of the patients were undetectable in the no‑GART arm so,
again, about a two‑fold difference between genotypic testing versus
clinical judgment alone.

These results have been remarkably consistent across these two trials
that had somewhat different methodologies.

Also of interest, both trials used the same algorithm to interpret the
data for genotyping. The algorithm is actually contained in table 8 of
the Stanford Guide for the Management of HIV‑Infected Patients. It is a
little pocket guide.

\[Slide.\]

So in choosing an effective salvage regimen for patients who are failing
on combination therapy, I think we have a number of clinical parameters
available; number and duration of prior antiretroviral drugs, knowledge
of cross‑resistance patterns between the drugs.

This data can be supplemented with resistance testing. I think the
bottom line is to have an effective salvage therapy in patients who fail
combination regimens. You need to be able to find two or three drugs
that remain active against the patient\'s circulating virus.

\[Slide.\]

The current dilemma is even with the availability of repeated genotypic
testing, we can only get 30 percent of patients suppressed below 500
copies per ml. This just emphasizes the need for us to continue to get
salvage drugs available for these patients.

\[Slide.\]

In the last few minutes, I would like to go over the public‑health data
looking at resistance. This is the percent of patients with AZT
resistance by year. Before 1987, we never actually saw an AZT‑resistant
virus in an untreated patient. In 1987, the drug entered clinical
practice. It was available to about 20 percent of patients because you
had to have late‑stage disease to get access to the drug.

So, from 1987 to 1990, about 20 percent of our patients had access to
AZT and there was about a 1Êpercent level of transmission of
drug‑resistant virus. In 1990, because of the 116, 119 results of the
ACTG, there was an expansion of the use of AZT to patients with less
than 500 CD4 cells. Two years after the increased indications for AZT
usage, the transmission rate jumped to 7.5 percent and then actually
moved to between about 8 and 10 percent for the next five years.

\[Slide.\]

So AZT resistance was seen at about an 8 to 10Êpercent level in new
seroconverters from 1993 through about 1996. In 1996, 3TC became
available within a year. Because of a single‑point mutation,
3TC‑resistant transmissions were seen. The most recent data, as we have
moved to a very broadened use of combination therapy, is that we are
seeing an even increased risk of transmission of drug resistance. This
is data from both the military and a cohort led by the group at San
Diego.

What they showed was that, looking for resistance by phenotype and
genotype, they found a level of somewhere between 20 and 30 percent of
new infections were infected with drug‑resistant virus in 1999. What has
become a bit scary to the practicing clinician is an increasing number
of these patients actually have multi‑drug‑resistant virus with both
nucleoside‑ and either protease‑ or non‑nucleoside‑associated mutations.

\[Slide.\]

So I think we can actually categorize a number of high‑risk populations
for drug resistance; patients who have lost virologic control on a
combination antiretroviral regimen, new HIV seroconverters, HIV‑infected
infants of HAART‑experienced mothers‑‑we don\'t have very many of them
but when they occur, these children are at very high risk for drug
resistance‑‑and occupational HIV exposure of healthcare workers. These
are four categories of individuals who are at high risk of
drug‑resistant virus.

\[Slide.\]

Some unresolved issues. For genotypic testing, I think the companies‑‑I
am not aware of any company that has actually brought a
technical‑validation panel to the FDA. I know the panels are being
developed. I think this is probably one of the big issues for the
companies is to prove that they have a kit where three different techs
and four different labs can get the same result with the same sample

I think that is coming and I think you will see that type of data very
soon. Interpretation of complex genotypes is difficult in these
patients. The ultimate clinical utility, if you want to go to long‑term
durability or clinical outcomes, has not been proven but at least at
time frames of three months to year, there is a clear benefit of using
genotypic testing to get better virologic suppression.

\[Slide.\]

From our studies, and in the CPCRA, it has become clear that there are a
number of instances where phenotyping does have significant utility,
potentially more utility than the genotyping assays. One is in patients
who are failing with indinavir resistance because we can tell you, from
a genotype, that you are likely to be cross‑resistant to the other
agents but can\'t tell you which ones you are likely to be sensitive to,
whereas the phenotyping can actually identify the individual drugs to
which the virus remains susceptible and then complex genotypes of
apparent multi‑drug‑resistant phenotype where, in a potential of
mutational interactions, you can find a drug or two by phenotyping that
you won\'t be able to detect with our knowledge of genotyping.

\[Slide.\]

For phenotypic resistance testing, I think technical validation remains
an issue as well. Of bigger concern are the current susceptibility
breakpoints where they are actually set somewhat arbitrarily not related
to either clinical progression or to loss of virologic control. I think
there is going to be a major effort by the companies to get these
breakpoints better established.

A concern is, right now, that it appears that the non‑nucleoside
susceptibility breakpoints from all the current assays may be set a
little bit too low for sensitive virus and they are calling a few false
positives for low levels of resistance.

Clinical‑utility data is clearly coming from these types of assays but
there are no prospective trials available to report at this time.

\[Slide.\]

So, where are we? I think, for biologic plausibility, this is a slide
similar to the slide I presented in 1996 to this committee for
viral‑load measurements. I think, for biologic plausibility, we
certainly have that for both genotypic and phenotypic resistance. There
is good retrospective data for quite a few drugs that both genotypes and
phenotypes can predict response to drug and can predict loss of activity
to the drug.

For prospective data, the short‑term data of three months to twelve
months for genotyping from two trials, ongoing trials for phenotypes.
There are long‑term trials going on for both types of assays at this
time.

I point out to the committee that, when it was presented with the
decision for viral‑load measurements, an approval of viral‑load
measurements, there were no prospective studies available to the
committee when they had to make this decision. At this point, there are
two prospective studies for resistance measurements.

Technical validation is ongoing for both types of assays and
standardized interpretation in getting the standards out there is also
ongoing for both types of assays.

I thank you.

DR. HOLLINGER: Thank you, Doug.

Andy, do you want to go on to Dr Murray?

DR. DAYTON: I will leave it up to you.

DR. HOLLINGER: Let\'s see if there are some questions here of Dr.
Mayers.

DR. CHAMBERLAND: In the packet of information that we got, there was a
recent Lancet publication on the results of the VIRADAPT study. Has the
GART trial been published?

DR. MAYERS: The GART trial has been in submission to JAMA for over
eleven weeks right now so that if they ever release it, we hope they
will publish it.

DR. CHAMBERLAND: Because one of these papers, I think, referenced an
abstract for the GART study. Could you just clarify, in the GART study,
in the methodology, in the GART arm, physicians got results of genotypic
testing. In the non‑GART arm, what information‑‑I wasn\'t clear,
exactly. It looks like they got the recommendation from‑‑

DR. MAYERS: No.

DR. CHAMBERLAND: No; they didn\'t get anything? What did the non‑GART
get?

DR. MAYERS: What the non‑GART got was that the team gave them the
current recommendations and they gave them regular updates from the
ongoing meetings for salvage regimens in that population. So, basically,
we sent out to them‑‑after each meeting, we would send out to them an
update; \"Here is what we are seeing with these drugs in these types of
patients.\"

So we did an educational component, but we did not give them direct
recommendations.

DR. CHAMBERLAND: So they just got general guidance about current
thinking for salvage therapy‑‑okay. But even in the non‑GART arm, would
you feel that clinicians were probably getting more information than the
average treater gets because‑‑

DR. MAYERS: I think that is fair. I think the thing that has encouraged
us that this was not biased in a significant way is the French study
where there was no expert advice given at all and all they got was the
genotype given back to them. And the fact that GART and VIRADAPT
essentially lie on top of each other at similar time points suggest that
there was, probably, not a huge bias in that.

DR. CHAMBERLAND: Can you tell us more who the physicians were who
participated in the GART and the non‑GART arm? Where I am going is that
I think there is a spectrum of treaters out there who treat HIV
patients. At one end of the spectrum, we have folks like yourself, very
knowledgeable, involved in research and, at the other end, are treaters
who‑‑and I think they may constitute the majority of treaters‑‑who
really are trying very hard to keep up with a moving target.

They have these publications from the Public Health Service and from
these advisory committees about what to do, but they are not really
well‑educated about genotypic, phenotypic, information, et cetera and
they get these very complicated reports from these laboratories. They
are tough to interpret. I do very limited clinical work and it is tough.

DR. MAYERS: I have the same problem, myself, getting some of these
reports.

DR. CHAMBERLAND: So I kind of wanted to know, because we don\'t have a
publication, unfortunately, who was in the GART trial, where to they
fall in this spectrum of treaters because I think this is important to
the committee ultimately having to vote on this issue, to have a kind of
an understanding of what information is going to be‑‑

DR. HOLLINGER: Yes; and how was it determined who was non‑GART and GART?

DR. CHAMBERLAND: Exactly.

DR. MAYERS: Basically, I want to apologize to the committee for giving
you the GART study but the rules that the FDA operates under are if I
give it to you, I have to put it out on the table out front. Since it is
still in submission to JAMA, I could not give it to the committee.

The clinicians throughout the CPCRA‑‑these were the community docs in
the CPCRA system, so they were at all the sites in the CPCRA, randomly
out there. Any doc who sent a sample in could participate from the
CPCRA.

The randomization was done in such a way that the patient\'s provider
would send a sample into the team, the group of virologists would look
at the sample, interpret it and get the report done, submit that report
to that stat center not knowing if they were going to randomized or not,
and then the stat center would roll the dice and randomize them after
they had received the report from the virologist back to the field.

So, basically, this was a large group of community physicians throughout
the United States and the reports were done the same if you got the
report or didn\'t get the report as far as the virologists were
concerned. We didn\'t know who was going to get a report when it went
out.

MR. DUBIN: So any one physician who has seen multiple patients,
sometimes he is going to get GART and sometimes not?

DR. NELSON: Yes; there were some physicians who treated a few patients
with the genotyping and a few patients without it. That\'s correct.

DR. HOLLINGER: And decisions for changes by the non‑GART was based on
CD4s and HIV concentrations that they received back?

DR. MAYERS: The clinicians and the virologists in the study knew CD4s,
viral loads, and they also knew the treatment history of each individual
patient. So you knew how many drugs they got and what drugs they had had
toxicity or not had toxicity on. So it was the data that would be
conventionally available to a doctor treating an HIV‑infected patient.

DR. HOLLINGER: And he would make a decision, or she would make a
decision, based upon the results that came back to that person.

DR. MAYERS: When the patient came back to the clinic for their
randomization visit, the doctor would either get a GART report and have
to tell us how it impacted his decision making or her decision making,
or they would not get a GART report and have to use the data that they
had had available to them prior to make a decision as to which drug to
switch to.

DR. TUAZON: In terms of having‑‑once this test had been approved, where
do you see the clinical utility of both assays? I think, for the
experienced, PI‑experienced patients, you probably would just go ahead
with the phenotypic. Accounting for the cost of both of the assays, what
are the practical uses of this?

DR. MAYERS: I think one of the real surprises that we have seen across
both studies has been that the relative benefit has been the same across
rounds of therapy. But that is relative benefit in the face of a
shrinking response.

What I see happening at this point is going to be in newly infected
patients who you know are newly infected, not patients who walk in with
PCP but newly infected, that they are at fairly high risk and I think
there is going to be a move to take this testing to look for newly
infecteds fairly soon because the rates are clearly above 10 percent in
that population right now.

For other patients, I think we will use CD4 and viral load like we
currently do. A person who is below 50Êcopies and is doing well without
a genotype, I don\'t need the test. I think, on early rounds of failure,
you will probably see genotypic testing used on those patients because
it has a fairly quick turnaround time which will probably start to drop
to less than a week as market forces develop and it is less expensive.

I think that, for people, as they get to the point where the genotype
becomes different to interpret and they can\'t find the drugs they need,
you are going to see a shift toward phenotypic testing because it can
find holes that you can\'t find with the genotype testing in these
individuals. That current assessment is based on cost and turnaround
times.

If the phenotypic companies can get their cost down in the same range
and the turnaround time in the same range, I really don\'t see a great
deal of difference in early failures between either methodology. They
can both show you where there are potential holes to get active drugs
and they can both show you were resistance exists.

So a lot of it is going to be how fast they turn them around and how
much they charge you. I think the interpretations are clearly improving
a lot recently. The reports clinicians used to get back a year ago, and
even with some companies, as was stated, get now can be difficult to
interpret.

I know they are difficult to interpret when one of my docs brings it in
to me and I look at it and scratch my head and try and figure out what
they are saying so that I can tell him what to do. I think that this is
an area where there really does need to be some work by industry to
develop a standardized reporting format.

I can tell you that there are some groups that develop computerized
algorithms that give a very nice report that says, sensitive, partially
resistant, resistant, just like you would get from your microlab for a
bacteria. And you can do it for both phenotype and genotype if the
companies want to.

DR. NELSON: Again, back to the GART trial. You gave the randomized
physicians recommendations for which drugs to use. Did you also measure
how the recommendations were followed by the patients and the
physicians? Was that done?

DR. MAYERS: Yes; we did. Actually, the scariest comment from my first
IRB was when the head of the DSME asked me did I actually think the docs
were following my recommendations. The honest answer is that some did
and some didn\'t. Some used the data in their own way‑‑

DR. NELSON: It is not only the doc. It is the patient.

DR. MAYERS: Yes; I understand. The bottom line was that for docs who
took the advice regularly and consistently, the difference actually
increased to almost a log difference between the GART and the non‑GART
arms. For the docs who didn\'t use the advice given, it narrowed down
considerably. I think that this is one of the things that is going to
drive HIV care, especially for the experienced patient, into the special
provider and take it out of the primary‑care realm.

This is just too complicated to deal with the cross‑resistance issues
and try and deal with the drug interactions to select an effective
non‑toxic regimen for these patients.

DR. HOLLINGER: Doug, along those same lines, you obviously have patients
who are receiving information that you are imparting to them in the GART
test and I presume the same thing was true in the other study.

So what was the compliance? We now know that probably the greatest
challenge is making patients compliant. Those patients who are not
compliant with their medications are the ones who different resistance
the fastest. So the issue would be is that in the group that was not
getting this information, did you measure compliance, other than just
asking the patient. Were there any other basic measurements to be sure
that these patients were taking their medication as were the ones who
were on the GART trial

DR. MAYERS: We are currently going back into the trial. This trial, when
it was originally done, was done as a pilot study that Tom Merigan and I
and John funded off our laboratory internal budgets. So there was a
certain limit as to how much testing we could do for free.

But what has happened is those restored samples done at every time point
on these patients and we are now going back into these samples doing
genotyping, phenotyping and drug‑level measurements at every time point
for every patient with support from a number of the companies. And we
will have that data to bring back.

We did not have timing so I won\'t be able to tell you high/low. But I
will be able to tell you, yes, they had drug or no, they did not have
drug, of a very sensitive assay. The data from the French trial that was
recently completed with de‑escalation of therapy suggests that this is
adequate data to at least predict were they taking drug at all or not
taking drug.

And so we are looking at that but it is not available at this time.

DR. McCURDY: It appears that even though there are certain mutations
where it is pretty well established that either alone, or in
combination, they confer resistance. The question that I have is suppose
a new mutation or a new group of mutations seems to correlate with
resistance, perhaps, to a new drug or something like that.

How is the decision made as to how this new work is interpreted? Is this
based on limited data and then you follow along?

DR. MAYERS: Basically, I can tell you how we do it in the CPCRA where I
have a little control. Basically, if the mutation associated with loss
of viral activity of a drug or is associated with a clear change in
phenotype, we will add it into the algorithm fairly early on and then
look for its impact prospectively.

I think what is developing over time is a number of groups, the CPCRA, a
number of industrial groups, the ACTG, are developing very large
databases that include mutation\'s response to the next round of
therapy. So what is going to happen fairly quickly is that as soon as a
mutation is detected, or what we think is a polymorphism today is shown
to be a true resistance mutation, you are going to be able to have two
or three groups very rapidly tell you, yes, we see this to be true or
no, this appears to have been an artifact.

So I think the ability to actually confirm or rule out these mutations
in a very rapid fashion is actually getting much better almost by the
day.

DR. McCURDY: Dr. Stroncek made the analogy to HLA typing. For a number
of years, there were workshops that got together that developed‑‑wet
workshops and others that got together to define new types. Is this sort
of thing happening? Are the databases getting together or is this an
individual entrepreneurial activity?

DR. MAYERS: The honest answer is it is not happening as much as it
should. One of the problems is that each of the major commercial
sponsors have developed a proprietary algorithm which they are
trademarking and patenting as quickly as they can so that we don\'t have
sort of your blue‑collar framework everyone agrees to at this point for
either breakpoints for phenotyping or genotypic interpretation.

I think this is an area where we can do better and this is an area where
I think there could be some useful work to develop NCCLES type of
standards for genotypic and phenotypic reporting.

At this time, most of the systems give fairly much the same results. A
184, you have got 3TC resistance. They all tell you that. I think the
areas where there is a lot of debate is in those types of drugs I showed
you in the far right‑hand corner of the slide where they don\'t have
much of a phenotype and the mutations that are associated with that
low‑level phenotype have not been well worked out. And so there is a lot
of debate, for example, on whether something is D4T partially resistant
or susceptible resistant.

But I think for most of the major drugs, there is a growing consistency
across the reporting formats.

DR. McCURDY: That would seem to me to be one of the major potential
barriers to switching from so‑called class III to class II is how one
deals with new changes as they come down the pike.

DR. BOYLE: Quite frankly, that is probably the easiest solved problem if
there was a barrier. All it would take would be the desire of industry
to get together and do it because the data is there.

DR. McCURDY: So?

DR. HOLLINGER: If there are no questions right now for Dr. Mayers, I
think we will go on to Dr. Murray who is going to speak now.

**CDER Perspective**

DR. MURRAY: I am Jeff Murray from the Division of Antiviral Drug
Products from CDER, Center for Drug Evaluation and Research.

\[Slide.\]

I am here today to kind of give you what the CDER perspective, or our
division\'s perspective, is on the current strengths and weaknesses of
resistance testing and why we are interested in this and, hopefully, to
give you some assurances that it is not only the assay companies that
develop, figure out what is important as far as genotype and phenotype
but, really, a lot of the work goes on during the development of the
drug.

\[Slide.\]

What we are not going to use resistance testing for is as a basis for
approval. This is just to go over the division\'s current
recommendations for approving antiretrovirals. We have accelerated and
traditional. Accelerated is an earlier approval for drugs that show some
meaningful therapeutic benefit over existing options or can treat
patients who are intolerant or have failed existing options.

For accelerated approval, we base it on 24‑week changes in HIV RNA. For
traditional approval which, up until about two years ago was just based
on clinical endpoints only, it can now be based on 48‑week changes in
viral load or HIV RNA. Our preferred endpoint now is a proportion below
the assay limit which is 400 or, now 50, or time to virologic failure
above and assay limit.

As I said, resistance testing will not change primary study endpoints
but we see it as important information on how to use the drug much as
information on how to use a drug for renal impairment and that sort of
information, how to characterize a drug.

\[Slide.\]

Our interest is that we think monitoring prevalence of resistance is
crucial. Doug showed you that the prevalence of transmitted HIV that is
resistant to current drug seems to be increasing. We think that it
provides very useful clinical information in the label much as other
drug‑interaction information, other safety information and dosing
information would.

We think that including the information in the label will not only help
clinicians use a drug but would stimulate further research in defining
clinical resistance and assay development. We are interested in it to
provide a level playing field for drug sponsors so that a standard or
kind of routine set of data describing how their drug affects viral
mutations and susceptibility.

So we see the need for a level playing field and to aid in negotiation
of fair and balanced promotional ads which might use resistance data to
promote their drug.

\[Slide.\]

For instance, a hypothetical example is a drug sponsor might say, \"Use
our drug, Drug X, first because there is less drug class
cross‑resistance after failure on Drug X compared to if you start with
Drug W, or Y, or Z.\" Sometimes, this is just the supporting data. It
might be just from a retrospective analysis of patients pooled from
several studies and there might be less than 50 patients.

So we want to try to have a more uniform standard of resistance data
submitted so we can figure out if these sorts of label claims and
characterizations are valid or not.

\[Slide.\]

We are so interested in this that we are going to host and advisory
committee meeting‑‑it is more like a workshop‑‑to cover the following
issues in four sessions. We are going to dedicate some time to
performance characteristics and limitations of the currently available
both genotypic and phenotypic assays.

Session 2, we are going to evaluate the relationships between HIV
resistance testing and treatment outcomes. So we will go over some of
the same data that Doug Mayers just summarized. We are going to talk
about practical considerations for the use of resistance testing and
clinical trials in drug development. In the fourth session, we are going
to talk about potential roles of resistance testing in drug development.

The purpose of this meeting, really, is to get feedback on how much,
what type of data would the committee think is necessary for us to
fairly characterize resistance data in the label knowing that this can
be pretty important for promotional claims.

\[Slide.\]

There are a lot of available assays commercially. This is not a
comprehensive list but these are some of the assays, genotypic and
phenotypic, that are being used in clinical trials and that physicians
are also getting a hold of now using it as a research tool to make
decisions on their patients.

There are probably more available genotypic assays. Some use PCR
amplification and sequencing techniques and some use hybridization and
there are pluses and minuses to either of those. There are probably less
available phenotypic assays. The ones that are more commonly used would
be the recombinant viral assays where, as Doug said, where the RT and
the protease gene are inserted into a lab‑type strain or a backbone, and
then there is a cell‑culture step.

\[Slide.\]

This is from the Hirsch paper that you should have received as
background. Just some relative advantages of genotyping versus
phenotyping is availability, quicker results, cheaper, technically less
demanding and actual mutations may proceed phenotypic changes so you
might get a jump on some important information.

For phenotyping, there are some advantages to that, so that is what we
usually think about from the antimicrobial paradigm. It is a direct
measure of susceptibility. It is clinically familiar. You have break
points and it takes into account increases and decreases in
susceptibility in combination therapy because some genotypic
mutations‑‑not all genotypic mutations are bad. Some of them actually
can increase, perhaps, sensitivity to other drugs.

\[Slide.\]

Some relative limitations; this is just kind of the reverse may of the
other slide. Genotyping is an indirect measure of susceptibility.
Certain mutations may not always correlate with a change in phenotype.
With thirteen drugs and lots of different mutations, sometimes expert
opinion is required for interpretation, as we talked about.

Both assays could be very insensitive for minor species. And then I
mentioned the effect of sensitizing mutations. For phenotyping, its
limitations would be restrictive availability, a longer processing time,
technically a bit more demanding, clinically significant cutoffs not
defined for all drugs and, again, insensitive for minor species.

\[Slide.\]

Our division thinks that probably the major limitations of the assays
are not so much the clinical correlations but the analytical
limitations. I think this was true with HIV RNA is that we were very
anxious for the assays to get reviewed and approved by CBER so that we
could know what the lower limit bounds, what the limit of quantification
and the variability of the assay so that we could use it.

In fact, for HIV RNA, the clinical correlations that eventually
supported a prognosis indication, we saw those clinical trials maybe a
year or two before, so we felt pretty comfortable with the clinical
correlation of the HIV RNA test even before it was approved for the
indication of monitoring.

Likewise, where I think these genotypic and phenotypic assays which are
probably several magnitudes of order more difficult analytically than
just an HIV RNA test, we think that it is the analytical limitations
that really need to be focused upon such as amplification sensitivity,
how high does the patient\'s viral load have to be to pick up new
mutations, analysis sensitivity‑‑what proportion of minor quasi‑species
can be detected. 20 to 25 percent is an estimate‑‑reproducibility and
quality control‑‑is it reproducible between labs, between different
people running the labs.

Also, interpretation of results is a problem. There are complex
mutational patterns for phenotypes. we don\'t have break points for all
the drugs. So that still is a limitation as well. Another limitation of
the assays is that, at this point, they are a bit technically demanding
and they is a turnaround time and cost associated with that.

\[Slide.\]

Other considerations; clonal versus population sequencing. Are resistant
mutations all on the same genome? Clonal methods be much more
technically demanding so this is something that maybe needs to be
addressed. Studies would indicate that, for the most part, they are
linked on the same genome. Are plasma samples good enough or should we
also be looking in other viral reservoirs, lymph node, gut. Of course
that wouldn\'t be feasible for clinical use.

And then other considerations are timing of when you get the sample
because if you are off a drug, quite often, you will see reversion to
wild type.

\[Slide.\]

Reproducibility; I think this is data from Schuurman et al. This was
recently presented at a resistance conference in San Diego. There still
is some problem with correct calls of genotype between labs. In five
samples that were sent to 60 labs with results reported from 33, the
labs were pretty good at making correct calls for 100 percent wild type
with reverse transcriptase. They have a perfect record for that and, for
protease, about 94Êpercent correct calls.

If they are 100 percent mutant samples, about two‑thirds of the calls
were correct. But if they were viral mixtures of 50 and 50 percent for
RT and protease, the percentage of correct calls was less. So I think,
clearly, there is room for improvement in lab‑to‑lab reproducibility for
viral mixtures which is what we are very likely to see in the clinic.

But, again, this is a technical limitation.

\[Slide.\]

As Doug showed you, I think the evidence supporting clinical relevance
is that there are two prospective studies. There is no completed
prospective study for phenotyping but there are some ongoing. And there
are several retrospective studies.

As far as the retrospective studies, some show predictive value of
certain mutations at baseline and how a patient will respond. Others
show the more gross associations that show a relationship between the
number of mutations and outcome and the number of sensitive drug classes
available but not, perhaps, specific mutations and outcome were seen in
the retrospective studies.

\[Slide.\]

So for the prosecutive studies, two of similar design. Again, the
difference between viral‑load response at 3 and 6 months for GART and
VIRADAPT, respectively, was about a half a log. So it is very similar.
For GART, it looked like each sensitive drug added about a 0.28 log
reduction.

Criticisms have been the expert opinion in GART but, as that was not
seen in VIRADAPT, it seems to allay concern related to that criticism.
Shorter‑term follow up for GART; that was three months. But VIRADAPT had
a longer follow up so that helps. In the VIRADAPT study, there were more
zidovudine mutations in the control arm which might have made a
difference but that didn\'t seem to be a problem in GART.

So, as in drug approval, we do two studies because no study is perfect,
but these studies are pretty much complementary and I think help to
confirm the results. I might say a half a log difference in HIV RNA we
do think is clinically significant. If this were a drug, it would
probably confer a clinical benefit in terms of decreasing morbidity

\[Slide.\]

As far as retrospective studies, I think Doug mentioned most of these,
the Zolopa and Deeks study. What I might say is that not all of the
retrospective studies necessarily showed the relationship of a specific
mutation but with the number of mutations, perhaps, and treatment
outcome. This is just because in these studies, it is 50 patients here
and 50 patients there tested so they might have not had power for each
individual\'s specific loci.

\[Slide.\]

Also, as Doug suggested, even before the prospective studies and the
retrospective studies looking at baseline mutations and eventual
treatment outcome, for zidovudine, in ACTG116 and 117, there was a
definite correlation between the presence of zidovudine mutations and
clinical outcome. Both the risk of disease progression and the risk of
death was increased in patients who had both the 215 and a 41 mutation
associated with zidovudine.

This also correlated with the phenotypic susceptibility; those who had
215 and 41 versus wild type had about a ten‑fold decrease in the in
vitro phenotypic susceptibility. So it really kind of pretty much hangs
together for zidovudine.

Also, for the non‑nucleoside reverse‑transcriptase drugs which do lose
their susceptibility sometimes after one‑‑may times after one mutation.
In the current nelvirapine immune package insert, resistance issues come
up in the warning and the indication section based on data from 24
patients in phase I/II trials. It should be 100 percent of patients had
a greater than 100‑fold decrease in susceptibility at 8 weeks. This is
when nelvirapine was being used as sometimes monotherapy or only dual
therapy not the way it should be appropriately used.

All of these 24, with decrease in susceptibility of greater than
100‑fold, had one or more characteristic mutations. The mutations are
listed there, at 103, 181, 188, or 190. 80 percent of them were at 181.
As it turns out, the 181 is in the RT binding site of the drug. So not
only did this fit with the virologic outcome, it fits in how we know
this drug is interacting with the enzyme. So it has near perfect
biological plausibility.

\[Slide.\]

Other correlations between genotype and phenotype. Virco has a good,
large database. I guess this was presented at the San Diego conference
of 7,000 samples or, perhaps, more that show good correlations between
genotype and phenotype for many drugs including 3TC for the 184 mutation
and for multiple zidovudine mutations and for several protease‑inhibitor
mutations, particularly for nelfinavir.

Other retrospective correlation between genotype by Harrigan et al.,
also presented at the same conference, showed strong correlations
between genotype and phenotype for many antiretrovirals except for, in
his study, 59 patients. Less for abacavir and D4T which had moderate
correlations and lower correlations for ddI and ddC. I think Doug
brought up the fact that there are certain drugs for which I think it
will be harder to maybe correlate a genotype and its relationship to
treatment outcome.

It is more a characteristic, I think, of the drug rather than the assay.

\[Slide.\]

There are a lot of experts and panels who get together frequently to
decide how genotype correlates with treatment outcome, and to devise
these panels to be used in clinical trials and for clinical use, mostly
based on consensus opinions of the experts, as you saw a table similar
to what I am talking about in the Hirsch article.

It is based on literature abstracts, data from industry and academia,
like the IDSA consensus algorithm. The GART and the VIRADAPT used a
similar algorithm. And then a resistance collaborative group which is a
group made of academia and industry and government has also come up with
an algorithm for defining genotypic resistance.

These will be modified and are diligently worked on by a lot of
different hard‑working groups to define these relationships.

\[Slide.\]

As Doug mentioned, proposed clinical use of HIV resistance testing will
be, of course, crucial to monitor the prevalence transmission of
resistant virus. It will probably be used more and more in adult‑naive
patients, especially in high‑risk areas or high‑risk groups for
resistance such that you might consider starting them on different
regimen if they had got infected with a resistant virus.

The problem here is that wild type tends to outgrow resistant virus in
the absence of drug pressure. For use in pregnancy, especially in naive
patients in high‑risk groups. Also in the treatment‑experience patients
to help protect vertical transmission. It is a little controversial at
this point.

Probably the biggest use of these assays now, kind of by clinicians who
are getting them, are after first virologic failure to help guide in the
selection of second‑line treatment and, in subsequent virologic
failures, to try to put a new drug regimen together when you have failed
several.

The problem is that we are kind of limited by the number of drugs we
have on putting new drug regimens together because of cross‑resistance.
Again, if you are taking the sample when you are not on drug, you could
come up with the wrong conclusions, perhaps.

\[Slide.\]

So I think our division\'s conclusions would be that knowledge of
genotypic data appeared to affect treatment outcome in two randomized,
controlled prospective trials. The effect in HIV RNA was of the
magnitude that would potentially support a drug approval.

Retrospective studies also have shown associations between genotype or
susceptibility in treatment outcome although some of the retrospective
studies showed more gross associations. Zidovudine mutations have been
shown to be prognostic for clinical progression.

\[Slide.\]

Clinicians desperately need guidance in selecting second‑line regimens.
However, I think the current limitations mostly in assay analytic
sensitivity, specificity, reproducibility and lack of clinical
correlations for some drugs prohibit recommendations for routine
monitoring of individual patients for all drugs.

Another conclusion is monitoring prevalence and transmission of HIV
resistance to HIV is crucial to the whole field. Compared to HIV RNA
testing, HIV RNA resistance testing is drug specific, much like
therapeutic monitoring of drug concentrations. Mutational algorithms and
breakpoints will need to be revised for each new drug that enters the
market.

Really, an efficient use of resources would be for the antiretroviral
drug sponsors to characterize both the clinical relevance of genotyping
and phenotyping susceptibility in the context of drug development
because you don\'t have mutations if you don\'t have the drugs.

Really, I think the best and most convincing data could come from the
randomized, controlled clinical‑trial setting. So if this could be
folded into drug development, we could have information by the time the
drug hits the market on how this could be used and what resistance
testing means for that particular drug.

That\'s all of my comments for today.

DR. HOLLINGER: Any questions of Dr. Murray?

DR. McCURDY: I was a little bit concerned about the report of the
variability between laboratories in detecting subpopulations and so
forth. I was disturbed by a couple of things. One as the variability and
the other was that approximately half of the laboratories that were
involved in this did not reply or did not provide data.

I was wondering what kind of assurance does one have that these tests
are likely to be done well in the laboratory. Is this something that may
be regulated or is regulated under CLIA or some other way to be sure
that once the tests are approved, as class whatever, they are actually
going to be done well?

DR. MURRAY: I don\'t know if I am the person to answer that question. I
used that information from an abstract to just illustrate a point of
where I saw the limitations. I thought technical and quality control
were a big part.

There might be somebody else who could better answer that question. I
know that certain assay sponsors have looked at CLIA certification and
that sort of thing. As with any test, it is a very important thing to
iron out. Probably most of our discomfort with using HIV RNA was not its
relationship to clinical outcome which I think has the most impact for
the decision you have to make today, but it was with the more technical
aspects of the assay; can it really measure what it is saying it is
measuring.

I think if those areas are controlled, the clinical use of the assay
will fall in place as it is defined in clinical drug development and as
it is defined in the clinical setting among the experts.

MR. WILSON: One the issue of CLIA control, I think you would have to
refer to HCFA, generally who controls the CLIA regulations. Typically,
there is a reimbursement in CLIA control over tests which are approved
or cleared by the Food and Drug Administration. You would have to talk
to them specifically about how that applies.

The second point that I would like to bring up is that, as part of a
premarket review process, be it a 510(k) or a PMA, we would typically
ask for three or more sites to run the test and then have, for example,
certain types of controls being run concurrently to make determinations
as to how well the instructions for use are written, how well known
positives can be recovered, et cetera.

The point I wanted to make is that whether it is voted as a class II or
a class III, those types of evaluations would be embedded in either
premarket approval process.

DR. BUCHHOLZ: I was about to say something although not what Len said.
It seems to me that as we talk about a number of things that we have
discussed this morning‑‑we have hit clinical acumen, we have hit
promotion and claims, education of physician, labeling content, adequacy
of performing, testing, QC‑‑that there is a blurring here of things that
I think would be issues whether this is a class II or a class III.

I think it is very confusing for the panel to have the information that
has been presented which, in fact, blurs these distinctions and really
gets us into an area that I don\'t think we are being asked to make an
assessment about.

I think we are being asked is this a class II device or, in fact, should
it be a class III device. But whether physicians can use it adequately
or whether there is CLIA testing and compliance, it seems to me that
should be an issue for these products, whatever classification it is.

So can I just ask you to help me understand and, perhaps, help some of
the other panel members understand what our charge is here because it
seems to me we are being presented with information that is far more
than we need to make the assessment I thought we were being asked.

DR. HOLLINGER: I think you are right. To me, I understand we are being
asked whether this should be reclassified since it would ordinarily be
classified as a class III just because there is no predicate test
available or anything, an equivalent test that they can compare it to.
This will be classed as a class III and they are asking if it could be
now classed into class II for a variety of reasons, primarily the one
that premarket approval is not being required, although we have learned
that they could ask for clinical trials also and make it as stringent in
classÊII as it is in class III.

Is that correct?

DR. DAYTON: Yes; that is absolutely correct. We wanted you to see the
science today so that you would have an idea for what is out there. If
nothing were known about these, it would be a very different story. So
we are asking you to realize that an awful lot is known out there and
that we can make good judgments based on that.

As I said, it would be a very different story if there were no track
record of clinical and scientific data.

DR. HOLLINGER: I am going to call on the committee here, but just to
give you some idea of where we are going here in terms of this, in terms
of your questions, and so on. We still have an open public hearing of
which there are at least four people who have asked to speak, mostly
from companies involved with these products.

So we are going to do that, but I want you to sort of understand this
because we will probably take a break right after this here for about
fifteen minutes and then return for the open public hearing.

DR. NELSON: One of the things that confuses me a little bit is the fact
that this isn\'t actually‑‑if you look at it technically, it isn\'t one
test. What we are looking at is that there are dozens of different
genotypes, some of which the association with an outcome or clinical
application is clear and has been well‑‑and there are others where it is
very fuzzy in which the data are not clear.

So it is a little different. Maybe that is why it is a device. I don\'t
know. But it is different than the question we are often asked.

DR. HOLLINGER: I think that is why they have called these HIV mutations
test which is going to be the name, I suppose, of what you are doing.

DR. DAYTON: Or something like that. But, in general, most of these
sequencing assays, in particular, will look across and entire region and
give you a sequence. So, in a way, they are all looking at the same
thing, basically. But then, for each of the individual codons, then
there is a distribution of knowledge.

DR. NELSON: But I mean for some tests where the meaning of a result
isn\'t clear, let\'s say a codon is identified and, with regard to this
drug, you don\'t know what it means. The FDA would not allow that‑‑or
there would be a different report or a different standard.

DR. DAYTON: You would have a claim‑specific issue.

DR. NELSON: Right.

DR. BOYLE: I am confused, and I am confused because I took away from
this excellent presentation three points that don\'t seem to quite add
up to me. I would like to find out which of these I am wrong on. It
looks like that what is being presented is that the data on drug
resistance is critical to the optimal management of HIV.

The data that is presented seems to be very clear on that point.

Secondly, genotyping and phenotyping analysis from HIV drug assays can
provide that kind of information for optimal management. Of course, the
converse side is if it is done wrong, then it is worse than random.
Basically, the information is critical.

The third piece, though, seems to be moving this type of thing that is
life‑sustaining from class III to class II classification, in looking at
these comparisons, the main difference is that clinical data is not
always required in class II but in class III, you have to have clinical
trials.

Having convinced me how important this is and how the tests have to be
done right or you basically are in serious trouble, why are we proposing
not requiring clinical trials for a particular test or test kit?

DR. DAYTON: First of all, we don\'t know that wrong results are better
than random. It may actually not be the case. It may be equal to random.
And then our essential approach here is is there enough information in
the literature to say that these things are useful. Actually, we see two
studies, the GART and VIRADAPT, are saying, actually, in practice they
are useful.

And we have seen, particular for AZT, evidence where individual
mutations are quite well validated. So we have to come back to that
point. I think those are the key points to keep coming back to.

You don\'t want to get off on the tangent of saying, \"Well, this is all
very complex science and it isn\'t all worked out.\" That is true, but
it is not a barrier to getting something out there that is useful.

DR. BOYLE: Then is this the equivalent of approving a class rather than
a drug?

DR. DAYTON: No; you are not approving anything. You are not approving
anything. You are just classifying it. We are not here to approve any
particular individual test. We are just categorizing at what level we
regulate them.

MR. WILSON: Maybe I can help here. Number one, these products have not
been approved or cleared by the FDA. In the regulations, there is a
section that describes what is to placed in the package insert. In the
package insert, there has to be adequate directions for use in detail.
Now, I am going to assume that because these tests that are out there
that are being used as home brew haven\'t had this level of scrutiny and
that is why we have an FDA to evaluate these things.

So, oftentimes, we will review the package insert procedures or
interpretations, et cetera. This is not going to run clearly by
technologists at a reasonable level of competence, et cetera. So a lot
of times‑‑all the time, to the level of the state of the art, these
types of issues get cleared up. So I think what you are seeing is that
we have a new test coming into being used, and this kind of happens
routinely. It is not all organized and standardized as well as it could
be two years from now, but the idea is in a premarket review, the
labeling requirements for the 510(k) are the same as the labeling
requirements for the PMA.

The other point I would like to make is that, as I had stated in my
slides earlier, a special control could be additional labeling. And what
I was hearing from the presentations is that there is some difficulty
interpreting results.

The committee can take the position that if they elect to vote for a
class II, that is special‑labeling consideration should be made. Let me
give you an example, but it is up to the committee. It may be a boxed
warning that states that the interpretation of such results need to be
carefully considered by physicians who are engaged in whatever, or it
could be in a section called the limitations of the procedure. It
doesn\'t have to be a boxed warning.

There could also be recommendation by the committee to have some
pretesting of some of the labeling, some of the instructions or some of
the interpretations as part of the review process to better insure
absorption by the physicians who would be using this test.

What would happen in that type of a situation, we would get a
study‑design proposal for the interpretation and it would be known
correct answers, and how absorbable is this information. And the
manufacturers then would modify the labeling to control that.

So this kind of thing can be controlled under class II classification.

MR. DUBIN: I think one of the problems is for those of us that have had
a lot of experience with AIDS drugs, this is not a new picture because,
really, from \'93 on, this issue is coming up before other committees
quite regularly. I think in the BPAC, we don\'t face this kind of issue
very often where something needs to go to market in a rapid way that
might directly impact care in the way we are facing.

I think, from our perspective, that is the core of the issue and it is
the context with which we need to look at within. I think, John, you are
right, we are looking at‑‑and you said the same thing‑‑we are looking at
a body of tests. We have better handle on some, on some we don\'t.

I think, from our perspective, reclassifying this will put more
flexibility in the clinicians\' hands. As I said earlier, our experience
is that that is a necessary tool right now. Certainly, I can only speak
for hemophilia, but I also chair California\'s‑‑just finished as Chair
of California\'s HIV AIDS working group. The resistance issues are
coming right to the fore in every community and everybody is concerned,
as they are about side effects. That is why I raised the issue of
postmarket and our concerns there.

So I think this is critical and it is important to get this into
clinician\'s hands. My concerns, and I think they can be addressed‑‑I
think some of them just were. I think we, as a committee, can set some
labeling standards to educate physicians because I do think‑‑Mary, you
said something really important that is our experience, too. Some of our
clients are with Dr. Gottlieb in Los Angeles or some very
well‑known‑‑and then we have got clients in rural areas who are with
hematologists, who are busting their butts to stay on top of this.

But it is difficult. It is not their area. I think the second thing you
just said that is important is the review process of the labeling
considerations. Let\'s say you all decide to start with a box insert. I
would like to see, personally, some review written into that so if you
all discovered that the doctors weren\'t really absorbing that, maybe
you would go to another way of getting that information across.

But I do think that is important. I do think this is evolutionary. And I
do think it is important. I certainly support reclassifying this because
of our experience. We discussed this at length within our medical team
and a lot of our people who do a lot of Washington work. We think this
has got to happen but we also think that it has got to happen the right
way.

And that is why I raised my earlier concerns about postmarket and some
difficulty because postmarket is a big job. In some areas, it seems to
have been more difficult for FDA than others. Now, I don\'t have a lot
of experience in devices. I admit that. I have heard, repeatedly, that
is the strongest part of the agency, actually.

Regardless of my concerns, though, I think this is important to do and I
think it is a little more complex than you were saying because I don\'t
think it is so cut and dry because I do think we need to look at
labeling considerations and ways to insure that the information needed
to go with these tests to the clinicians because the top clinicians are
going to know how to deal with it and they are going to understand the
limitations and others aren\'t.

DR. DAYTON: If you remember the questions we proposed, whatever decision
you make, you have an opportunity now to suggest specific additional
controls for labeling requirements.

MR. DUBIN: That is what I am talking about.

DR. DAYTON: And also when the draft guidance document is publicized,
there will be an opportunity for public contribution to that. So there
are at least two opportunities that we identify to do that.

MR. DUBIN: I think if we look at it in this kind of broader context, it
is a little different than we normally do, it is not so confusing. And
there is a way through this that I think the committee can make some
good recommendations and, just to underline the one part, and build in
certain reviews to insure that there is an ongoing review of certain
aspects that we have concerns about.

DR. FITZPATRICK: The essence that I understand of what we are going to
do is accelerate the time line‑‑

MR. DUBIN: It is fast‑track.

DR. FITZPATRICK: ‑‑that FDA is required to review these things and
impose the same restrictions and structure that they would to bring it
to market under a class III. And that doesn\'t appear to be a bad thing.
And we have the opportunity of putting those restrictions now and that
seems what we should be focusing on.

DR. BUCHHOLZ: I am a little concerned that there was an impression left
in the asking and the response to an earlier question about a class II
device and a 510(k), that there was no clinical data required. I work
for Fenwal Laboratories which makes blood‑collection and processing
equipment. We deal mostly with device applications.

I have sat here for a while trying to think of a 510(k) submission that
we have submitted that we have had not had clinical data. I can\'t
believe that we are that different from the typical device that CBER
regulates. So I would like to ask somebody what is the percent of
510(k)s that have clinical data because I think it is very valid concern
if the level of scrutiny here is significantly less between a 510(k) and
a PMA.

But, at least in our experience, there is clinical data that is
routinely required.

DR. HOLLINGER: Does anyone know that information or, Len, can you give
maybe just a little bit of a hint?

MR. WILSON: I will do my best. I don\'t think that the statement is
incorrect. I think what the question really is for the table here is
what type of clinical data. For example, in this particular instance, we
were looking, as Dr. Dayton described regarding known panels of samples,
some retrospective testing, some repositories.

That would be, in a sense, clinical data as opposed to a full‑blown
prospective clinical trial. So what we were looking at here was trying
to get some testing validity with some real samples and some analytical
testing. That is kind of where we were coming from, if that gets to the
point.

DR. MITCHELL: I had a couple of clarifications. One is about the drug
resistance assays so I would assume that that would apply to both the
phenotypic as well as the genotypic tests; is that correct?

DR. DAYTON: Well, we are actually just bringing for the classification
of the genotypic assays in this meeting. We are not bringing forward the
classification of the phenotyping assays. Phenotyping assays can be used
in direct clinical situations. That is what we are discussing right now.
But there are also phenotyping assays that are done in vitro to validate
the genotyping assays.

So, at the moment, we are only discussing the classification of the
genotyping assays in direct clinical use and we are not addressing the
classification of the phenotyping assays in direct clinical use.

DR. HOLLINGER: That was clear to me, either, Mark. I am glad you asked
that.

DR. MITCHELL: The second question I had was about the minor typing. I
guess I am very concerned about minor types because, obviously, once you
treat the major type, it is going to be replaced and that is going to be
the new major type. So I am very concerned about the sensitivity of the
tests and picking up minor types.

So I am assuming that one of the things we can do is ask for some level
of minor type that a test would be able to pick up.

DR. DAYTON: Absolutely. It will probably be in the neighborhood of 25 to
30 percent of the overall species. Yes; the ability to pick up a minor
type is a major concern. But, of an even larger concern is, even if you
are only able to pick up major types, is that of clinical benefit. I
think the answer is yes.

But we certainly are concerned about minor types and we will ask
sponsors not only to claim or what is the lowest percentage of a species
that they can detect, but also to titer through that so we know just how
quickly assay performance deteriorates when you go below what they
claim.

So we are concerned about that.

DR. MITCHELL: My next question, then, is do they even know‑‑I mean, is
it easy to characterize a percentage of a type. Do we know whether the
major type is 60 percent or 95 percent.

DR. DAYTON: You can do that in research settings. So you could certainly
do that on spiked samples. You can do that in panel type specimens where
you can make multiple subclones and multiple sequences of each of those
clones so that you can identify what the swarm is.

So, yes; you can do that in a research setting.

DR. McCURDY: I have a certain amount of objection to the implication
that we might reclassify this to get it out faster. I think it ought to
be gotten out right and, if it is a right to have it a class II with the
appropriate kind of controls, and I am currently tending in that
direction, then that is fine.

But I think the idea of getting it out faster by reclassifying it is not
the right way to go.

DR. FITZPATRICK: I don\'t think it will necessarily mean, by
reclassifying, that it would go out faster but it requires the FDA to
review it faster.

DR. STRONCEK: I may come from a different view. I think this makes a lot
of sense. I have worked with HLA, the field, and we do genotyping. When
you are on the cutting edge, manufacturers don\'t make the kits. You
make them in‑house in laboratories.

I assume that Dr. Mayers\' tests were developed by himself. He orders
the primers. He orders all the reagents. So this field is going to
progress. Now, he has published this data or he will. He is showing it
is effective. So now we are in a situation where we have an effective
test but we need lots of clinical trials to show that it works. And
there are no commercially available tests to further the field.

So manufacturers can\'t sell these tests to make them widely available
until they go through the FDA. So the field is in a situation where
commercial tests are not available to have the field progress, yet there
is data in the literature, peer‑reviewed literature, that says it is
effective.

So I think it makes perfect sense to go this as a class II based on the
data in the literature but then, as you are proposing, to closely
monitor the kits that go out to make sure‑‑to try and do some premarket
evaluation as best you can and then to try to monitor them afterwards.

This is going to be a very fast‑moving field, too, so it is very
important to have a structure where you can change things quickly. I
think what you are proposing will do that.

MS. KNOWLES: I would support a change from class III to class II based
on having strict controls, the standardized reporting form, close
postmarketing monitoring, and then Dr. Murray\'s last comment about
including some of the issues of testing in the pre‑drug development.

DR. MACIK: I kind of look at it, too. Two reasons get you into class
III; either it is a life‑or‑death‑type experience or there is no
predicate device. One of the things here is that it will help
management, but the bottom line is that you are still going to be
looking at viral load and you are going to be looking at CD4 count.

So if this test told you something wrong, you know about it. At best, it
gives a running leap at the right guess, but there is still a good
follow up to know whether that test gave you the right answer and it is
no worse than where you were before if you didn\'t use the test.

So, in my mind, it really is‑‑clinically, it has a good backup. I think,
from that standpoint, would make me want to put it into a class II type
category.

DR. HOLLINGER: I think Dr. Gutman, who is the Division Director of the
Clinical Lab Devices at CDRH wants to say‑‑

DR. GUTMAN: I just want to clarify. I realize there are a lot of very
complex issues on the table and I have absolutely nothing to do with the
product line at all, so I am absolutely free to speak, although,
obviously, the decision you make would be of interest to folks over in
the devices area as well.

I just wanted to clarify that when we look at the scientific review
process, which is quite complex and possibly multilayered here, that we
feel quite comfortable, frankly, in carrying the exact same rigor of
science between the PMA and the 510(k) program, that we have no
difficulty at all if we think appropriate clinical information is
necessary to characterize a product to have immensely complex and
intense reviews and requirements for manufacturers in the 510(k).

It sounds to me, as an outsider, that there are very complex clinical
issues to be dealt with in the context of the guidance that would be
developed to support this, the special controls to support this and that
there, in fact, might be various approaches to different analytes within
the context of that guidance.

Although I realize you might shy away from trying to provide
administrative relief, it sounds to me, again, as an outsider, that what
this division or this group is saying is that they do have a fair amount
of scientific knowledge to draw from, that they do understand the
questions of safety and effectiveness that they would like to apply to
this product line and that they think they can do good scientific review
on your behalf and the public\'s behalf in the context of the more
flexible 510(k) program.

From my perspective, we have lots of experience doing this and we do
everything we can as we move across administrative paths to preserve
scientific thresholds. We have done this with‑‑the closest that I think
in our shop to this product, the scary product, was tumor markers and we
downclassified a variety of tumor markers because we had such a rich
literature and methodology and experience and statistical methodologies
to draw from.

I think what we have done in that case is serve the public well because
we have made it easier for us and for sponsors to bring out a wider
array of tumor markers and to improve choice.

I realize there are a lot of complex issues but I just wanted to assure
you that whatever decision you make, this group‑‑I know and love this
group. This group isn\'t going to sell the scientific product short.

DR. HOLLINGER: That is probably not a good example about tumor markers.
I will tell you that they don\'t have a lot, sometimes, of clinical
application and we do spend a lot of time with AFPs and CEAs and CA125s
with high values that don\'t have much meaning at all. So I am not so
sure that clinical application would not have been very useful there.

Just from my standpoint, I will say, so far, I sort of share initially
what Mary brought up here. We have no data. There was one study here
which is the GART study. We don\'t have the paper to look at. There are
some major issues about its utilization.

I don\'t think there is any question that resistance does make a
difference and does make a difference in terms of treatment. The
question is whether the data is there to tell us if the tests are going
to make a difference in the management of these patients over and above
what we have today which are CD4 count and HIV viral loads and so on.

While it may, and the data looks like that, there are some really
difficult issues that have not been addressed. Certainly, the question
is, in class III, at least you are required to do a PMA evaluation
whereas we have to accept the fact that it may be asked for by the FDA
but it is not a requirement.

So, right now, at least from my standpoint, I am looking more at this
not to reclassify but I am going to be listening to what others have to
say here plus the other material that is going to be presented in the
open public hearing.

DR. BUCHHOLZ: I think one thing that the committee may not be aware of
with a class III device‑‑I mean, I think there is general agreement that
it takes much longer for regulatory review and approval of a PMA‑type
device or a class III device. That is a double‑edged sword because I
think the regs read something that you are required to file a
submission, be it a 510(k) or a PMA, if you have a significant change in
an existing product, a significant change that impacts safety or
efficacy.

I know from personal experience that Fenwal has had some situations
where we find a problem in the product that is marketed and we say,
\"Oh; well, we want to fix that.\" We are perfectly willing to implement
that change. I think any reasonable reviewing group would say, \"Yeah;
it makes sense to fix that. That is an unforeseen problem.\"

Yet, with the PMA situation, we may go through a year or more of putting
the file together which takes longer than a 510(k) and also getting that
regulatory review and blessing to make that change when it is a change
that improves the product, that enhances safety, that enhances efficacy.

So that is a double‑edged sword in terms of the PMA process in that it
can significantly lengthen the period of time simply by virtue of the
more complex review that it takes to implement good things in an
existing product.

DR. HOLLINGER: Can I have one more response from Dr. Chamberland and
then I think we are going to take a break. I think people need a break
for a minute. And then we will come back. So, Dr. Chamberland?

DR. CHAMBERLAND: I guess I have just been trying to put together
everything that I have heard presented formally and then the discussion
so far among the committee. At least, I hope I have this right. If I
don\'t, somebody correct me. But what I have heard is that FDA is asking
us to‑‑they feel that downclassifying these types of tests from a III to
a II is okay for two reasons. One is that there is a body of performance
data out there about these assays. It tells you about how good
sensitive‑specific reproducibility‑‑the data may not have been derived
in the traditional clinical‑trial approach, but they feel that there is
adequate data out there to address it.

The first conclusion, though, on Dr. Murray\'s slide said that the
knowledge of this genotypic data‑‑and this is the second reason that FDA
gave us, at least what I heard, why they felt this downregulation or
downclassifying was indicated was that there was a benefit \"to public
health,\" that clinicians need this kind of information.

The first conclusion, in Dr. Murray\'s talk, that knowledge of genotypic
data appeared to affect treatment outcome in two randomized prospective
studies. I think, for me, that is‑‑my gestalt tells me that that is
probably true. But I don\'t think we, at the committee, have the amount
of detailed information to have a sense that data from these two trials
is readily generalizable to the larger field of practicing clinicians.

I think that your ability to generalize really depends on how these
patients and physicians were selected for both of these prospective
trials and, secondly, the kind of information that was presented to the
clinicians, how these genotypic test‑results data were presented.

In looking at the Lancet article, it seems like the physicians got
information about‑‑and this was the VIRADAPT trial‑‑they got information
about what the mutations and the codons were which, for most clinicians
doesn\'t mean, necessarily, a whole lot. You know, V75T. But they also
gave the clinicians information on the drug, then, that they would not
suggest you choose, that there was some interpretation to these data.

So I think the question is still out there a bit on the utility, the
usefulness, the public‑health benefit of these tests. I think it really
rests on how the information is presented to clinicians in a way that
they can use on a day‑to‑day basis that is interpretable.

So I have some reservations about the statement that we have two
prospective studies which appear to demonstrate that knowledge of
genotype impacts significantly on clinical coursing in the patient
because I think there are only two, the selection of the physicians to
participate in the trial is not clearly outlined, and then I think it
made a big difference on how the data on genotypic results were
presented.

DR. HOLLINGER: We are going to take a break and then we will come back
to other discussions later on.

\[Break.\]

DR. HOLLINGER: We have four speakers in the open public hearing
who‑‑four companies have asked to speak and their representatives. The
first one is from Visible Genetics. That is going to be Dr. Curtis
Scribner.

**Open Public Hearing**

DR. SCRIBNER: My name is Curt Scribner. I am here presenting on behalf
of Visible Genetics. They were rained out because the planes weren\'t
flying from Toronto last night so I am here to present their
information.

\[Slide.\]

Visible Genetics is developing a true‑gene HIV I procedure which comes
as a complete kit. The first few sections up here are all done using
standard laboratory‑based criteria. Then there is a bidirectional
sequencing of the material presented her, separation by electrophoresis,
analysis by our gene objects, a computer system with, then, the report
that comes in.

\[Slide.\]

The report comes out initially looking like this. Unfortunately, this is
the fax because this got taken care of by Floyd as well, but we see that
we have resistance with the protease inhibitors, the non‑nucs and the
nucs, with a further report here with these two pages of exactly what
kind of information we have seen and the scientific basis, the
literature basis, upon which we have made these decisions.

These decision‑tree recommendations‑‑not determinations, but
recommendations‑‑of those drugs which may not be useful are based on a
scientific committee which meets on a regular basis to evaluate all
scientific data and put them together.

\[Slide.\]

However, for Dr. Chamberland, of course, we always put this together
which shows definitively the types of mutations or changes that are
demonstrated in our process.

\[Slide.\]

Performance of any kind of a kit is vitally important. These are the
types of studies which are already ongoing which you are going to be
looking at. We have taken collection of plasma from nine people with
viral loads from anywhere from 1300 to 300,000 which have now been
aliquoted in a blinded fashion and will be separated and sent to
multiple sites for validation looking at site‑to‑site, day‑to‑day,
technician‑to‑technician to make sure that the sensitivity, specificity
and reliability of the test are adequate and important.

We have a multicenter study already going for reprodicibility and
accuracy and we are concurrently working on the freeze‑thaw studies
using multiple viral‑load samples to make sure that we understand the
differences or the problems with freeze‑thaw, a difficult problem, as we
have already known from the viral‑load PCR testing.

\[Slide.\]

Interfering substances, of course, are important. These are the types of
things we are already looking at, other pathogens, including viruses,
biochemicals, including drugs, and with the antiretrovirals. We are
looking at mixtures to address the question of what is the sensitivity
looking at a mixture of wild type versus resistant, and we are using
various ratios working from 100 percent wild type down to 100 percent
mutant.

We are as concerned as you are with the NVA II study. Since there are
sixty sites around the country, apparently, which are doing this, we
believe that is vitally important that this information be readily
available and published for people to examine.

We are doing plasma‑extraction studies as would be necessary depending
on the type of plasma that would be needed and anticoagulants. Everyone
has understand the limitations of heparin. There are multiple other
anticoagulants which are also available, each of which will be
determined.

\[Slide.\]

Our clinical trial is base on search. It is a twelve‑month, prosecutive
controlled study. It is ongoing using 300 randomized subjects. The
randomization in this case will be to those people who will have the
genotyping provided and those who will not.

We have almost completed enrollment into the trial. The basic difficulty
is that, as you all realized, this type of testing is already readily
available in the United States at the present time through the home
brews through several large clinics, through several large laboratories.

All of the subjects have had pre‑treatment and are failing. The primary
endpoint is fixed at 24 weeks and we will examine the change in viral
load from baseline and then carry it on out to one year.

\[Slide.\]

At the same time, we are looking at the studies, both GART and VIRADAPT,
which you have heard today, with the reanalysis of all of their samples
looking at the ability of our device to find the same types of mutations
or changes in the clinical trials so that these data could be used by
reference in our application.

\[Slide.\]

Also part of the PMA submission‑‑I say PMA submission with the
understanding that it is our assumption it might take as along as 18 to
24 months in order to get these types of final rules finally completed.
We will have more than 400 assays performed at greater than eight sites
looking at the device characteristics including reproducibility.

Clinical utility will have at least 400 assays looking at the various
samples that we have already talked about before, done at two to three
sites to make sure that we can have good reproducibility.

I also have three comments that I would like to add based on what we
have seen before. We have not, of course, seen the guidance document
that has been presented to you in incomplete draft form but we have
serious concerns about the use of genotyping with clinical validation if
the IC50 or IC90 in an in vitro process is greater than eight‑fold.

It is very difficult to find these patients. We would very much welcome
suggestions on the appropriate clinical methodology to treat these, to
find these, patients and to have appropriate reproducibility for those
studies.

We also would like to point out that it is very difficult to do studies
right now with a randomized process. With the availability through the
large clinical laboratories of unpublished genotyping testing, it is
difficult for a person in a clinical setting to decide whether or not
they will use genotyping since it is readily available commercially.

We find that it would probably be almost impossible to do clinical
studies after approval based on the fact of having an approved or
cleared test already in place. That is a subject you might want to keep
in mind.

Finally, we want to note that the Visible Genetics Organization is in
the process of enrolling a clinical study to address the issues that we
had talked about before of reproducibility across populations as well as
reproducibility of looking for new genotype changes by enrolling up to
30,000 people over a long period of time such that this would form the
basis for evaluation of new genotypes that would be reported.

Thank you very much.

DR. HOLLINGER: Thank you. We appreciate it.

Just so the speakers will know, I am going to limit you to seven
minutes. Just so you will know that ahead of time so you can get to the
critical issues.

The next one is from Innogenetics, Michael Ussery.

MR. USSERY: Thank you. We appreciate the ability to speak to you today.
Since we are not actually talking about approval of our specific test, I
am not going to go into great detail. I have provided copies of the few
slides that I have brought with me and there are a number of papers in
the open literature about the performance of our test.

\[Slide.\]

The line‑probe assays, as were mentioned before, are quite different
from the sequencing‑based assays. There is an amplification step and
then there is a reverse hybridization with lines on a nitrocellulose
strip. Where we are looking, on each strip, there is a mutant and a wild
type oligonucleotide that will provide a line for either mutant or wild
type or, in the case of mixtures, for mixtures.

There are some advantages and disadvantages to this kind of approach. It
is rapid. It is very cheap, relatively, and it is very good at picking
up mixtures. We have clinical data that shows an ability to pick up
5Êpercent mixtures, readily.

Sensitivity; the studies that we have so far, routinely, we can detect
500 copies per ml and we have, down below that, at even 50 copies per
ml, we can detect about half of the samples and give you a readout. But,
anyway, that data would be provided in either our PMA or our 510(k).

I wanted to comment on just a few of the issues that were raised from an
industry standpoint. Dr. Murray mentioned that a lot of the data on the
clinical relevance of specific codons is not going to come from the
diagnostic companies. We provide our tests to the pharmaceutical
companies in their clinical trials and we would, of course, agree with
the FDA that this clinical utility of a particular codon has to be
established, but most of that data will come from the pharmaceutical
companies in the course of approving a drug.

They are asking for quite a bit of this information and I think we would
fill in the holes and the gaps where they were necessary.

One of the things that I did want to mention. This is our
reverse‑transcriptase strip. There is another strip on the next slide
for the protease mutations.

\[Slide.\]

The other thing I wanted to mention was a little bit of the real‑world
situation in terms of trying to plan well‑designed prospective trials.
We have, at least from experience recently with a well‑designed,
randomized prospective trial, similar, in some ways, to the GART and
VIRADAPT, with our test that the IRB at Johns Hopkins said was really no
longer ethical because of the results of those two trials.

There are certainly other kinds of clinical‑utility data that we can
gain and I think that what we hope to gather from this process would be
a better definition from the FDA of what studies we really need to do.

But the concern there was that, even though these tests that are home
brew are not being reimbursed, if we are actually going to do the test
in two different arms of patients, then, at this point, they feel that
the relevance of the testing information is so important that we have to
let the doctors know. We can have a group of doctors that would not know
the outcome of our test even though it is, as of yet, unapproved.

So that makes some kind of randomized prospective trials difficult.
There are other kinds of performance clinical trials that certainly need
to be done and we hope to work with the FDA as I am sure all the other
sponsors do in defining what exact trials would be acceptable and we are
supportive of this proposed change.

\[Slide.\]

I just wanted to mention a few pieces of information that apply to all
the resistance tests that the different manufacturers are talking about,
not just ours. There was data that was mentioned by Doug on the GART
trial. I think this just really goes to the issues of risk/benefit, of
allowing these kinds of tests on the market a little sooner.

If you looked in that study, the patients that did not‑their management
was not based on GART, they refused fewer drugs that were active against
the strain of HIV that they were infected with. So, as a corollary to
this, they were exposed to toxicities of a higher number of drugs which
were inactive against their virus strains and, thus, had little or no
clinical benefit to add to their management.

The fact that these patients were treated often with only two active
antiretroviral drugs and, in 10Êpercent of the patients, only one
because they didn\'t have the genotypic data, makes these patients even
more likely to rapidly develop resistance to those few remaining drugs
that they were susceptible to.

I think that that is an important thing to keep in mind. One of the
observations was made that the genotypic data will not be looked at by
clinicians alone. There will be CD4 and viral load data and that can
serve as a check in case there are some wrong calls made in genotyping.

\[Slide.\]

Finally, I just wanted to mention a study that was reported at the San
Diego workshop looking at the VIRADAPT study from a pharmacoeconomic
analysis. It was interesting that even in these short studies that there
still was a significant trend towards a reduction in the cost of
antiretroviral drugs in the genotyping arm and that the cost of
genotyping‑‑in this case, it was by sequencing which is, maybe, somewhat
more expensive than our test, but, anyway, that cost was offset by the
savings in antiretroviral drug costs. I think that is also important for
the management of our patients.

I think that is all I have today.

DR. HOLLINGER: Thank you.

The next speaker is Tony Lam from Applied Biosystems.

MR. LAM: My name is Tony Lam from Applied Biosystems and PE Biosystems.

\[Slide.\]

Before I start, I want to point out one thing, that the PMA also has the
requirement of manufacturer information submitted and also a preapproval
for quality system inspection. So these are additional to just the time
line that you have to submit the 510(k) which is going to be a lot
slower and a lot of time to get ready.

\[Slide.\]

This is our product. Our product is basically a genotype system with
sequencing‑based HIV genotyping and utilizing PCR sequencing and
software technology. It is an RNA assay to give you nucleotide sequences
of DRT and the protease gene in the HIV of the patient. The genotype is,
actually, compared to a known HIV antiviral drug resistance mutation on
a public database.

Two reasons that the downclassification is that the background is that
the HIV drug resistance has been identified with treatment already,
failure already, and the patients and all the other parties are actually
using it regardless of approval. But in the absence of a cleared
product, cleared HIV product, will make sure that the inconsistency is
still going to be there and the delay would also create a public‑health
risk of substandard testing.

\[Slide.\]

So the technology is very commonplace now and the main thing is the
intended use should be falling under the purview of the Food, Drug and
Cosmetic Act but not the Public Health Service Act. The reason is that
this is to provide guidance to physicians not used as a blood‑banking
diagnostic as a primary test.

\[Slide.\]

To compare class II to class III, will require flexibility from the
regulatory agency. And, as I mentioned before, class III also needs
manufacturing data and, also, a preapproval inspection plus all the
other 180‑days and all that long kind of review.

The class II is a lot more flexible as a lot of people have already
mentioned. It will give you a lot of flexibility and have fast approval
process and it is easier to update for improvements and changes.

\[Slide.\]

We have an any for this. CBER has already accepted a concept of a
similar HLA device. I put them next to each other. The first point is it
could be validated by an outside academic consensus group similar to the
HIV which has already a public database compendia and independent peer
review.

And then the new information will be incorporated in diagnostic labeling
claims without any more submissions. This should be the same, that the
database is continually updated with new resistance, mutation
resistance.

\[Slide.\]

We should focus on analytical performance because 510(k) or PMA, at this
point, is lacking a standard and what should be done and how should it
perform. The 510(k) proof of performance should use some panels, but not
very many, for mutation and then it will be the same for the new
mutations. It should not require a lot of data and isolets. The benefit
will be that it will avoid delay in the process in clinical access for
this kind of information and also to avoid expensive large‑scale
clinical studies which are not necessary.

\[Slide.\]

Also evidence of analytical performance is there is an ongoing database
which will enable the incorporation of new resistance data. This will be
continuously updated and improved by the independent peer review and not
based only on the submission of on PMA from one manufacturer, limited
resources.

\[Slide.\]

Again, more analytical performance. And, if it is available in a fast,
short time frame and it could be used by the pharmaceutical companies
for their antiviral drug develop. And it reduces inherent available and
unknown performance of home brew.

\[Slide.\]

Another important point is to adopt a standard or guideline. Right now,
the HIV Resistance Collaborative Group has already drafted a proposal
which provides clear, and a key word is, technology consensus because
that is what we don\'t have at this point. So we have an analytical
performance to validate the assays for the 510(k).

This is consistent with the FDAMA Congressional mandate that the FDA
should favor consensus guidelines. Together with the use of this public
database and the guidelines will protect public health.

\[Slide.\]

If we don\'t downclassify, it will result in delayed use of the clear
products and then encourage home brew, create a public misconception
that FDA is raising high hurdles for approving products and delay
patient access to more effective existing and new antiviral therapies.

\[Slide.\]

In summary, it is low technology risk because it becomes commonplace and
the intended use is not a stand‑alone but guidance and not diagnostic.
We require flexibility from regular agencies to serve public health,
interests. We should focus on analytical performance and then make use
of the public database compendium and adopt or create a consensus
guideline by the FDA so we could use it for clinical validation as basis
for a 510(k) clearance.

\[Slide.\]

So this, basically, will end up as a Tier III which is identical to the
technical and scientific requirement of the PMA and the FDA could still
exercise appropriate oversight.

Thank you.

DR. HOLLINGER: Thank you.

The last speaker is Brendan Larder from Virco.

MR. LARDER: Thank you for the opportunity to speak here. Virco is not
actually a kit manufacturer. We are a service‑based company and we
provide both phenotyping and genotyping in the U.S. and the rest of the
world.

\[Slide.\]

The reason I am here is really to make a few comments about
interpretation which, I think, is quite appropriate, or interpreting
genotypes, is quite appropriate considering some of the discussion
earlier this morning.

\[Slide.\]

By way of background, and this has, obviously, been touched on quite a
lot this morning, that phenotypic testing is complex and it requires
specialized central labs, specialized equipment and well‑trained
scientists. I don\'t think anybody really thinks that phenotypic testing
is ever going to become a kit‑based assay. I think it would be very
difficult for this to happen.

As such, this is now regulated in the U.S. under CLIA, the CAP and New
York State\'s regulations which we adhere to. That actually puts a lot
of the validation and regulatory processes in place in the actual lab
and is quite exacting and demanding.

Obviously, genotyping assays, as we have heard, are more amenable to
kit‑based formats although, again, they are being used by centralized
labs, so‑called home brew. But these also are regulated and can be
regulated by CLIA. I would just like to point out that the Rob Sherman
study, those 30 labs, most of those labs were academic labs that
weren\'t carrying out genotyping under CLIA regulated conditions.

But the real crux, I think, is relating complex genotypes to phenotypic
resistance. This is really quite difficult. Doug Mayers touched on this
as did Jeff Murray. Really, to interpret genotypes in a sensible and
informative way, these large phenotype‑genotype databases really should
come into their own in facilitating interpretation and enhance the value
of the genotypic testing.

\[Slide.\]

Just as a quick overview, these are the assay principles of the assays
that we carry out at Virco and by LabCor for providing the testing in
the States. ABI‑based sequencing, computer analysis an interpretation,
which I will touch on a bit later to give the Virco genotyping report.
And then recombinant virus assay for phenotyping where a PCR fragment is
recombined into homologous virus. The available virus is grown up,
titered and tested against drugs. That is the antivirogram report.

\[Slide.\]

This is the antivirogram. You can see it can give a fairly simple and
direct readout of phenotypic resistance. This shows the drugs tested,
the panel of drugs tested, all in one test. This shows the assay range
and sensitivity to each drug is where the blue dot is.

Just, in summary, you can see red for resistance, green for
no‑resistance, et cetera, so it is very easy to read off. These values
are based on cutoffs of around about for intermediate resistance or
resistance greater than four‑fold or ten‑fold.

\[Slide.\]

When we come to genotypes, and I think you have seen lots of mutations
already today so I won\'t, obviously, dwell on this, but the list of
mutations is enormous. This shows nucleosides, non‑nucleosides, protease
mutations. This is not exhaustive. The problem is the more work we do,
and the more samples that we analyzed, and we have analyzed thousands
and thousands, the more mutations you come across. So interpretation
become a real problem, particularly since they are not seen singularly
but in complex mixtures.

\[Slide.\]

This is some data that we presented at the San Diego meeting a few
months ago on samples from routine testing greater than 5,000 samples,
just showing the percentage, for example, 215 mutation and 50 percent
184 mutation, non‑nucleoside mutations, protease‑inhibitor mutations.
There is a lot of resistance out there and, as more people get tested,
we find more mutations and more complex patterns of mutations.

\[Slide.\]

Other examples here are new mutations that we can find, again, using
database‑type analyses, again some work we presented. This was quite a
surprise but when everybody says, \"Yeah; we know what 3TC resistance
is, it is the 184,\" well, actually, that is not the whole story.

We found here that, in the absence of the 184, there are quite a
substantial number of samples from patients that show phenotypic
resistance to 3TC. This is due to what we consider polymorphisms in a
background of AZT mutations. Without having this consistent back
reference phenotype to genotype, we will never discover this sort of
information.

If we just look at the genotype, we are really kept in the dark.

\[Slide.\]

Again, if just concentrate on individual mutations, and this is just an
example for non‑nucleosides, again we can make some probably wrong
decisions. So, for example, a common non‑nucleoside mutation, 198A,
phenotypically, the virus is resistant to nelvirapine but susceptible to
the other non‑nucleosides.

You can see, as we get more complex mixtures of these mutations,
sometimes you can see resistance to all three, sensitivity to one here
or another here by phenotypic testing.

\[Slide.\]

One of the answers that we feel is really to direct comparisons with
genotypic and phenotypic databases; our database at the
moment‑‑actually, this is a bit old‑‑has more than 15,000 genotypes and
over 30,000 phenotypes with all the drugs. What we do know is we don\'t
depend on algorithms because I think algorithms, once you establish
algorithms of what mutational patterns might mean in terms of phenotype,
it is a static thing. You need something that takes into account that
everything is changing all the time.

So this database continues to get updated with genotypes and phenotypes.
Now, through the software that we developed, we can input a sequence.
The software can recognize complex patterns of mutations and scan the
genotypic database and find matching samples that match and then, with
all the samples that match with the same patterns of mutations, pull out
all the phenotypes and then condense that down into a relative risk, if
you like, of a virtual phenotype and to say what percentage of these
phenotypes were resistant, what were intermediate and what were
sensitive in terms of this original sequence.

So what we have done is taken the sequence and turned it into a
phenotype through this database matching.

\[Slide.\]

This is the kind of report that we soon will be launching as our version
II report. It is fairly similar to the antivirogram but shows mutations.
This is just genotyping information. It shows drugs. That
interpretation, via distribution of matching phenotypes from the
database, showing how many matches there are‑‑some of these are about
8,000 and some are a few hundred‑‑and then showing distribution so you
can quickly read this off, easily read this off, saying, \"Well, there
is a large amount of resistance of red here so the virus is likely to be
resistant to this drug via this pattern recognition of matching the
genotype with the phenotypes in the databases.\"

\[Slide.\]

The other thing I should say, and I think this is important for the
committee to consider, that the phenotype/genotype interpretation, the
interpretations on algorithms can be tested and they should be tested
statistically.

This shows a little bit of data where we took a whole bunch of
phenotypes where all these viruses were phenotypically resistant to the
protease inhibitors. We ran the sequences through our database and said,
\"What is the prediction just from the sequence, for each of the four
proteases that we looked at showing that, in most cases, there was a
high level of good prediction of high‑level resistance just by taking
the sequence and saying, \"How do they match and what sort of phenotypes
do we see?\"

You can apply statistics to this and I think that should be done in
terms of interpretation. It is really essential. If people are saying we
have an algorithm or system for interpretation, then it should be tested
statistically.

\[Slide.\]

Just to conclude, I think everybody is in no doubt now that there are
numerous different combinations of specific mutations that are
frequently seen in routine clinical practice. Somehow, predictable
phenotypes, 184 3TC resistance‑‑some have less predictable phenotypes
or, in fact, are not even known at the moment.

What we are trying to work towards‑‑we are not making kits but we are
trying to enhance the interpretation of genotypic information through
use of a large relational phenotype‑genotype database which enables us,
now, to generate these virtual phenotypes that can be derived just from
the sequence, comprehensive sequence, data.

We feel now that this is really going to be a valuable tool in helping
genotypic interpretation.

Thank you.

DR. HOLLINGER: Thank you very much.

Let me just find out, is there anyone in the audience, before we close
the open public hearing‑‑does anyone else need to respond or comment?

If not, then I am going to close the open public hearing. I am going to
ask Dr. Tabor to make a few comments here and then we are going to open
it up for the committee discussion on the question.

DR. TABOR: We have been spending the morning discussing an issue that
has become more and more complex as we have heard more and more
presentations. I would like to try to clarify some of that for you,
perhaps reiterating some of what I said before.

What you are being asked to do, as a committee, is not to rule on the
approval or disapproval of any particular product but to give an opinion
on an approach, in a regulatory approach, to a certain category of
product, the genotyping assays for mutation detection in HIV.

We are only talking about the genotyping assays at present and that was
what was in the public announcement and that was the intention of the
FDA in bringing this to you at this time.

What we are talking about whether something that, in the absence of your
acting, would be a class III device requiring a PMA, a longer review
time, essentially mandatory levels of clinical information. We are
asking you to decide whether the category of device can be regulated as
a class II device.

We can still ask for as much clinical information as we want of a class
II device. The difference is on the impact, or the potential impact, in
the health of the patient and the public safety. So, if we have an
application that we decide‑‑let\'s just say that you say it can be a
class II device; if we have an application that deals with well‑known
genotypes with well‑known associated mutations, we can ask for less
clinical data than if we have an application that is dealing with new
mutations or areas that are not as well studied or as well known.

We can ask for the same amount of clinical information if we want as we
would ask for a class III. It is just that it gives us the additional
flexibility, if we are dealing with something that has minimal direct
impact on the patient health and where there is a lot of information
available already.

With the issue of genotyping versus phenotyping, you have heard a lot of
really good data and you have seen how extensively both areas have been
studied. All we are asking you to look at today are the genotyping
tests. We will come back to you at another BPAC meeting in the near
future to ask you the same question with regard to the phenotyping test.

So I am asking you to set aside a lot of the scientific information you
have heard and, certainly, I am asking you to set aside the specific
information about specific tests that were heard in the open public
hearing and save some of that information for the next meeting, and only
decide, at this point, whether the genotyping assays can be regulated as
class II devices because, otherwise, they will be regulated as class III
devices.

DR. HOLLINGER: Thank you, Ed.

I am now going to ask Dr. Smallwood to read the charge to committee.

**Charge to the Committee**

DR. SMALLWOOD: The Blood Products Advisory Committee is sitting today
for this issue as a medical‑device panel. This is permissible under the
charter of the Blood Products Advisory Committee which states that it
allows the committee to sit as a medical‑device panel when there are
such issues which would involve classification issues and the setting of
standards as this discussion today.

I know you have heard a lot of information regarding this. What I would
like to do is reiterate the salient points of procedure to assist you
when you are making your deliberations on this particular topic.

As has been explained, we are asking you for a recommendation for
reclassification from class III to class II. You have heard the
definition of a class II. I will just state, again, the devices which
cannot be classified in class I because the general controls, by
themselves, are insufficient to provide reasonable assurance of the
safety and effectiveness of such devices but for which there is
sufficient information to establish special controls to provide such
assurance.

Examples of special controls include performance standards for which you
have heard postmarket surveillance, development and dissemination of
guidelines. They may include clinical data on a 510(k). They may address
labeling content regarding indications for use, instructions for use,
contraindications, warnings, precautions and adverse effects. Also,
design controls.

It is discretionary that FDA may find it necessary to implement other
controls to protect the public health or provide the safety and
effectiveness data.

What we need from the panel, essentially; a recommendation for
reclassification of the devices that are the subject of this panel
session. These recommendations may include a summary, or summaries, of
the reason for the recommendation and a summary of the data upon which
the recommendation is based and identification of special controls for
class II which have been presented to you in the concept memo.

What will follow after these deliberations and your recommendations will
be a decision on the appropriate class. Obviously, FDA has presented
their concept and their thinking regarding this. There will be published
a public notice of panel recommendation to reclassify these devices.

There will be a review of all comments and, finally, there will be a
published Federal Register notice of reclassifying these devices. All
committee members were provided with Form FDA 3428 which is entitled In
Vitro Diagnostic Product Classification and Questionnaire.

I know that it may seem overwhelming to you but I hope that I can help
you in making it a little easier. Essentially, questions 1, 2, 3, 4, 5
and 7 would pertain to these deliberations. I believe that after you
have engaged in the discussion here and have decided what your
recommendation will be that you will be able to easily complete this
form.

As has been mentioned before, if there are any particular special
controls that you feel should be implement or that you may recommend,
please include these on the form.

You also have a supplemental data sheet and that is only needed if you
have additional information that cannot be filled out on the first form,
FDA 3428. After completion of this form, I would request that it be
mailed to me not the address that is on the form after this meeting
within two weeks.

If there are any further questions, you may contact me regarding this
after these deliberations.

Thank you.

DR. MACIK: Very quickly, what is the generic type of device? What are we
supposed to call this?

DR. HOLLINGER: Do you want to call this HIV mutation test for right now?

DR. DAYTON: Why don\'t you call it HIV genotype drug resistance test.

DR. SMALLWOOD: I believe Mr. Wilson had displayed a slide which
indicated how these would be described.

MR. WILSON: That is a proposal, so I would defer to Dr. Dayton\'s
language.

MR. DUBIN: How about HIV drug resistance assay test/genotype.

DR. DAYTON: That\'s okay. The key words are genotype and drug resistance
and HIV.

MR. DUBIN: And they are all there.

DR. SMALLWOOD: Are there any further clarifying questions that I can
answer at this time?

DR. HOLLINGER: Thank you, Linda.

**Committee Discussion and Recommendations**

DR. HOLLINGER: I am going to now open this up for committee discussion
but, Dr. Mayers may have to leave. I would like to ask, first of all, if
there are any clinical questions that you would like to address to him
regarding any of the studies or what your thoughts are or anything like
this before he has to leave.

DR. MAYERS: Dr. Hollinger, I have rescheduled his afternoon.

DR. HOLLINGER: He has rescheduled his afternoon, but we could still ask
him the questions anyway.

DR. TUAZON: Doug, in your opinion, for what percent of AIDS patients
would this test for clinically useful?

DR. MAYERS: Over the course of their illness? Essentially all of them on
multiple occasions. It has been shown, I think for newly infecteds, this
is clearly becoming increasingly important. The French ANRS has actually
made a recommendation to their government that newly infected patients
with less than one year since their seroconversion should all have
resistance testing done.

If it is more than one year, they are recommending not doing the testing
because their is a very low rate and because of the concerns of back
reversion that Jeff Murray mentioned. But, then, subsequently, I think
it is going to become the practice to provide additional data as you try
and find late rounds of therapy.

DR. TUAZON: I think, eventually, you probably would need this
information because if the transmission of the newly infected ones will
be infected by resistant strains, then you would need this in your
primary management of patients.

DR. MAYERS: The fundamental problem is that, when we checked our clinic
at Henry Ford Hospital in Detroit, 48Êpercent of our patients have seen
at least two PIs in the non‑nuc and have positive levels of RNA. So
right now, there is a huge population of patients with
multi‑drug‑resistant virus potentially going to transmit to the next
generation of patients.

DR. NELSON: I think that I agree with Dr. Mayers. I think that this will
be extraordinarily useful data to the practicing clinician. One of the
concerns I have, and I don\'t know if it really relates to the class II
versus class III issue, is I see the possibility of some abuse because
of the fact that it is a gene, or two genes, that are being‑‑or segments
of the gene that are being analyzed.

Data could be reported on a genotypic variation or mutation to which
there is not good clinical relevance. I could even see a scenario where
a pharmaceutical company that had developed a new drug, or had a drug,
was also doing resistance testing and was using this for commercial gain
or what have you, not necessarily for patient benefit.

The issue is there are some genotypes described by Dr. Mayers that are
clearly related to AZT resistance, nelvirapine resistance and individual
or combinations of drugs. But there are others in which the data are
unclear.

I guess my question is how will that be regulated? Will that be on the
brochure of the product insert or will the company that is doing the
genotype testing can only report genotypes to which there is some
scientific data to back up its importance? How will that occur?

I can see where it could be regulated by FDA whether or not there was a
class II or a class III approval process. I don\'t understand that issue
very well.

DR. TABOR: I think your point is a good one but I really think, at this
point, we ought to really focus on whether this should be a class II or
a class III device and then go on to the special controls that the
committee would like to see because that is what we really need to
accomplish today.

DR. NELSON: To simplify my question, is my concern relevant to the class
II versus class III, or is it a secondary issue?

DR. DAYTON: It will be handled adequately and in either class II or
class III. Yes; the assays will make occasional errors but, on average,
they already seem to be doing better. But class II or class III, we can
handle that equally well.

DR. HOLLINGER: Doug, I have got a couple of questions on this issue. I
know you have a conflict of interest here because this is what you
really are interested in. You are also the expert in the area. You got
to have both ways.

There was a thoughtful editorial by Judith Faloon on the Lancet article.
I hope you have read it. Without putting you on the spot, she makes some
very interesting observations like there are no clinical outcome data
and few data correlating baseline genotype with viral‑load response. She
talked about several other issues about this and the data.

Do you believe, at least right now, that there is enough clinical
data‑‑and I know what we are talking about, but this has to do with the
classification of III and II because III requires premarket approval. It
requires clinical data before it is approved. It is a longer process but
it does require‑‑we vote on a lot of things that later on we say, \"I
wish we had done that study and got the information because we will
never get it after this.\"

So I would like to know whether you think there is sufficient evidence
under these two things, with small numbers of patients in each one of
these studies and with the data and with the questions that we brought
up about compliance and other things, which you don\'t have the data on
yet‑‑but give me some feeling about where you are with this and some of
her response, if you would.

DR. MAYERS: I think, to a certain extent, it becomes is the glass half
full or half empty. In this particular instance, I think the glass is
probably about 80Êpercent full. I do not believe that you are going to
be able to get clinical‑endpoint data for this issue in a similar way
that drug development is having trouble getting clinical‑endpoint data
anymore because your original test and the clinical outcome are going to
be so far apart that their relationship will be vague even when you do
get the outcome.

I personally have the same problem that the Hopkins IRB had in that
knowing that I can get a patient that is twice as likely to be
undetectable with the test as they are without the test, I have problems
taking them against no test anymore whereas if I take a genotype against
a phenotype, I think that is a very doable trial, but I think the sample
size approaches that of the infected population of the United States, so
I am not sure that that one is doable either.

I think with the data available, we know that we can manage patients
more effectively in the short term with the data than without it. I
think that the concerns the committee has expressed about both quality
control for testing and standardization of interpretation are both very
valid concerns.

To my mind, I think that making the companies prove that they can detect
the mutation accurately and consistently and, if they market a kit, that
that kit gets the same mutation no matter who does the assay is a very
reasonable requirement of any company.

I might suggest, from having listening to this discussion, that,
perhaps, it might be useful, since I don\'t think any of these companies
want to prove that a mutation‑‑they have to and individually prove that
their mutations that they can detect with their kit are clinically
relevant‑‑it might be very useful for the FDA to consider having an
expert panel that actually meets for them to decide what mutations have
reached that level in which they are comfortable with it and what
mutations have not because then the issue becomes does the company
measure the mutation accurately.

If the company measures the mutation accurately, that would be the basis
for what the company would have to do. What mutations does it cover
could be addressed more globally by has this mutation reached a level of
validation that the FDA is comfortable saying if you can detect it that
you can report it as having this meaning.

So you might have to break the process in two. I am not sure, but that
is my own personal opinion, though, Blaine. I think we are to the point
where we can use it and use it usefully and it gives useful information.
There are some areas of greyness. Some of them may be resolved and,
quite frankly, some of them may never be resolved.

DR. HOLLINGER: You feel that outcome would be beneficial‑‑might be‑‑if
you could do it long enough, even more so than what we currently have
available.

DR. MAYERS: I think that the outcome gets better if you can do repeated
measures similar to those done by the VIRADAPT group. If you can repeat
the test on multiple bases, you can‑‑but I think the bottom line is, in
1999, with the drugs available to the clinician, that, right now, you
are going to hit a wall and it is about 30 percent of your patients.

When you hit that wall, you cannot break through it no matter what test
you use because we just simply do not have the drugs to bring those
patients\' virus under control.

DR. HOLLINGER: Thank you.

DR. McCURDY: I think he put it fairly succinctly in my thinking on this.
I think there is very little question that the technology can detect
mutations. So the issue is does the individual test kit detect the
mutations that it says it does. This is solvable on review, I think. The
interpretation of it is also a very difficult one although there appear
to be, from the presentations, some mutations which are pretty commonly,
or almost universally, associated with resistance.

I think that this can be taken care of in the labeling and relabeling if
new mutations come along. The idea of an expert panel dealing with
mutations that do cause resistance or multiple mutations that cause
resistance is a good one and it is analogous to what both Dave Stroncek
and I have referred to in the HLA‑‑the designation of certain HLA class
I and class II alleles.

So I think that it is reasonable to reclassify this to a class II device
and that it can be managed with the controls that have just been
mentioned here and that can be put in place by the agency.

DR. HOLLINGER: Thank you.

Other comments before we put the question up on the screen? All right;
let\'s put the question on the screen. The question is, if we could make
the amendment, then to this question, because you want to say genotype;
right?

DR. DAYTON: Yes.

DR. HOLLINGER: If I may, I am going to make a recommendation that we
change it to, \"Does the committee support the reclassification of HIV
genotype drug resistance assays from class III devices to class II
medical devices?\" I would like to vote on that change, if you will.

All those in favor of that change, raise your hand.

\[Show of hands.\]

DR. HOLLINGER: All opposed.

\[No response.\]

DR. HOLLINGER: Any abstaining?

\[No response.\]

DR. HOLLINGER: With that change, then, we will have a vote on this. All
those who are affirmative with this or want to vote yes to have this
change, reclassified from class III to class II medical devices, so
indicate by raising your hand.

\[Show of hands.\]

DR. HOLLINGER: Those opposed?

\[One hand raised.\]

DR. HOLLINGER: Abstaining?

\[No response.\]

DR. HOLLINGER: Would you please read the results.

DR. SMALLWOOD: The results of voting for question No. 1 as modified, and
I will read the question as modified; \"Does the committee support the
reclassification of HIV genotype drug resistance assays from class III
medical devices to class II medical devices?\"

The results of voting; 13 yes votes, one no vote, no abstentions. At
this time, I would ask the recommendation from the industry rep.

DR. BUCHHOLZ: I vote yes.

DR. SMALLWOOD: The consumer rep left. However, she did leave her vote
which I will read. Her recommendation was yes for genotype assays to be
reclassified to class II. And she did have a commentary; \"with strong
recommendation of standardized reports as part of the controls and close
postmarketing monitoring, and also to include the statement coming from
Jeff Murray\'s last point of using genotype/phenotype testing in new
drug development.\"

DR. HOLLINGER: Thank you, Linda.

Now, we have the hard part‑‑maybe the easy part. Now, let\'s have the
second question because we are not going to deal with the third. The
second question is, \"If the answer to No. 1 is yes, what additional
special controls or requirements, if any, does the committee
recommend?\"

I know we have had several made here already that can be gleaned from
all this data. But, specifically, would somebody like to make some
comments on this?

DR. MACIK: I think the easiest way to address that is to look at the
form where it says \"controls,\" and just vote on each of those and then
add in anything that is left. For example, it starts out with postmarket
surveillance. Maybe we could vote on each of those and then add in
anything else that was extra.

DR. HOLLINGER: I don\'t think we have to vote on this. I think, mostly,
and correct me if I am wrong, but I think you are asking for
information, Andy. But can you please help us?

DR. DAYTON: Somebody correct me if I am wrong, but my understanding is
that you have to vote on a), classification, which you have done, and
special controls. In this case, we would propose that special controls
would be postmarketing surveillance such as you have just identified and
the formulation of a guidance document the highlights of which we have
discussed.

So if you feel that the discussions are such that we will know what to
put in the guidance document and we know what to put in postmarket
surveillance, you could vote to accept those as is, for example. Does
that clarify the situation? And there might be more.

DR. BOYLE: Would the guidance document include performance standards and
testing guidelines?

DR. DAYTON: Oh, yes. I didn\'t go into that because that was assumed,
obviously.

DR. HOLLINGER: On the form, just as you know, if you all see 3B, they
talk about postmarket surveillance, performance standards, testing
guidelines‑‑that is the guidance document, part of that‑‑device tracking
and then other.

First of all, do the members all feel that at least the first four, the
ones I read‑‑not the other, but the four‑‑

MR. WILSON: Not device tracking.

DR. HOLLINGER: Sorry; what is device tracking, anyway?

MR. WILSON: Device tracking is where you would track the individuals
individually who the device is used on in the event that there has to be
a follow up to the company.

DR. HOLLINGER: Okay. End users. So the three. does the committee at
least certainly agree‑‑and I would just ask you for a quick vote at
least on the postmarket surveillance, performance standards, testing
guidelines or guidance document, if you will.

All those who certainly agree that those are some of the special
controls, raise your hand.

\[Show of hands.\]

DR. HOLLINGER: Any opposed?

\[No response.\]

DR. HOLLINGER: Any abstaining?

\[No response.\].

DR. HOLLINGER: What about the \"other.\"

MR. DUBIN: Labeling, because I don\'t see labeling listed in this
breakout so I think in the \"other,\" we should talk about labeling.

DR. HOLLINGER: How do you mean labeling?

MR. DUBIN: One of the things we talked about earlier is in terms of how
the information flows to physicians. If you kind of juxtapose an
infectious‑disease doctor who is on the cutting edge with a hematologist
treating hemophilia who is treading water to stay on the cutting edge,
it seems to me it is important that FDA have some sense of how to
ascertain how the information is being taken in and used. That could be
done in a labeling environment and a review of that, some kind of
outcome assessment, that lets you know that information is being
internalized. That is what I am suggesting.

DR. DAYTON: We certainly are open to suggestion for labeling. Many of
these things we normally would handle in any labeling procedure.
Probably the best thing, if you want to focus on labeling which, of
course, is a reasonable thing to do, is try to focus on things that we
might otherwise not normally do.

MR. DUBIN: You would do everything that I just articulated?

DR. DAYTON: What would be the list, then?

MR. DUBIN: Labeling in terms of the information needed by physicians
using the test, understanding that there is quite a gradient between
physicians in terms of understanding.

DR. DAYTON: Oh, yes.

MR. DUBIN: And some type of outcome review of that labeling so you know
if it is being internalized out there in the world.

DR. DAYTON: That is a tough one. We could do that.

MR. WILSON: In other words, this would be voted on as a special control
and, in the premarket review of the product, as part of the 510(k), we
would be asking the companies to evaluate the reports in terms of how
the physicians interpret them appropriately.

MR. DUBIN: Absolutely.

MR. WILSON: If they are getting it all wrong all the time, we will not
clear the product.

MR. DUBIN: Right; that is what I am talking about.

DR. HOLLINGER: I\'m sorry. Excuse me a minute. Linda needs to read the
response to what we voted on just a minute ago.

DR. SMALLWOOD: This is for clarification so that everyone will
understand the action that the committee just took on their last vote.
There was a unanimous vote for additional special controls or
requirements. What the committee included in that vote were postmarket
surveillance, performance standards and testing guidelines.

DR. HOLLINGER: Thank you.

MR. DUBIN: They were going to answer. He was in the middle of answering.

MR. WILSON: We did not make a recommendation, although the committee
can, relative to performance standards. Performance standards are, for
example, voluntary or involuntary national and international standards
that would apply to various elements of the performance characteristics
of the product.

There would be none existing for this type of product currently. It
takes an extremely long period of time to develop standards. In lieu of
that, what FDA does in term of develop criteria for the clearance of the
product, is embed some of that information in the guidance document.

So what would happen is that if the committee were to approve the
performance standards, none exist formally so we would not be able to
apply that. Maybe if some become available, the committee can recommend,
if available. But none exist currently.

The safety and efficacy is largely going to be framed out in the
guidance document.

DR. CHAMBERLAND: Is it standard procedure for the FDA to have the BPAC
review draft versions of the guidance document?

MR. WILSON: If the guidance document were to be available, we would have
provided it to you. It is still under development. Lots of things are
moving very quickly. However, the process of the approval of the
guidance document would be to publish it in the Federal Register. We
could certainly provide that to the committee selectively, also.
Comments can be made on it. They can be made by anyone who reads the
Federal Register.

We are obligated to review every one of the comments so that you can get
your input in as everyone else.

DR. CHAMBERLAND: I think that is somewhat what I am personally
struggling with which is it is hard to know if additional special
controls are needed when the postmarket surveillance and testing
guidelines have not been spelled out in a very detailed way. So it is
hard to know where the gaps might be.

DR. HOLLINGER: I agree with you, Mary. You have got a document. We
haven\'t seen it. I think that what I would like to see, at least right
now, is at least for us to express what things we ought to do. And they
can take them as recommendations, not necessarily voted on.

We have discussed this throughout this session today. Then we can see
where we are going to go from there.

MR. DUBIN: We were still on labeling. I don\'t want that to get lost. I
don\'t want it just hung out there. That is the one we didn\'t vote on.

DR. HOLLINGER: Tell me what‑‑

MR. DUBIN: FDA just made a proposal back that sounded decent.

MR. WILSON: The \"other\" on the box is what we‑‑normally, 510(k)s are
obligated to have labeling consistent with 21 CFR 809.10. So you already
get labeling.

MR. DUBIN: I understand that.

MR. WILSON: What we would be asking for here is what we would call
\"special labeling.\"

MR. DUBIN: That\'s right. That is what I am talking about.

MR. WILSON: That would be at the direction of the committee on some of
the interpretational issues that were discussed earlier. You could make
that recommendation to us and then what would happen is that, based on
those recommendations, we would exercise that in the review process.

MR. DUBIN: Right. I think what we were suggesting was twofold, in terms
of labeling and them some review of the doctors are internalizing that
labeling because there is such as gradient between people who are
practicing infectious disease in HIV AIDS on the cutting edge and people
who are not.

That is not to make a negative statement about‑‑it is just the truth of
what is out there.

DR. TABOR: I think we want to be careful not to get too bogged down in
details. I think, as Dr. Hollinger suggested, you can make a group of
suggestions that we would take into consideration in the review of
specific products. The question that is up there, question No. 2, is
asking about specific special controls or requirements.

I think some of what you are suggesting are in the category that Dr.
Hollinger was referring to which is discussion items that we should take
into consideration during the review of these products.

Here, you are talking about something that would apply to every class II
device in this category.

MR. DUBIN: Let me back up and try to be clear. The question gets asked
is is this dangerous. Obviously, this does not pose a direct health
risk. However, if this test is used incorrectly to inform‑‑used
diagnostically and it is not used correctly and the diagnosis is
misdiagnosed, I think we would all agree that could cause some problems
for the patient, and the doctor, as well.

So I don\'t know if we are just lost in the part of this that is just
loose recommendations. I think there has been expressed some serious
issues about labeling at this table. I have been hearing them. I don\'t
want to just write it off as \"other.\"

DR. HOLLINGER: Dr. Boyle, do you want to respond, also, to this?

DR. BOYLE: Just in that it may not be a labeling issue so much as what
has been said is that there is an interest in a standard for
interpretability of the assay findings for the average user. That is a
separate issue. That is one issue that has come up here and it would be
one thing that I would put on the table.

DR. TABOR: I think that is the kind of thing we want to hear and to take
into consideration.

DR. HOLLINGER: Because the question is, if you are out there‑‑what is
\"partially resistant\" going to mean? Does that mean you jump in and
you do another‑‑for the general clinician that is out there who sees
something that says, \"partially resistant,\" or an AZT that says,
\"resistant,\" do they stop their medication? Do they not? Should there
be guidelines for that kind of thing?

Let me see how you perceive that because that is what is being asked
here in two places about interpretation and what the FDA needs to, then,
sort of generate in their guidance document and other things as it
relates to this because it sounds like it is a pretty important
question.

DR. MAYERS: As I sort of said earlier, I am not sure if the FDA is going
to invite me back, but I think this really comes down to two issues. One
issue is a technical issue which is can you measure a mutation and, when
you say the mutation is present, is it there. I think that is a very
reasonable expectation for the companies, to prove that they can measure
it, to prove to what level they can measure it, to prove what is the
reproducibility of their product is. I think that is a very reasonable
standard.

DR. HOLLINGER: It is it relevant.

DR. MAYERS: I think it is very relevant.

DR. HOLLINGER: I mean, and is the mutation relevant.

DR. MAYERS: But that is where I don\'t think the company should have
responsibility. I think that there should be some standard place
where‑‑and I think that CDER is probably a better place than CBER, quite
frankly, because I think it should be part of the drug‑development
process.

I think the company should, as part of their package when they submit,
find out what mutations cause loss of activity of the drug and what
mutations when someone enters the trial caused their drug not to work
and what level of resistance causes their drug not to work. This should
be part of the approval process for a drug.

As part of the evaluation of that drug approval, that part of the
package should be looked at. So I think there should be someplace,
somewhere in the system, in which we say, \"When you have a 184, we have
validated that this is associated with this, this and this. When you
have a 215, we have validated this, this and this.\"

That should not be on the back of each strip manufacturer and each
sequencing company. What they should be able to prove is, \"I have got a
good product that gives me a good sequence. When I report the sequence
out, the sequence is clean and you get the same result if my tech does
it, your tech does it or somebody else\'s tech does it.\"

But then, I think it probably is a good idea because of the issue about
politically interpreting results to have some group which has some
vested authority which says, \"We believe this has reached a level of
validity that, once you have proven you can measure this mutation,\" and
for a strip manufacturer, they are going to have to prove they can
measure 184 in that strip.

For a sequencing person, that is a little bit different. They are going
to have to prove they can get a sequence that is clean across the whole
stretch. But, once you have got that, it goes across all the
manufacturers. If you find a 184, it counts no matter who finds it, by
which technology, it has the same interpretation.

So I think it might really be better to split the technical validation
of an assay, which I think is a very strong‑‑something that the company
should do‑‑from the interpretative result of that assay which, I think,
also needs some sort of controls placed on it.

But I think it should go across the whole system. If you can find it, it
counts.

DR. McCURDY: Blaine, I was going to suggest that we recommend a
consensus designation or determination of new or resistance mutations.
There are certainly, now, a number of consensus‑‑and exactly how that is
done, but I would second what was just said that it needs to be done and
it should be done by some type of consensus group in or out of the
government or whatever.

It is part of the situation with the kits because the kit manufacturers
may make, or want to make, labeling claims that they can detect mutation
X which is a resistant mutation. They need to be sure that that is
consensus resistant mutation.

DR. TABOR: Paul, I assume you are using the word \"consensus\" in the
literary sense and not in the molecular‑biology sense. If I am right, I
think you may be placing too much of a constraint on the review process.
I really think that, in a changing field like that, the reviewers need
flexibility to make their own decisions as a group based on whatever
expert opinion they can get at the time.

I certainly don\'t think we want to set up committees or advisory groups
to determine what are resistant organisms and what are not because it is
a changing field at all times.

DR. McCURDY: I think I am using the word \"consensus\" more generically.
I think that it should not be something that is reported once in the
literature or at a meeting or something and then immediately leapt upon
by everybody. There ought to be a certain amount of confirmation that a
given mutation is responsible for. This could be done in the review
process.

DR. TABOR: I think this is just part of the review process.

DR. HOLLINGER: It could be like an NIH consensus conference. Are you
talking about something like that, Paul?

DR. McCURDY: No.

DR. HOLLINGER: Nothing like that?

DR. McCURDY: No; no, I was not.

DR. DAYTON: If I could address this point in particular, I did mention
this when I was reviewing the highlights of the guidance document‑‑in
the guidance document, we are trying to lay down requirements for just
how much validation we need to see in the literature.

I gave you an example of, for instance, if we see a certain change in
the IC50 or 90, we may or may not accept that as prima fascia evidence
that it works. The point is that that is going to be a major focus of
the debate on the guidance document. So, if you trust the process, the
guidance document will provide an answer to that.

DR. HOLLINGER: Is that okay?

DR. McCURDY: Yes; I think that is‑‑

DR. FITZPATRICK: The guidance document and the review process can focus
on that, but when we started doing western blots for HIV for diagnostic
and clinical samples, there was a great deal of difference in the
interpretation of that western blot. It took consensus and
standardization before we got the same answers from the same
laboratories or we diagnosed patients the same way based on the
western‑blot results.

This test seems to be in that same stage of development to me. We can
validate the test and we can know that the test is providing us the
right codon, but we need a way for everyone to interpret those tests
correctly. I think it is going to need to go beyond the review process
to get that.

DR. HOLLINGER: I am assuming, Dr. Smallwood, that since we were all
given one of these copies here that, literally, I mean, basically, we
can put down what we want to under \"other.\" It doesn\'t have to be a
consensus for this, so I presume, Corey, that this is an opportunity for
you to write in‑‑there is a supplemental sheet. I guess, if you want to
write four or five pages, you can do so.

But I think that is important because these are issues that they would
want to speak do.

Are there any other issues before I bring this meeting to a close?

DR. STRONCEK: I have a question on question 4. It is addressed to device
II and III. Are there any suggestions on what we should consider if we
check that answer off, 4A?

DR. HOLLINGER: About the performance standards?

DR. STRONCEK: Yes.

DR. HOLLINGER: I think what he was saying is they don\'t have any
performance standards.

DR. SMALLWOOD: Right.

DR. HOLLINGER: But I don\'t think that he said that they would not be
useful if they had them.

DR. SMALLWOOD: Essentially, they do not exist. That is what was stated
by Mr. Wilson.

DR. HOLLINGER: Thank you, Linda.

DR. BOYLE: My form, 7A, do we have to restrict it in terms of who uses
it? I am not sure what the intent there is.

DR. HOLLINGER: Could you explain that, maybe just to those of us who are
not‑‑

MR. WILSON: Restricted equals by a prescription. That is the short
interpretation. There are very few restricted devices that are in
distribution.

DR. HOLLINGER: Unless you wanted to have a prescription, you would
answer \"yes\" on something like that.

MR. WILSON: Correct.

DR. STRONCEK: No; you would answer \"no.\"

DR. HOLLINGER: Okay. No; you would answer \"yes.\" The answer would be
yes. If you want prescriptions on this, then answer \"no.\"

I want to thank this committee again for all their hard work, as usual.
Everybody was prepared and came and we appreciate it. We are not going
to have a meeting in December. The next meeting will be in March or
June? Linda, do you have the times so we can mark it?

DR. SMALLWOOD: The next regularly scheduled meeting is tentatively for
March. It will generally be the third week in March, that Thursday and
Friday, pending availability of appropriate facilities. The meeting
following that would be scheduled for June and then September,
accordingly. We will talk about whether there will be a December meeting
in the Year 2000.

DR. HOLLINGER: Thank you all very much.

The meeting is adjourned.

\[Whereupon, at 1:13 p.m., the meeting was adjourned.\]

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