U.S. FOOD AND DRUG ADMINISTRATION

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GENERAL HOSPITAL AND PERSONAL USE DEVICES PANEL

OF THE

MEDICAL DEVICES ADVISORY COMMITTEE

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THIRTY-FIFTH MEETING

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TUESDAY,

AUGUST 9, 2005

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The above‑entitled matter met in Salons A, B, and C of the Hilton
Washington, D.C. North, 620 Perry Parkway, Gaithersburg, Maryland, at
8:00 a.m., Charles E. Edmiston, Jr., Ph.D., Chairperson, presiding.

[PRESENT]{.underline}:

CHARLES E. EDMISTON, JR., Ph.D, Chairperson

MATTHEW J. ARDUINO, D.Phil, Voting Member

RICHARD O. BUTCHER, M.D., Voting Member

YARDIN B. DAVID, Ed.D., Voting Member

BONNIE M. WORD, M.D., Voting Member

TERRY LAYTON, Ph.D., Industry Representative

CAROLYN N. PETERSEN, M.S., Consumer Representative

CHIU S. LIN, Ph.D., Director, Division of Anesthesiology, General
Hospital, Infection Control, and Dental Devices

SCOTT A. COLBURN, BSN, RN, LT, USPHS Executive

Secretary

[FDA PRESENTERS]{.underline}:

THOMAS GROSS, M.D., M.P.H., Director, Division of

Postmarket Surveillance, Office of

Surveillance and Biometrics

SHEILA MURPHEY, M.D., Chief, Infection Control

Devices Branch

ANTHONY D. WATSON, M.S., M.B.A., Chief, General

Hospital Devices Branch

JASON F. LIPMAN, Lead Reviewer, General Hospital

Devices Branch

SHEWIT BEZABEH, M.D., M.P.H., Medical Officer,

Division of Anesthesiology, General

Hospital, Infection Control, and Dental

Devices

DAYAWANSA G. RANAMUKHA-ARACHCHI, Ph.D., Molecular

Biologist/Genomics, Office of Science

and Laboratories, Division of Biology

[INVITED GUEST PRESENTER]{.underline}:

MARTIN FRIEDE, Ph.D., Initiative for Vaccine

Research, World Health Organization

[INDUSTRY PRESENTERS]{.underline}:

DARIN LEE ZEHRUNG, Program for Appropriate

Technology in Health (PATH)

MARK KANE, Program for Appropriate Technology in

Health (PATH)

LINDA D\'ANTONIO, D\'Antonio Consultants International

KATHLEEN CALLENDER, Genesis Medical Technologies

[PUBLIC SPEAKER]{.underline}:

HARRY HOOKS

HCVets.com

A-G-E-N-D-A

INTRODUCTIONS 5

Executive Secretary Colburn 6

CONDITION OF APPROVAL STUDIES: RECENT CHANGES IN CDRH

Dr. Gross 13

DIVISION/BRANCH UPDATE

Dr. Lin, DAGID Division Director 21

Dr. Murphey, Chief Infection Control

Devices Branch 23

Mr. Watson, Chief, General Hospital

Devices Branch 27

PUBLIC HEARING SESSION

Harry Hooks, HCVets.com 38

PRESENTATIONS BY FDA

Introduction and welcome,

Mr. Watson 50

Mr. Lipman 51

Dr. Bezabeh 59

Dr. Ranamukha-arachchi 72

Questions by Members to FDA presenters 86

PRESENTATIONS BY CDC AND WHO

Dr. Friede, WHO 102

PRESENTATIONS BY INDUSTRY

Dr. Zehrung, PATH 134

Dr. Kane, PATH 154

Ms. D\'Antonio, DCI 179

Ms. Callender, Genesis Medical

Technologies 180

PANEL DELIBERATIONS 181

OPEN PUBLIC HEARING 246

Dr. Kane, PATH 246

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

8:06 a.m.

CHAIRMAN EDMISTON: Good morning. I\'d like to welcome to the 35th
meeting of the General Hospital and Personal Use Device Panel.

I also want to request everyone in attendance at this meeting to sign in
on the attendance sheet that is available on the table outside the door.

I will note for the record the voting members present constitute a
quorum as defined by 21 CRF Part 14.

At this time I would like each panel member at the table to introduce
him or herself and state his or her specialty position, title,
institution and status on the Panel. And I\'ll start with my left, Dr.
Lin.

DR. LIN: Hi. Good morning. My name is Chiu Lin. I\'m the Director of
Division of Anesthesiology, General Hospital, Infection Control and
Dental Device in FDA.

MS. PETERSEN: My name is Carolyn Petersen. I\'m a web editor at Mayo
Clinic in Rochester, Minnesota. And I\'m here as the consumer
representative.

MR. DAVID: Good morning. My name is Yardin David. I\'m Director of
Biomedical Engineering Department at Texas Children\'s Hospital in
Houston and Assistant Professor at Baylor College of Medicine,
Department of Pediatrics.

EXECUTIVE SECRETARY COLBURN: Good morning. My name is Lieutenant Scott
Colburn. I am the Executive Secretary to the General Hospital and
Personal Use Devices Panel.

CHAIRMAN EDMISTON: My name is Charles Edmiston. I am a faculty member at
the Medical College of Wisconsin and hospital epidemiologist.

DR. WORD: Hi. My name is Bonnie Word. I am on faculty at Baylor College
of Medicine also at Texas Children\'s Medical Center where I\'m the
Chief of the infectious disease clinic and travel medicine clinics.

DR. ARDUINO: Hi. My name is Matt Arduino, and I\'m the lead
microbiologist in the epidemiology and laboratory branch at the Division
of Health Care Quality and Promotion at the Center for Disease Control
and Prevention.

DR. BUTCHER: I\'m Richard Butcher, a physician a San Diego, general
practice with Care View Medical Group.

DR. LAYTON: Good morning. I\'m Terry Layton, a biomedical engineer. I\'m
industry representative on this Panel. And I\'m from Laytech,
Incorporated out of Chicago, Illinois.

CHAIRMAN EDMISTON: Thank you.

Lieutenant Scott Colburn, the Executive Secretary, would like to make
some introductory remarks.

Lt. Colburn?

EXECUTIVE SECRETARY COLBURN: Before I start the remarks, I\'d like to
introduce Ms. Mary Ann Killian from the Ethics Integrity staff to read
the conflict of interest statement for the members of the Panel.

MS. KILLIAN: Thank you.

The Food and Drug Administration is convening today\'s meeting of the
General Hospital And Personal Use Devices Panel of the Medical Device
Advisory Committee under the authority of the Federal Advisory Act of
1972. The Advisory Panel meeting provides transparency into the
Agency\'s deliberative processes. With the exception of the industry
representative, all members of the Panel are special government
employees or regular federal employees from other agencies and are
subject to the Federal Conflict of Interest laws and regulations.
Consequently, in the interest of transparency and the spirit of
disclosure, the following information on the status of this Advisory
Committee Panel\'s compliance with the Federal Ethics and Conflict of
Interest laws covered by but not limited to those found at 18 USC 208
and 21 USC 355(N)(4) is being provided to the participants in today\'s
meeting and to the public.

FDA has determined that members and consultants of this Panel are in
compliance with Federal Ethics and Conflict of Interest laws. Under 18
USC 208 Congress has authorized FDA to grant waivers to special
government employees who have limited financial conflicts when it is
determined that the Agency\'s need for a particular individual\'s
service outweighs his or her potential financial conflict of interest.

Members and consultants who are special government employees at today\'s
meeting have been screened for potential financial conflicts of interest
of their own as well as those imputed to them including those of their
employers, spouse or minor child related to the discussion of today\'s
meeting. These interests may include investments, consulting expert
witness testimony, contracts grants, creative teaching, speaking,
writing, patents, royalties and primary employment.

Today\'s agenda involves a discussion on methods to assess the potential
of disease transmission by multi-use nozzle jet injectors; that is jet
injectors for which the fluid path for the injection is used more than
once. The discussion will also include premarket testing,
recommendations to address this issue. This is a general matters meeting
during which the topic of discussion is limited to recommendations or
considerations of broad legislative proposals, regulatory initiatives or
policy developments that affect an industry, group of manufacturers or
health care providers. So any conflict of interest waivers granted for
this meeting are broad and general in nature.

A copy of the written conflict of interest waiver statement may be
obtained by writing to the Agency\'s Freedom of Information Office,
12A30 of the Parklawn Building.

Based on the agenda for today\'s meeting and all financial interests by
the Panel participants it has been determined that all interests in
firms regulated by the Center for Devices and Radiological Health
present no actual or appearance of conflict of interest for today\'s
meeting.

The following Panel participants have not received a conflict of
interest waiver to participate in today\'s meeting: Dr. Charles
Edmiston, Dr. Matthew Arduino, Dr. Richard Butcher, Dr. Bonnie Word, Dr.
Yardin David and Ms. Carolyn Petersen.

In addition, Dr. Terry Layton has been invited to participate as the
industry rep acting on behalf of all related industry, and is employed
by Laytech, Incorporated.

With regard to FDA\'s guest speakers, the Agency has determined that the
information provided by these speakers is essential. The following
interests are being made public to allow the audience to objectively
evaluate any presentation and/or comments made by the speakers:

Dr. Bruce Weniger, who is a guest speaker with us today, has
acknowledged that his employer, the Centers for Disease Control and
Prevention, has financial interest in firms at issue. The financial
interests and professional relationships are in the form of research
contracts and educational projects involving multiple-use jet injectors.

Dr. Martin Friede, who is also a guest speaker with us today, has
acknowledged that his employed the World Health Organization has
interest in today\'s topic in the form of pending clinical trials. As
guest speakers, these individuals will not participate in Panel
deliberation.

Members and consultants of the Committee are reminded that if the work
of the Committee moves from matters of general applicability to matters
that are more specific, for example product or firms identified, the FDA
shall end the discussion promptly and each special government
employee\'s financial interest will be reexamined in relation to the
particular matters so that a determination may be made on whether
exclusion from further discussion is required. All exclusions will be
noted for the record.

Finally, in the interests of public transparency with respect to all
other participants, we ask that they publicly disclose prior to making
any remarks any current or previous financial involvement with any firm
whose products they may wish to comment upon. This statement will be
available for review at the registration table during this meeting and
will be included as part of the official meeting transcript.

Thank you.

EXECUTIVE SECRETARY COLBURN: Thank you, Ms. Killian.

The FDA seeks communication with industry and the clinical community in
a number of different ways. First, FDA welcomes and encourages
premeetings with sponsors prior to all IDE and PMA submissions. This
affords the sponsor an opportunity to discuss issues that could impact
the review process.

Second, the FDA communicates through the use of guidance documents.
Toward this end, FDA develops two types of guidance documents for
manufacturers to follow in submitting a premarket application. One type
is simply a summary of the information that has historically been
requested on devices that are well understood in order to determine
substantial equivalence. The second type of guidance document is one
that develops as we learn about new technology.

The FDA welcomes and encourages the Panel and industry to provide
comments concerning our guidance documents.

I\'d also like to remind you that the tentative dates for the next
meeting on the General Hospital and Personal Use Devices Panel is
scheduled for September 27, 2005. You may wish to pencil in this date on
your calendar, but please recognize that this date is tentative at this
time.

The first item on our agenda is a presentation by Dr. Tom Gross from the
Office of Surveillance and Biometrics. He will discuss the conditions of
approval studies and recent changes in CDRH.

Dr. Gross?

DR. GROSS: Good morning.

As was stated, I\'m Tom Gross. I\'m the Director of the Division of
Postmarket Surveillance in our Office of Surveillance and Biometrics.
And I\'d like to take a few minutes of your time today to talk bout
recent changes in our conditions of approval study program.

Before I do that, I\'d like to touch based on some of the essential
functions that our office serves for the center. And those are presented
in this slide here.

First and foremost, we provide support for premarket review. We have a
large group of statisticians who address all statistical aspects of
premarket submissions. We also have a group of epidemiologists who are
involved in PMA review teams and help design condition of approval
studies.

We are also responsible through our nationwide passive surveillance
systems to detect signals of potential public health problems. That\'s
our Medical Device Reporting system or MDR system. And our network of
user facilities throughout the United States for our MedSun network.

Thirdly, we\'re responsible for risk characterization and analysis of
these potential public safety issues. This is done primarily by our
epidemiology staff doing everything from systematic literature reviews
to de novo studies.

We also coordinate our center response on these public health issues. We
convene committees of center experts to deliberate these issues and to
present their recommendations to center senior staff for action.

And lastly, we have a staff who interpret our medical device reporting
regulations; what needs to be reported under what circumstances, and
also to follow-up on violations of those reporting requirements.

Now let\'s turn to our condition of approval study program. As most of
you know, these studies are ordered as a condition of approval of our
PMA products. And the regulations clearly stipulate the following:

That post approval requirements can include continuing evaluation and
periodic reporting on the safety, effectiveness and reliability of the
device for its intended use. This regulation gives us our broad
authority in ordering these post approval studies.

Next slide.

Now about the middle of 2002 our office took a snapshot of the center\'s
activities with regard to the condition approval study program to see
how well the center was doing. And the study basically involved looking
at PMAs that were approved from 1998 through the year 2000. All tolled,
there were 127 PMAs that were approved during that period of time. 45 of
those had clinical condition of approval study orders.

At the end of the day what did we find? That CDRH had limited procedures
for tracking study progress for results, that our IT and other systems
were wholly deficient in this regard.

There\'s large turnover of lead reviewers that resulted in lack of
follow-up. Up to 40 percent of individuals who are lead reviewers at the
time the PMA came in the door were no longer associated with that PMA
when we did this study.

And lastly, there was lack of premarket resources. Those resources were
devoted to premarket submissions and there was little left for oversight
of condition approval studies.

Next slide.

So based on these results and based on an ongoing pilot we had of
epidemiologists involved with PMA reviews we decided there was need for
a change. And the goal for that change basically focused on the
following:

To obtain useful, timely and quality postmarket information on the
safety and effectiveness of devices as they move into the marketplace;

To better characterize the risk and benefit profile of these devices.
For instances, their long term performance, and to add to our ability to
make sound scientific decisions based on these timely and high quality
studies.

So what did we do in terms of change? The next two slides speaks to
this. We transferred the condition of approval study program from our
premarket side of the house, the Office of Device Evaluation, to our
postmarket side of the house, the Office of Surveillance and Biometrics.
We did that effective January of this year.

We did that for two reasons. One, our office has the resources to
oversee the program and we also have the resident expertise in
epidemiologists to be part of this program.

We developed and instituted an automatic tracking system for these
studies so we could acknowledge receipt of the protocols and interim
study reports, and follow-up when reports were not received.

Next slide.

Most importantly, we added epidemiologist to all the PMA review teams
for all the five review divisions within the Office of Device
Evaluation. The epidemiologists were tasked with the development of
postmarketing monitoring plans during the premarket review. These plans
spoke to the best means of monitoring the safety of these products in
the postmarket period.

Epidemiologists assumed the lead in developing and formulating
postmarket questions, the lead in the design of condition approval study
protocols and tracking those study results over the period of the study.
And throughout this process we collaborated very closely with all
members of the PMA review team.

Next slide.

In addition, we addressed motivation for study conduct, meaning how best
can industry do these studies and how best can FDA participate in these
studies. And first and foremost, obviously it\'s important to address
the important postmarket questions: What are the essential questions
that need to be addressed in these condition approval studies and to
develop a good study protocol to address those questions and objectives.

We had to acknowledge the receipt of these protocols and study reports
in real time, providing real time feedback to the industry.

As part of a guidance document we hope to issue soon, we hope to be
transparent with regard to these studies by posting the status of these
studies on CDRH\'s website.

And lastly, there are other authorities that we can levy if companies do
not perform these studies with due diligence. And those other
authorities give us leeway in terms of misbanding the product or levying
monetary penalties if the companies continue to fail to do those
studies.

Next slide.

And lastly, what\'s the impact on the Advisory Panel? We will attempt to
lay out the important post approval public health questions for the
Panel\'s deliberation and possible considerations. And we will also
inform the panel, that is FDA and industry, on a periodic basis about
the results of these studies that were approved.

Thank you very much.

EXECUTIVE SECRETARY COLBURN: Thank you, Dr. Gross.

Before I turn the meeting back over to Dr. Edmiston, I\'d like to ask
that all cell phones and pagers be turned off or placed in the silent
mode, please, so they do not interrupt the business during the time of
this meeting.

Dr. Edmiston?

CHAIRMAN EDMISTON: Thank you.

At this time we have several presentations from representatives of the
Division of Anesthesiology, General Hospital Infection Control and
Dental Devices.

Our first presenter will be Mr. Lin, Director of the Division of
Anesthesiology, General Hospital Infection Control and Dental Devices.
He will provide a very brief update of the Division\'s activities.

Dr. Lin?

DR. LIN: Good morning.

I thought I will spend a few minutes to talk about what the current
update. I know that since the last Panel meeting the Division has
changed significantly. So I will spend a few minutes to talk about what
the Division, and following my presentation the two branch chiefs are
going to give you an update what each branch chief\'s activities.

As you probably may know, the Center for Device and Radiological Health
composed of at least six office, and because of the time I don\'t want
to go into the detail, but next slide, please.

Office of Device Evaluation, where that\'s most of us work in the Office
of Device Evaluation, is composed of five divisions. And division is
divide according to product line that we are responsible for reviewing.
And the divisions of Anesthesia, General Hospital and Infection Control
and Dental Device are one of those divisions in the Office of Device
Evaluations.

Next one.

Currently the Division has myself is Division Director. And then we have
Dr. Ginette Michaud who is sitting in the audience. Dr. Michaud, can you
\-- she\'s my Deputy Director.

Next.

From the Division\'s name imply that we are responsible for four product
lines. One is the Anesthesiology and Respiratory Device branch. And at
current the branch chief is Ms. Ann Graham. And some of you probably
already met. We have a panel meeting not long ago.

And then we have a Dental Device branch, and the chair of the branch is
Dr. Susan Runner. Some probably also met. We also had panel meeting a
few months ago.

And then the General Hospital Device branch is headed by Mr. Tony
Watson. Is right here.

And Infection Control Device branch is headed by Dr. Sheila Murphey. Is
right here.

Next. And the FDA\'s, our divisions for your information we have three
major panel involved with our product lines. First one is Anesthesiology
and Respiratory Device Panel. And the second one is Dental Product
Panel. And the third one is what we are here now, that\'s General
Hospital and Personal Use Devices Panel, which is here by General
Hospital Device branch and Infection Control Device branch.

And Dr. Murphey is going to give you an update what Infection Control
Devices activity.

Thank you.

DR. MURPHEY: Good morning. I\'m Dr. Sheila Murphey, the branch chief for
the Infection Control Devices Branch.

Next slide.

Our branch has a number of scientific reviewers with different
backgrounds. We currently have three microbiologists, that will be four
in two weeks. We have just filled the open position mentioned.

We have a biochemist, a nurse and a biologist. We also have a fellow
whom we share with OSEL, whom we will have for another two months.

My own background is clinical infectious disease and hospital infection
control.

Next slide.

Our branch reviews a number of devices. We fall into two major
categories. We look at everything related to sterilization. All types of
sterilizers, the medical washers, washer disinfectors and endoscope
washer disinfectors.

We also review high level disinfectants and liquid sterilants.

We are responsible for looking at the reprocessing of single use medical
devices. We look at the sterilization packaging systems and the
indicators to indicate the adequacy of the sterilization process.

We also review personal protective equipment; gloves, gowns, masks and
such devices.

We also are responsible for reviewing needle disposal units and needle
destruction devices, which are PMA devices.

Next slide, please.

Recently published guidance documents for our branch include the
Guidance for Industry and FDA Medical User Fee and Modernization Act of
2002, The Validation Data in Premarket Notification Submissions For
Reprocessing Single Use Devices. This is a preliminary document. There
is work underway for a final guidance document. Also the Premarket
Approval Applications for Absorbable Powders for Lubricating a
Surgeon\'s Glove, the Surgical Mask Guidance, the Submissions for
Chemical Indicators Guidance.

Next slide, please.

We have several new guidance documents in progress. The one that we hope
will be available soon will be one addressing antimicrobial agents on
medical devices.

We are working on a guidance document for the reprocessing of single use
medical devices and also one for standardizing the reprocessing of
reusable devices. This will concentrate particularly on cleaning
devices.

We have a guidance document in progress for the germicides for
reprocessing reusable hemodialyzer systems.

May I have the next slide?

We are also working on revisions to existing guidance documents, the one
that covers surgical gowns and drapes, the one that address chemotherapy
gloves, medical sterilization packaging systems. Another for needle
disposal devices and biological indicators.

Can I have the next slide, please?

Review challenges for our division relate to the technology that we
review. Nontraditional sterilization technology is a fascinating new
area. There\'s a great deal of new technology coming along, and
validating the processes involved can be challenging.

The reprocessing of single use medical devices is progressing. We are
seeing increasingly complex devices being submitted for reprocessing,
the validation of this is a very complex process, as is the need for
standardization among the entities conducting the reprocessing of single
use medical devices.

And finally, the cleaning of medical devices, a general topic which
addresses not just single use medical devices but really all medical
devices, is something that needs validation and more standardization we
believe throughout the industry.

Thank you very much.

EXECUTIVE SECRETARY COLBURN: Thank you.

Next we have Mr. Anthony Watson, Chief of the General Hospital Devices
Branch who will give a brief update on the FDA General Hospital Device
activities related to this Panel.

MR. WATSON: Good morning. My name is Anthony Watson. As mentioned, I am
the Chief of the General Hospital Devices Branch, and I\'m going to give
you an update on what has happened in our branch since the last Panel
meeting.

Just to give you some idea of my background, I\'m a general engineer.
I\'ve been with the FDA for a little over 11 years. I was a reviewer in
another branch for 10 years and I took over this branch in spring of
last year.

This Panel last met August 2, 1999 and two guidance were discussed at
that Panel meeting, one for pen injectors and one for jet injectors.
Obviously, jet injectors are the topic of today. In particular, during
that discussion six years ago there was quite a bit of discussion
regarding cross contamination of jet injectors. And that is actually
going to be the focus for today\'s meeting.

As you might imagine, in six years there\'s some degree of turnover.
This branch has had a significant amount of turnover. As I mentioned, I
became the branch chief last year, March of 2004. Our branch right now
consists of seven members with varying backgrounds. We have three
nurses, three engineers of different backgrounds, different types. And
we have one microbiologist.

We have in our branch a lot of devices that have broad uses. As our name
implies, General Hospital, we have general use devices, needle-free,
obviously jet injectors as we\'re going to talk about them today and
well as pen injectors. We do both implantable and external infusion
pumps, syringes and needles and IV admin sets, and long term and short
term intravascular catheters.

In addition to that, we also do devices that have sharpes injury
protection features. These differ from the devices that Dr. Murphey\'s
group reviews in the fact that they deal with them after they are used,
and these devices actually incorporate sharps injury protection
features.

And one area that\'s really growing for us is the general use medical
software area. We\'re starting to see a lot more action in this
particular area.

We also review acupuncture needles, pharmacy compounding devices. And we
deal quite heavily with combination products. Those are products that
have devices and either a combination of biologics or drugs.

We\'ve also published a number of guidance documents. In 2001 we
published a Class C Special Control Guidance document for Pharmacy
Compounding Systems. And that was also concordant with the actual
classification of those products.

We put out a guidance document in 2002 for sharps injury prevention
features, which we are presenting in the process of updating.

And in 2004 we cleared an interesting device, implantable radio
frequency transponder system for patient identification, health
information. And in accordance with that process we also generated a
Class II special control guidance document.

The last, the most recent guidance document that was published was
intravascular admin set. This is a revision to an existing guidance
document. And that was published in April of this year.

We are in the process, we have quite a bit of guidance documents that
have been around for a while. And we are in the process of updating some
and actually generating some new guidance documents.

The pen injector and jet injector, as I mentioned earlier, six years ago
we had a discussion about what kind of information would go into those
guidance documents. We\'re now going to be actually generating those
guidance documents. And we\'re going to be revising our guidance
documents to infusion pumps, intravascular catheters and pharmacy
compounding devices.

We\'ve had a number of clearances over the years that have some
interesting issues and features associated with them. But perhaps the
one that\'s generated the most interest was this implantable radio
frequency transponder system for patient identification and health
information. And it\'s significant in a number of ways.

First of all, just to briefly describe the device, the device really
consists of three components. A chip that\'s implanted in the skin
that\'s about the size of a grain of rice, an introducer which is used
to implant the device and a reader. The reader actually \-- the device
itself, the chip only contains a patient identification number. It
doesn\'t contain any other information about the patient. But the reader
can extract that code, then using that code whoever is authorized to go
into a proprietary database can then take that information and pull up
the patient\'s information. That health information is supplied by the
patient. It is generated from any other location. So the patient
actually gets to tell the person what they want the person to know.

That device was cleared under the de novo review process, and it was
really \-- I was real proud of the review team because it was really a
cross cutting kind of product. We had people that looked at the
electromagnetic compatibility of the product, the bio compatibility of
the product. The MRI compatibility of the product. There was software
discussions about data security, data integrity.

And where\'s Gail? Is she in here? Am I missing anything, Gail? I think
I got it all.

The bottom line was it was under a de novo review process, which is a
process that\'s beyond the scope of me describing it at this Panel
meeting, but it required us to do all that within 60 days and generate a
Class II guidance document as well. So I was real proud of the review
team for that. And you may hear more about this product.

Next slide, please.

We have a number of challenges that we\'re facing in our branch. And I
have combination products up there because they\'re always a challenge.

Inter-center consults, getting consults with other centers to review
them in our statutory time frames is always a challenge. Our other
centers have been great for helping us with that, but it is a very
difficult thing to do.

Cross-labeling of combination products. There\'s always a question
whether the device component should reference the drug or biologic
component and vice versa, how much of that should occur. We\'re always
dealing with that.

And, as I mentioned, the growing area for us is software based devices.
One of the things that really is a challenge is that these devices
we\'re talking about a lot of times are just software. There is no
hardware associated with them. We\'re talking code, maybe put on a CD, a
DVD, placed on a server, something like that. And how do you regulate
that? What performance do you look for? I mean, what are the issues
associated with that?

And we\'re also dealing with a number of existing devices that have IT
technology applied to them, particularly in the area of wireless
communication through networks. And where does the device begin and
where does the device end? That\'s always a question there. But we are
seeing more action in that area.

Human factors: This one is basically related to our attempts to address
human errors due to human factors. Particularly in the area of infusion
pumps, there\'s always a question about whether these errors can be
prevented through proper human factors, considerations and the design
process. So we\'re really starting to emphasize that in our review
process. And it\'s not just infusion pumps, it\'s really any device that
we deal with that has a high human machine interface. We want to make
sure that we\'re asking those people to look at those human factors in
the review process at the design stage.

And one area that\'s really sort of exploded for us recently is the use
of \-- I have peripheral catheters up, but we\'re also talking central
catheters as well that are using power injection for contrast media.

Obviously these type of procedures generate high pressures, high flow
rates. A lot of catheters on the market are not actually tested to that
level. And we want to make sure that we\'ve got the proper testing for
that. That\'s a challenge because these devices are made with different
materials, different sizes. No two are alike, basically. So we\'re
trying to develop testing for that, is really a challenge for us. But we
do have some great ground work. Our reviewers have done a good job about
identifying the clinical issues and taking a look at the engineering
aspects.

And one other aspect that we are really concerned about is what
information do we need to provide for users. It\'s really critical that
the users know how to incorporate that in the way they\'re using the
products.

So that\'s the General Hospital Devices update. And thank you very much.

CHAIRMAN EDMISTON: Thank you.

We will now proceed with the first of our two half hour open public
hearing sessions. The second open public hearing session will follow the
Panel discussion this afternoon.

During this period public attendees are given an opportunity to address
the Panel to present data or views relevant to the Panel\'s activities.
Some individuals have already given advance notice of wishing to address
the Panel. Each speaker will be given a 15 minute opportunity to speak.

I would like to remind the public observers at this time that while this
portion of the meeting is open to public observation, public attendees
may not participate except at the specific request of the Chair.

We would also ask at this time that persons addressing the Panel come
forward, keeping in mind this presentation is being transcribed and
speak clearly into the microphone.

If you have a hard copy of your presentation, please provide that to my
colleague, Lieutenant Colburn or leave it on the transcription desk.

The following statement is to be read verbatim at the general matters
meeting. \"Both the Food and Drug Administration and the public believe
in a transparent process for information gathering and decision making.
To ensure such transparency at the open public hearing session of the
Advisory Committee meeting the FDA believes that it is important to
understand the context of the individual\'s presentation. For this
reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral comment to advise the Committee of any
financial relationship that you may have with any company or group that
may be affected by the topic of this meeting.

For example, this financial information may include a company\'s or a
group\'s payment of your travel, lodging or other expenses in connection
with your attendance at this meeting. Likewise, the FDA encourages you
at the beginning of your statement to advise the Committee if you do not
have any such financial relationship.

If you choose not to address this issue of financial relationships at
the beginning of your presentation, it will not preclude you from
speaking.\"

At this time I believe we have two speakers. We have a Mr. Hooks and a
Mr. Weidman, is that correct? Please come forward and introduce
yourself. At this time indicate your affiliation.

Each speaker is allotted a 15 minute period.

MR. HOOKS: Good morning.

I don\'t have any financial things with anybody, nobody paid for my way.

What we\'d like to do is address the military application for aspects of
the jet gun injectors.

I represent HCVets. com. It\'s a website.

Go to the next one. All right. I\'m getting ahead of myself.

Anyway, what we do is we have a website that allows veterans, military
members, their families or whatever to seek information on the
contamination or infection of hepatitis C via the jet guns.

If you look at this chart here you\'ll see that the majority of the
people that have hepatitis C are veterans, the largest portion of
Vietnam era. The reason that occurred is if you think about the military
at the time, was probably at their peak. The one thing we all share in
common is we were all inoculated with the jet guns.

The other thing is when you look at most of the studies referring to
this stuff you\'ll see they mention hepatitis B and HIV. Well, hepatitis
C is more infectious than HIV, it\'s also a lot harder. It\'s a lot
harder to get rid. So the cleaning and all like that is very important.

Next one, please.

If you look at the VA Administration and all like that statistics,
there\'s 25 million plus veterans still alive in this country. Only
about ten percent of these folks go to the VA. So the numbers that
you\'re going to see are smaller, I believe, because there are a lot of
veterans who do not use the Veterans Administration as their health
service.

If you look at the numbers from the CDC and the Veterans Administration
right now, out of the 25 or so, comes out to about 458,000 veterans have
hepatitis C. But I think the numbers would be quite larger than that if
you took into account the whole population.

Next one, please.

If you take the numbers in with all, add the 2 percent and everything
like that for the population, of course there\'s really been no studies
on this since \'94, so these numbers wee taken with the CDC at different
times and all, and the 2 percent was added, you know, for the population
growth and stuff like that. And you come up with these numbers here. Out
of the 33.4 million veterans or people that are infected with hepatitis
C, 2? million would be veterans.

Next one, please.

Based on the infection rates quoted by the VA and the CDC, approximately
75 percent of the estimated people with hepatitis C are military
veterans with infections longer than 20 years. Out of the estimated 3
million chronically infected stated by the National Institutes of
Health, an estimated 2.2 million had this disease for over 20 years, a
projected 20 percent or 450,000 veterans are expected to develop
sclerosis or 90,000 are expected to develop cancer now.

Next one, please.

I\'m sorry about the picture. It didn\'t come up. It was a graph.

The role of the jet gun in the transmission of hepatitis C. The
Ped-O-Jet was introduced about 1950s, developed under a U.S. military
contract for mass vaccinations of recruits of 600 to 1,000 injections
per hour. The WHO document says an hour and a half.

If you go on an hourly basis, that\'s about six injections at 600 or 3.6
injections a second per hour. If you go to an hour and a half, it\'s 9
seconds per injection or 5.4 injections per second. That\'s a relatively
rapid fire. I think anybody\'s that\'s been around in those lines
understand there\'s no time to waste. Real close quarters and you\'re
hustled through.

Next one, please.

This is a picture of the old apparatus that was used. I believe up until
about \'94. It wasn\'t me.

Okay. Next one, please.

The Air Force Infectious Disease and Control Epidemiology Board,
Department of Defense Wide Review of Vaccine Policies and Procedures
said that injector nozzles were frequently contaminated with blood. What
they did is they had \-- I think it was probably a surprise visit to
Parris Island. And they witnessed a mass injection of a lot of recruits
coming in. And they noted in that document that there the nozzles were
frequently contaminated with blood. There were no wiping or precautions
taken.

Next one, please.

The problem with the jet injector gun during the Board meeting in 1986,
Captain Michael Stek, Jr., MC, USN presented data and press clippings to
suggest that contamination of the jet injector gun which had been used
in a private clinic in California in 1985 was responsible for causing
hepatitis in 64 patients. The possibility was also raised that HIV
infection might be transmitted by the jet gun when biological products
such as gamma globulin were administered. In numerous meetings the board
recommended in 1988 that an injector gun be used only by authorized
military and technical parts and sterilized according to standard
procedures.

Next one, please.

What are the standard procedures for the jet injections?

Next one, please.

That would the manufacturer\'s recommendations.

Next.

The manufacturer\'s recommendations recommended the devices be wiped in
between each injection. There was a meeting, I guess, of this
organization in \'99 where a representative of the company was here and
they stated that in 35 years they were always wiped and never had an
issue.

I\'d like to bring out at this point in time probably you never had an
issue with hepatitis C by the simple fact a majority of people are
asymptomatic and it takes decades before you find out you\'ve got a
problem. Thirty-five years is not a stretch in this area. The majority
of the people won\'t have a problem until at this point in time.

There was a study done in England where it came out that they could
infect 31 out of a 100 if the guns weren\'t wiped. There was a statement
made that there\'s nowhere in the world recorded that the guns weren\'t
wiped.

Well, we have \-- the next one, please.

The website did a survey, and this a partial selection of people that
answered the survey. We have answers from medics that administered the
shots and received the shots, we have all different bases and military
branches, and comments from the individuals that state the guns were not
wiped. I personally can attest to that. They didn\'t wipe them before
they nailed me or anybody before or after me.

Next one, please.

The expectations fell short. As I stated earlier the people in charge of
the basis and the medical, and stuff like that, were under the idea that
the guns were being wiped in between each injection. That\'s not the
case. The human error factor, for whatever reason, the things weren\'t
followed. I\'ve talked to some medics that had this duty when they were
in the military, and this is what they considered to be a great job. You
go in in the morning, you throw a bunch of shots out, you get done
early. You got the rest of the day off. You know, that was just the way
they looked at it. There was no harm, no fault in my mind because they
had no idea with the little bit of training they had what they were
doing. They had no understanding of the infection rates. Hepatitis C at
the time wasn\'t even something described. You were non-A, non-B if you
were diagnosed at all.

The next one, please.

In dealing with the VA, it\'s been an uphill battle for a lot of folks
because the simple fact is they don\'t fit into the prescribed methods
of transmission for hepatitis C. The CDC and all have kind of left out a
whole generation of folks, and it makes extremely hard for someone who
has no other reason except for their injections, to get hepatitis C.

Back in 2003 there was a claim that was based solely on the jet
injectors. The veteran won that one, but it had to go to Cleveland to
the Tiger Team to get there.

Next one, please.

Here\'s some of the documentation that was used and the studies that
were used to validate the claim.

I\'d like to mention, too, besides the hard copies, I have CDs that if
you go on line the links will work and link you to these studies. It
would take too long to get into them.

Next one, please.

This is the DoD\'s needle-free injection policy chronologically. It
shows when they started to stop using the jet injectors and the reasons
why. The dates and the organizations, and their orders that came out.
Once again, you know, the links will take you to the full study.

Next one, please.

Okay. For infection rates we\'re talking picoliters of blood, that\'s
very small. It doesn\'t take a lot. And there\'s been numerous studies
on that.

Hepatitis B, basically, can be transmitted at about 10 picoliters.
Hepatitis C runs in, I believe, at about 35 or HIV at about 40.
Somewhere in that range. There hasn\'t really been any hard studies that
I\'ve seen, or found or heard about that relates to hepatitis C. That\'s
something that really, really needs to be looked at because it\'s not a
problem that\'s going way. I mean, this whole thing with me not knowing
that I was infected, I in turn infected my wife. She wasn\'t real happy
about that, but I\'m not the only one that has done that not knowing.
I\'ve donated blood up until like \'92, and then I stopped for physical
reasons not because I was tested with hepatitis C. So we have a larger
epidemic then what\'s showing up in the numbers. And it really needs to
be looked at. We have to stop it any way we can. And by ensuring that
these guns or any other device that has the ability to transfer blood in
any amount is designed in a fashion that can\'t happen. I don\'t want
anybody else to have to go through what I\'ve been through, or a bunch
of other fellows, either.

Next one, please.

This is a CIA report, which once again the link will take you to. What
we have here, basically they did a study in the areas of the sub-Sierra
and Southeast Asia, and stuff like that. They had an upheaval with HIV,
and all like that.

The other problem you\'ll see and where our folks are right now serving
us with great courage, they\'re also hot beds for hepatitis C. I think
that the fellas and gals that are over there now should be checked. If
they\'ve had any injections and stuff, they should also be checked and
nip in the bud before it gets like it did with us 20/30 years down the
road.

Next one, please.

Once again, this study is taken not in this country, we really haven\'t
taken the time to do in depth studies for hepatitis C. We have some on
HIV and some on hepatitis B. So most of the studies you\'ll see are from
foreign lands. We haven\'t really addressed it appropriately.

Next slide, please.

That\'s my idea of the beautiful world and all reality. Like I said, any
device that transfers blood, the needle jets specifically, they need to
be addressed appropriately. I know there are some modifications that
have been made like caps and disposable ends and stuff like that. I\'ve
seen where they\'re working on things. But they really do need to make
sure these things don\'t transmit blood in any fashion.

That\'s all I have.

CHAIRMAN EDMISTON: Thank you very much, Mr. Hooks.

MR. HOOKS: Thank you.

CHAIRMAN EDMISTON: At this time I\'d like to invite members of the Panel
who may have questions or clarifications of Mr. Hooks\' presentation to
please address the speaker. Are there any questions from members of the
Panel?

Thank you very much.

Do we have any other speakers who wish to address the meeting?

I think at this time since we\'re ahead of the game here, we\'re going
to go ahead and take a brief 15 minute break. The next presentations
will be from the FDA, and there\'s a continuity of those presentations
so I\'d rather not break them up.

So let\'s take a 15 minute break and convene at 9:15.

(Whereupon, at 9:00 a.m. a recess until 9:17 a.m.)

CHAIRMAN EDMISTON: I think we\'ll reconvene the meeting now. I\'d like
to ask all the Panel members to take their seats, please.

I\'d like to make a very brief announcement. It was initially announced
that Dr. Weniger from the Centers of Disease Control would be here
giving a presentation. But, unfortunately, he will not be able to be
here to make that presentation.

We will now proceed to the FDA presentations for the Panel. The first
speaker will be Mr. Anthony Watson, Chief of the General Hospital and
Personal Use Devices Panel. Mr. Watson?

MR. WATSON: Thank you. And I\'m just going to introduce the speakers. We
have three speakers today.

Mr. Jason Lipman is an engineer in the General Hospital Devices branch.
He will be discussing the regulatory history of jet injectors.

Then we have Dr. Shewit Bezabeh, who is a medical officer in our
division. And he will discuss the safety history with these devices.

And then following him will be Dr. Daya Ranamukha, who is a
microbiologist. Is that correct? Molecular biologist. I apologize. A
molecular biologist from our Office of Science and Engineering
Laboratories. And he will discuss potential methods for testing for
these devices.

So now I\'d like to ask Mr. Jason Lipman to come to the podium, please.

MR. LIPMAN: Good morning. My name is Jason Lipman. I\'m reviewer in the
General Hospital Devices Branch. If you haven\'t figured it out yet,
we\'re here to talk about jet injectors.

CHAIRMAN EDMISTON: Excuse me. Could I ask you to speak directly into the
microphone.

MR. LIPMAN: Oh, sorry.

CHAIRMAN EDMISTON: We\'re having some problem hearing you.

MR. LIPMAN: Is that better?

CHAIRMAN EDMISTON: Yes. That\'s great.

MR. LIPMAN: Okay. Jet injectors are also known as needle-free or
needleless injectors. As defined by the Code of Federal Regulations a
jet injector is a nonelectrically powered device used by a health care
provider to give a hypodermic injection by means of a narrow, high
velocity jet of fluid which can penetrate the surface of the skin and
deliver fluid to the body.

Next, please.

Jet injectors are Class II devices. They regulated through the 5.10(k)
premarket notification process. And jet injectors must demonstrate
substantial equivalence.

Next, please.

There are two main types of jet injectors. There are single use devices
and there are multiple use devices.

Single use devices are devices in which the entire device is discarded
after one use.

There are three types of multiple use devices. There\'s single use
cartridge devices in which the fluid contacting components are discarded
after one use. There are devices that are labeled and sold for only one
patient. These devices can be multiple use, but only one patient is
using them. And there are devices that have a reusable fluid path. As
indicated by the yellow, these are the devices that we will be focusing
on today. These devices typically have a large medicinal vial that fills
an injection chamber after each subsequent injection. Reusable fluid
path injectors are also known as multi-Use Nozzle Jet injectors or
MUNJIs, for short.

Here\'s a picture of a bunch of jet injectors. As you can see, many of
them do have that medicinal vial at the top of the injector which I just
mentioned.

Next, please.

I want to talk a little bit about how a jet injector works. Jet
injectors must create high pressure, usually by the use of springs or
compressive gas. This high pressure forces the medicinal product out of
an injection chamber through an orifice and into the body.

There are four target tissues for injectors; mucosal membranes, dermal
tissue, subcutaneous tissue, intramuscular tissue.

Next.

There are two primary uses for MUNJIs. That\'s immunization and
administering anesthesia during dental procedures.

There are several advantages of MUNJIs use. They include high delivery
rates. It doesn\'t take very long to prepare for a subsequent injection.

There are several needle-free benefits for MUNJIs use. There\'s no reuse
of needles, no chance of contaminating needle-stick injuries. And
there\'s no patient fear of needles because there, obviously, is no
needle.

There\'s a reduction of volume of clinical waste.

And these devices are economical because the device is reused.

There are a couple of disadvantages for MUNJIs. The focus of our
presentation today is the first one, the potential for blood
cross-contamination or disease transmission.

The second is the potential for laceration injury from improper
technique. And this can occur since the jet stream has such a high
velocity of jet stream that if you were to actually lift it off the skin
prematurely, you could lacerate the skin from that high velocity jet.

Next, please.

There has been one documented case of cross-contamination. This was in
California in 1985 at a weight loss clinic. It resulted in a hepatitis B
outbreak. In addition to that outbreak, there have been in vivo animal
studies and bench laboratory studies that also link these devices to
disease transmission. This will be talked about in more detail by
subsequent presenters.

So I want to talk about how the cross-contamination occur. It can occur,
as we heard before, about blood actually the skin contacting surface on
the injector or that blood or serum can actually go up into the fluid
path. And there a couple of theories as to how that can actually occur.

One is splash-back. Again, the high velocity jet can actually bounce
back off the body and back through the small orifice. Or there\'s also a
thought that the injection, the pocket of fluid in the body is
pressurized and pressurizes the tissues around it and those tissues can
actually push on the fluid and push back up through the orifice.

In either way, the residual infected blood or serum can be injected into
the subsequent patient causing a blood-born illness.

Manufacturers have attempted to mitigate that risk of
cross-contamination. The primary design of the mitigations are
single-use patient contacting components, such as caps, spacers or
sheaths. But there have been no validated methods to assess the
effectiveness of these components.

Next, please.

So the challenge of evaluating the potential for disease transmission
exists because there\'s no consensus on the amount of blood
contamination that can potentially transmit disease, and there\'s no
validated test method for detecting blood cross-contamination. And,
again, this will be talked about in more detail in subsequent
presentations.

There is global concern about using these devices, the new devices as
well, the new MUNJIs. The World Health Organization recommends against
MUNJIs use. The Centers for Disease Control and Prevention recommend
weighing the risks versus the benefits; the risks of typical syringes
and needles versus the jet injectors. Hopefully, I\'m hoping that Dr.
Martin Friede will talk in a little bit more detail about their current
policies.

In 1999 the FDA held an Advisory Panel meeting to discuss the guidance
for jet injectors. This was talked about earlier today. This was to
figure out the evaluation criteria that would be documented in our
guidance document for evaluating jet injectors. During this Panel
presentation, or this Panel meeting we also discussed the potential for
cross-contamination, what we\'re here to talk about today.

At the end of that meeting there were two recommendations made by the
Advisory Panel to the FDA relating to this issue. The first was to
consider the postmarket surveillance. We have reviewed all of the
medical device reports on this issue. There has only been one medical
device report related to cross-contamination, and this was actually a
case of misuse and did not result in any blood-born disease, at least
documented blood-born disease.

Could you go back for a second? Thank you.

The second recommendation to the FDA was to investigate the possibility
of developing a standardized methodology to determine contamination. We
have reviewed all the current methods and even looked at some future
methods, and we will be talking about this more later today. But to date
there are no validates test methodologies available.

Next, please.

These are the references that I\'ve cited in this presentation.

Next, please.

I just want to talk a little bit about the purpose of today\'s meeting.
We\'re here to discuss the cross-contamination risk associated with
MUNJIs and to discuss the methods that might be used to assess this
risk.

This concludes my presentation. I hope it gave you a good background for
what we\'re going to discuss today.

At this time I\'d like to call up Dr. Shewit Bezabeh who will give a
clinical perspective on this issue.

Thank you.

DR. BEZABEH: Good morning. My name is Shewit Bezabeh. I\'m a Medical
Officer with CHRH, the FDA.

My background is both public health and epidemiologist. Also I\'m an
internist. I\'m also active in a clinical practice. I have been with the
FDA for the past four years as a Medical Officer.

Next slide, please.

Today I will give you an overview of MUNJIs. The device has history. The
public has need. The effectiveness experience with these devices, the
history of safety concerns and the concerns for current use.

Next slide, please.

Jet injectors are needle-free delivery devices that facilitate the
administration of medications under high pressure stream into tissue.
These devices can administer vaccines and other medications into
subcutaneous tissue, intramuscular tissue and also dermal tissue.

People have categorized these devices into three categories. The first
one, the first one I\'ll use is usually used for single use can also be
reused with the same person. We see these devices being used with a
number of diabetics.

The second category is low work load. About 30 injections per health
care worker.

And the third category, which is the focus of today\'s meeting, will be
high work load, injection of a 100 injections per health care worker.

Next slide, please.

The history of these devices, they start in the 1860s, was initially
developed in France to administer a number of liquids.

In 1936 the first jet injection device was attempted in New Jersey.

In the \'40s the first commercially available jet injector was
Hypospray. It was initially devoted for single use, self administration
for diabetics. It was designed to overcome childhood needle phobias.

From the mid-\'40s to the \'60s it was introduced massively into the
military for clinical use.

From 1976 to present up to now it is cleared by the FDA as a Class II
pre-amendment medical device.

The need for public health for these devices is multiple \-- for a
number of reasons. These devices are needle-free, so they avoid the
needle entrance risk due to needle injuries.

Globally there\'s high risk with needles and syringes because of
improper recycling, and also reuse with proper sterilization. WHO
experience with that, half of the injections in the developing world are
unsafe and result in about from 8 to 16 million hepatitis B virus
infections per year, 2.3 to 4.7 million hepatitis C infections and about
100,000 HIV infections.

In the U.S. there are about 87 health care workers contract hepatitis B
virus due to occupational exposure, of this there\'s about 200 cases per
year.

The risk of infection after a needle stick injury with an infected blood
for HIV is about 3 in a 1,000, hepatitis C the range was from 1 to 7
percent and hepatitis B, which is the most highly infectious, about 30
percent.

The other aspect of need for these devices, they can be used in response
to bioterrorism because they can rapidly immunize first responders,
exposed populations. They can be used in pandemics, regional epidemics
and emerging infections. They have been used with meningococcal
meningitis, yellow fever, influenza.

There is a global need for this eradication. They have been used with
polio initially. Polio is almost eradicated. Measles is targeted for
eradication. Many of the program for immunization vaccines practices
require injections. And also as mentioned earlier, needles and syringes
have a number of limitations.

They also have potential need for future newer vaccines. They have been
tested for malaria DNA vaccines and also for emerging vaccines such as
when the vaccine is available for SARS and other infections.

The advantage of this device is included, it has a potential high rate
of vaccination. They can vaccinate over 600 people per hour. Can respond
to pandemics, regional and local epidemics. Can also respond rapidly to
bioterrorist attack. Can administer off-the-shelf vaccines.

They have a long history of use with many types of vaccines. They can be
filled at the end user or by a manufacturer. They eliminate the needle
stick risk and sharp disposal burden. They are also very cost effective
compared to needles and syringes.

The main disadvantage, which is the focus of today\'s meeting, is the
potential for blood cross-contamination. Also, they\'re believed to have
increased pain, especially the adjuvant added vaccines as compared to
needles to syringes. Also, improper technique may result in laceration
of injury. They\'re believed also more reactogenic than needles and
syringes. You\'ve seen increased erythema hematoma bleeding at the
injection site.

Immediately you see more erythema and hematoma. Some of the delayed
reactions includes soreness, erythema in duration and edema. Other local
adverse events include bleeding of injection site. As mentioned earlier,
there could be laceration, especially if improper technique is used. And
there have been very rare reports of traumatic injuries.

In terms of effectiveness expense. We have over 50 years of device use
delivering millions of injections. There have been a number of studies
which demonstrate effectiveness of these devices, mainly by measuring
immune response and immunogenicity. We have a number of randomized
control trials, review of clinical trials. Also respected comparative
studies.

I should note that even though these studies assess the effectiveness of
these devices, none of them have studied for their safety.

In terms of past use, the U.S. Department of Defense from 1965 to 1980
have given about 20 to 40 million injections to military personnel. The
global smallpox eradication program, 50 to 100 million. During 1976
swine flu epidemic, about 75 million have received vaccination using the
device. The African Meningitis Program, 1988 through 1998, about 80
million. The Brazilian Measles Eradication Program, an estimated 60 to
80 million people have received vaccination with this device. And
globally, from 100 to 500 million have used this device to receive
vaccinations in the past 30 years.

Even though we have extensive history of use and effectively, there have
never been no surveillance implemented to assess transmission potential
between this use.

Next slide.

Some of the vaccines that have been used with this device, include both
light and inactivated vaccines, measles, mumps, rubella, yellow fever.
Some of the inactivated vaccines include botulism, cholera, hepatitis A
and B, influenza and others.

Next slide.

In terms of the history of safety concerns, in the late \'60s early
\'70s people started noticing blood on the nozzle of these devices which
was initial concern for the purpose.

There was only one documented disease transmission which occurred in
California in 1985. A cohort of patients were receiving formal
injections, had clearly documented hepatitis B virus. We believe this
transmission was through this device.

In addition, we have some experimental evidence as well as some
epidemiologic evidence implicating this device, this is transmission.
Some of the experimental evidence include in 1985 Brink coworkers took
mice which were clinically infected with LDH virus. They had a cohort of
mice received injection and they were able to demonstrate that 16 out of
49 mice had acquired LDH virus through that injection.

In 1988 Zachoval, which have reported in the *Lancet*, took 5 patients.
Four of them had positive serologic markers for hepatitis B. The fifth
patient was HIV positive. They injected them with a jet injection device
and then they tested the nozzle and the injection site. While the nozzle
was negative for any markers, three out of four of the hepatitis B
carriers, the injection site was positive for hepatitis markers and the
HIV patient also positive for the marker. The theory being that if there
had been a subsequent injection, these markers would have been
transmitted to the next patient.

Next slide, please.

Some of the epidemical evidence so far include the 1994 about 2800
subjects were receiving routine immunization via jet injector. The
injected was tested instead of giving it to the next subject, it was
tested. It was collected in a test tube and tested for blood. And about
28 of them, which is about one percent of the subject recipients tested
for occult blood.

In 2001 there was an epidemiological survey done in Brazil where about
750 patients where hepatitis B virus carriers had a multi-variant
analysis to evaluate the risk factor for transmission. And out of the
multi-variate analysis, a cohort of people who had received prior yellow
fever vaccination via the jet injector was a risk factor as for
hepatitis B infection. Again, implicating the device as a vector for
disease transmission.

A field study done in Brazil again to look at the safety of the
injector. This investigator took two modes of injection type. One they
took noncompliant stimulating no interference between the device \-- I
mean, vaccine delivery. And the second mode was a confirmed compliance
mode where the nozzle of the device was swabbed with alcohol.

And they took the volunteers and injected them with buffered saline and
they collected three subsequent injected into a test tube and tested the
ejected for blood.

In the first injection in the noncompliant mode, about 30 out of 117
patients, which is about 11 percent, were positive for occult blood. And
then in the compliant mode, 9 out of 117 patient, which was about 8
percent, was positive for blood.

In the second injected, about 4 percent, 4 out of 117 in the
noncompliant mode. And the second mode, the complaint mode, 3 out of
117, which is 2.5 percent were positive for blood.

Whereas, the third injected there was no blood positivity.

Again, even with interference alcohol swab, as you can see both the
first and second injected in both the noncompliant and compliant mode
there was blood positivity. Again, implicating that this device possibly
delivers transmission.

In 1999 the Armed Forces Epidemiology Board observed frequent blood
contamination of the nozzle in high volume recruit immunization.

Next slide.

Based on this and other safety concerns and other studies, a number of
agencies come up with policies. In 1987 WHO restricted device use. In
1996 WHO also stated that MUNJIs is not recommended for mass use. In
1997 the U.S. military withdrew the use of the device. In 1999 FDA had a
Panel presentation meeting, as mentioned earlier. And the Panel meeting
was to discuss a guidance document. However, also the safety of this
device were discussed. And the Panel had two recommendations. The first
recommendation was to continue to do postmarket device surveillance. And
the second recommendation was to investigate the possibility of
developing a standardized methodology for the safety of the devices.

In 2002 the CDC Advisory Committee for Immunization Policies discussed
the use of these devices and they stated that MUNJIs use should be
limited weighing the risk versus benefit of MUNJIs with needles and
syringes.

And most recently, 2004, WHO had also discussed the use of these
devices. And the conclusion was it would not be possible to adequately
endorse the safety of these devices.

Next slide.

In terms of blood-born transmission, we know that hepatitis B virus is
more infectious than HIV and hepatitis C. And we also know that there
about 9 to 10 to 11 hepatitis B virus DNA copies per cc, which is about
1 to 100 hepatitis B particles per picoliter. There have been studies
where they have estimated that 10 picoliters being the smallest amount
for transmission of hepatitis B virus.

Next slide.

A number of assays have been tested and tried in the past to measure the
blood injected as a marker for assay. Some of the assays include serum
albumin measurement as an indicator of blood. There have been sensitive
ELISA assays. However, there is no acceptable limit of blood detection
to demonstrate safety of these devices. Some of the proposals which have
put forward include to do clinical trials with hepatitis B positive
population and also to test injected for hepatitis B virus by PCR.
However, we\'re not sure if these assay models are sufficient to
evaluate the safety of these devices, also are there any testing methods
to assay the safety of the devices.

The next presenter, Dr. Daya Ranamukha will go further into the testing
methodology and assays.

Thank you very much.

DR. RANAMUKHA: Thank you.

The title of my talk today is potential safety evaluation strategies for
MUNJI devices.

I\'m Daya Ranamukha-arachchi. I\'m a molecular biologist at the Office
of Science at the Center for Devices and Radiological Health. I have
over ten years of experience in molecular methods in human genomics.

So going back to the percentage, and Dr. Bezabeh before and others
talked about safety concerns for MUNJI use, and I want to stress the
important points here again.

MUNJI can exert local adverse events and it could be delayed for early
reactions, and again can lead to bleeding at the injection site. These
are more common in MUNJI devices than needle/syringe devices.

What I\'m going to talk to you today about mainly, the risk of
cross-contamination with blood. So I\'m going to put forward the
potential evaluation strategies in this context.

Next, please.

So the first question that comes to your mind is when you think about
cross-contamination, is there safe limits of blood cross-contamination?
Insights into this comes from virology data. If you look at the
hepatitis B carriers, they contain around 10 to the 9 to 10 to the 11
DNA copies per milliliter. If you go down in the volume, it\'s about 1
to 100 HBV copies per picoliter of blood. But it can also go in some
carriers, they go to like 10 to the 15 DNA copies per milliliter.

And there\'s one study that shows HBV may be transmitted with as little
as 10 picoliter of blood and using one animal model. This was published
in 1984.

So when you combine these two facts, is the 10 picoliter of blood or 10
to 1,000 HBV copies the limit that we want to dictate? And then the next
question is are there test methods to achieve the required limit of
detection? These are the questions that we need to address.

Next, please.

So if one were to evaluate the contamination risk, what are the
challenges we have to face between use cross-contamination. So these are
whole list of questions that comes to one\'s mind; collection of sample;
how we can collect the samples to evaluate between use
cross-contamination. Then what are the analytes? What are the molecular
methods? Then when you think about the molecular methods, what are the
limits of direction and accuracy, specificity and reproducability? And
then finally depending on all these answered, what are the safe
acceptance limits? Is there acceptance limit?

So addressing all these issues, I have divided my talk into three
categories. First, analyze for testing. Once we collect the samples, how
we can look at, what are the analytes that we need to test? Of course,
blood markers and then we can think about pathogenic contaminates, what
are the markers? Then what other methodologies;, molecular methods
available to determine contamination? Serology-based, then DNA
amplification based and combined approaches including DNA hybridization
technologies.

Then the third, cross-contamination study designs. We have animal
models, we have human models. So we can look at all that.

So coming back to the first part of my talk, analytes. Obviously, many
talk about blood cross-contamination comes to our mind the blood
markers. So we can look at blood markers like abundantly available
proteins such as serum albumin as surrogate marker for the presence of
blood. So this has been done before actually using sensitive ELISA
methods. But the disadvantages of using this serum albumin is it can
create false positives, false negatives and deduction limits. False
positives in the sense that serum albumin presents in everywhere saliva
and skin cells, so this can create false positives.

Then the false negatives. Under cold storage conditions serum albumin
can bind to collection tubes. So then when you think about ELISA, the
detection limits if very narrow. So you have to go through a series of
dilutions in order to get within the dynamic range of detection.

Then with regard to blood molecules, I want to stress the point that
what is the limit of detection 10 picoliter of blood. This number came
from one single study using one chimpanzee. This study was not meant for
actually looking at HBV transmission, but to evaluate it was
methodologic paper looking at ELISA versus DNA detections. And in that
what they did was they the serial disillusions of the saline, buffered
saline and they found out that 10 to the minus 10 dilution they could
infect one chimpanzee. But their aim, the object of the study was to
evaluate how good at analyzing detecting HBV contamination.

So what I mean to say here is that this 10 picoliter blood limit is not
statistically validated.

So coming to the next one, then the second class of analytes is the
viral markers which has the highest contamination potential. For this,
the infections come from needle stick injuries. If you look at HIV HCV,
HBV, HBV has the highest potential with 6 to 30 percent depending on the
status of the contaminating blood.

Then HBV has the highest potential for transmission due to
cross-contamination. Which is the most prevalent? Over 2 billion people
are infected with more 350 million chronic infections based on the WHO
report. Survivability is high and can be easily integrated into the host
genome.

Next, please.

So last year\'s WHO injector safety meeting they come to consensus that
HBV is an appropriate marker for determination of injector safety.

There are also certain group of advantages. If you are using HBV as an
analyte, there\'s presence of international, WHO international standard
and then availability of quality control panels. And availability of
molecular assays for HBV detection.

There are internal controls, such as murine cytomegalovirus for
evaluation of false positives as well as false negatives.

So all these advantages lead us to develop good test methods if you need
to.

Next, please.

Now the second part of my talk is the test methods. What are the test
methods available? There are a whole host of methods available based on
serology, DNA amplification and combined approaches using DNA
hybridization.

Now what I have summarized here in this table is the more sensitive
methods with the principle \-- actually those principle technologies.
Serology based uses serum antigen, surface antigen and also e antigen.

So then other methods uses HBV DNA. So the samples either serum or
plasma.

Then the limits of the detection, I want you to look at the last two;
real time PCR and NAT technology. NAT technology is the nucleic acid
testing technology based on PCR, DNA amplification, plus DNA
hybridization. So these limits of detection, I got it from published
data which gives like 100 copies to 10 to the 7 and 10 to the 9
sensitivity limits of detection.

So I want to stress the point here that there\'s test methods available
for single copy detection. If you want to look at single copy detection,
there is no test methods available.

Now next slide, please.

I just wanted to put this slide because what other emerging technologies
can do in this context. Obviously, nanotechnology comes into play. And
there\'s some published studies, one for DNA detection called biobarcode
DNA detection which can detect DNA at 500 zeptomolar level, which is a
quality detecting all available copies in a solution. Then again, when
you look at protein detection using the same technology, you can detect
antigens at atomolar levels.

So these are only research tools which is published recently. These have
not been validated under any diagnostic setting.

So the next slide, please.

And I want to stress this point before I move on to the next category.
Molecular methods for HBV testing. Molecular methods have a lower limit
of detection than conventional assays. And MUNJI cross-contamination may
be investigated using HBV-NAT or Taqman assays. However, this has yet to
be validated. Then there are studies to establish performance
characteristics of these assays for HBV detection in MUNJI device use
have not been conducted.

Next please.

Now I want to switch the gears here to talk a little bit about what are
the possible study designs we can look at. This is the last part of my
talk.

So we can look at animal versus clinical studies. If you look at animal
studies, what advantages does it give? Provide well controlled
biological uniform study designs and we can directly evaluate viral
transmission potential. However, we are to take into consideration the
substantial histologic differences that exist between human and animals
schemes and muscle development.

So then the clinical studies, on the other hand, use the direct impact
of injected device on cross-contamination in humans. Genetic variables
are also taken into consideration. But it is unable to get IRB approval
for direct human evaluation of viral transmission.

So next slide, please.

There\'s one published model, actually, using animals for evaluating
cross-contamination potential of MUNJIs devices in this study which was
published in 2001 in *Vaccine* by Hoffman et al. They used cows, young
cows of 8 to 12 weeks and they used the same set of cows repeatedly. And
what they did was instead of using the vaccine, they used a phosphate
buffered saline in a buffer at .5 milliliter per dose. And then t hey
injected to one calf and then collect the next ejectate before injecting
to another one into a separate container. That\'s in the real world
situation in an immunization program, that\'s the one that goes to the
next person. So they collected that and then evaluate the blood markers,
surrogate markers, serum albumin by sensitive analysis. And then they
compared the results with negatives based on preinjection doses.

Next slide, please.

So using this same method we can think about potential clinical studies
for evaluating cross-contamination. There are two types we can look at.
If you are to evaluate blood cross-contamination only, we can use
healthy volunteers, the number which has to be determined statistically.
Then we can use the same protocol, saline injection and then collect the
data after every single use.

And I want to make a note here. If you are using this device between
users, we are to sterilize the device.

And then the second thing is if you want to look at the potential for
HBV transmission, we have to change the population now. We have to think
HBV positive volunteers, but we can follow the same protocol.

So these procedures, actually, that I haven\'t proposed this but this
has been discussed before by, for example, Dr. Bruce Weniger at CDC. He
discussed this at Global Vaccine Research Forum in 2004 in Switzerland.

So this is all of the aspects that we have to think about when you
develop a strategy. So I want to stress the points again. What are the
constraints for developing a safety evaluation strategy? There are many
unknowns. Only animal studies, no clinical studies other epidemiology
studies. But if you look at the proposed number of HBV copies required
for transmission, there\'s 10 picoliter maybe inaccurate. So we have to
realize what is the lowest limit of detection that we want to achieve.

Then other test methods available to achieve the required limit of
detection, there are test methods but what is the limit? That is the
thing that we need to look at.

Then, again, one other point I want to stress here is that impact of
dilution factor that has to be accounted for. If picoliter blood is the
one that can transmit the HBV, can this be measured correctly when
diluted in the ejected, that is one that goes into the device. So these
are all the questions to ask yet.

So coming to the summary \-- next slide, please. So this presentation
summarizes the current available methods that can be used to assist the
safety of MUNJI devices. And we have HBV model, it\'s a good HBV model
for evaluating the contamination. And there are test methods available,
but none of these test methods are validated. And then we don\'t know
what the transmission limit we need to look at.

So based on this it is not clear that these methods can be applied to
the investigation of potential cross-contamination by MUNJI devices.

Thank you.

CHAIRMAN EDMISTON: Thank you very much.

MR. LIPMAN: All right. That brings us to our panel questions.

The first is identify the scientific questions that need to be addressed
to demonstrate whether MUNJI devices are safe for multiple patient use
in the United States.

Second, discuss the adequacy and feasibility of the currently available
methods to assess the potential for cross-contamination and the risk of
disease transmission by MUNJI devices.

The third, Feinman, et.al. in 1984 suggested that a volume of blood as
small as 10 picoliters can transmit hepatitis B virus in chimpanzees.
However, this finding is based on a single animal study. Considering the
potential public health benefit of MUNJIs is there a threshold volume of
blood contamination that presents an acceptable risk? If so, what
threshold would be considered acceptable?

CHAIRMAN EDMISTON: These questions will be part of the Panel
deliberation this afternoon, and they will be repeated again.

Before I go any further, I\'d like to ask for clarification from Dr.
Lin. In our discussion as we go through this this afternoon are we
addressing those pre-amendment devices that are currently in circulation
or are we considering answers to questions that will be incorporated
into future guidance documentation?

DR. LIN: I think that the answer is both. As you know, the pre-amendment
device legally it is still considered legally marketable. Every
presenter also mentioned that we also has clear some of those MUNJI
device after 1972. So when in your discussion you have to consider all
those potential \-- all those legally mandated device. So that
discussion will be built into our guidance document in this area.

CHAIRMAN EDMISTON: At this time I\'d like to invite the members of the
Panel to address any questions that they might have to the presenters
from the FDA. Yes, Dr. Word?

DR. WORD: I have a few questions. One, if you\'re looking for new
indications or seeking new, I guess, MUNJIs, or that they\'re all
referred to that; are you looking to utilize them in one segment of the
population or the entire population?

I guess my question because I come from a pediatric background. Are you
saying do you want it for everyone or do you want it just for adults?

MR. WATSON: Actually, I think the answer would be any suggestions you
wold have in that are would be helpful. Right now they\'re generally
used. There\'s no restriction on pediatric or adult. The assumption is
any appropriate patient that can be used for that vaccine this device
can be used on that patient.

So if you have suggestions about that, maybe you think there\'s a
population that is best suited for this, we\'d be grateful if you\'d
offer that suggestion. But to answer your question, right now they\'re
generally used. There\'s no restriction whatsoever on who these devices
can be used for.

DR. WORD: I guess the next question I had was when you looked at safety
with your chimpanzee data, you talked about I think it was 10 picoliters
were considered acceptable? Anything below that would be acceptable. But
yet you stated also that it was known to transmit hepatitis B even if
you went below that. And so I didn\'t quite understand how that number
10 came about. And the reason I say that because if you\'re looking at
using it in a population, we\'ve had universal hepatitis B immunizations
for the last 13 years. So we have all children up to 13 and we\'ve had
catch-up, and we don\'t have others. And as one of the public speakers,
we don\'t have hepatitis C that\'s routinely done.

And I guess my question, and I don\'t really know what the obstetricians
do, I don\'t know if they routinely screen for hepatitis C. I know they
do hepatitis B, and they may not do hepatitis C routinely. I don\'t
think they do. And if that\'s the case, then that may not even answer
the question if you\'re talking about using MUNJIs. You might talk about
hepatitis B, but still doesn\'t address hepatitis C.

MR. WATSON: Right. I think I might defer that question to Dr. Bezabeh.

My understanding of it is hepatitis B is the most virulent of the
strains and that\'s why we were looking at hepatitis B. But I\'ll leave
that up to Dr. Bezabeh.

DR. BEZABEH: Yes. What Tony said was right, you know. People have looked
at hepatitis B virus because it was the most high infectious and it\'s
easy to measure.

The 10 picoliters was from one study in 1984 trying to measure the
minimum amount of blood that can transmit infectious particles. And
serial dilutions, they have it right at 10 picoliters. But to our
knowledge there\'s no safe limit, accepted safe limit that would be
safely transmit between injection devices. And that\'s why one of our
questions is because what is an acceptable safe limit of blood?

CHAIRMAN EDMISTON: Are there any other questions from the Panel members?
Ms. Petersen? Mr. Layton?

DR. LAYTON: Yes, I have a couple of questions. The first is relative to
the intended use of the device. Are there separate \-- are any of these
devices, or are there separate indications depending on the use with
respect to intradermal, intramuscular or subcutaneous or can the same
device be used for all injections?

MR. LIPMAN: We do usually have different testing for those different
indications. Basically, that would be based on the depth of penetration
and the ability to get to the desired tissue that the injector is
indicated for.

DR. LAYTON: So there are different standards from that perspective?

MR. LIPMAN: Right.

DR. LAYTON: Thank you.

The second question goes back to the 2004 WHO International Conference.
Did they recommend a particular test method? I missed that if that was
\-- they did not? They recommended studies, but not a particular test
method.

Thank you.

CHAIRMAN EDMISTON: Dr. Arduino?

DR. ARDUINO: Mine go along with whether it\'s intradermal or
subcutaneous, whatever, intramuscular. For each jet injector are there
different settings that you could set or are they separate devices?

MR. LIPMAN: We\'ve actually reviewed devices that have \-- I mean, there
are a variety of means to deliver at different depths. I\'m familiar
with different size orifi, orifices, whatever the word is. Different
injection techniques potentially \-- I don\'t particularly know how
accurate the method is, but pinching the skin to actually attempt to
create more tissue to inject into versus, you know, letting the injector
just inject directly into the skin to reach, say, an intramuscular
injection versus a subcutaneous injection.

Does that kind of \--

DR. ARDUINO: Yes.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: Just a question related to, say, let\'s say if these MUNJIs
were available, one of the things when you looked at the adverse
effects, because when you came up with the swine flu, one of the things
that crossed my mind immediately is that I don\'t know what my mother
received, but I know she told me she thought her arm fell off when she
got her flu vaccine in \'76. And I don\'t know if they used one of
those. But if you\'re dealing with adverse effects and if you\'re saying
you\'re looking at who is administering them, because you\'re going to
have some of that variability. So I\'m wondering I don\'t know how you
control for that.

I mean, I can control for it, but easier with an injection. And with the
other, I\'m just not sure how do you control for that or have you
thought about how you control? Or when you talked about contamination,
how often do you check to see if there\'s blood in there?

MR. LIPMAN: The users of these devices would definitely ensure that at
least by visual examination that there is no blood remaining on the tip
of the injector. But I mean there\'s the potential for it to get back
into the fluid path. You can\'t always visually identify that there\'s
any presence of contamination present. And that\'s kind of the issue.

CHAIRMAN EDMISTON: Dr. David, do you have any questions?

MR. DAVID: Yes. I have three questions. One relating to previously asked
on the intended use, and mostly on the definition that you give the
MUNJIs. And my question would be why not look at some of the
cross-contamination principles and look at the device definition by the
way of possible contact with the skins exist. For example, devices that
might have continuous jet flow, devices that might have various distance
gap producing mechanism, etcetera, etcetera. And that would allow,
perhaps, some better design of devices and validation of their
performance because you\'re preventing cross-contamination to begin
with.

So that\'s one question.

MR. LIPMAN: We actually have representatives here from a company who is
having to design based on those ideas exactly. Felton International is
present here, and they will probably talk a little more in detail about
the testing they\'ve done on their jet injector. But, I mean, they do
actually create a gap. They have disposal skin contacting device you
have to inject through certain layers to actually get to the body; the
idea being that it would be much more difficult for any of the stream or
blood to get back up through that small orifice that\'s created by the
jet and into the fluid path.

So they have attempted to minimize it, but the question still remains
how can we evaluate whether or not they have mitigated that risk
sufficiently.

MR. DAVID: My second question relating to your conclusion about the
single MDR report that cross-contamination was result of improper use.
And since we are reviewing what is considered proper use, I wonder had
you reached that conclusion?

MR. LIPMAN: It actually wasn\'t even a MUNJI device. It was a device
that had \-- actually it may have been a MUNJI device. But either way,
it was supposed to be used for one person only and then either
sterilized or replace the fluid contacting components. But instead, the
device was actually used for five patient consecutively, and that
wasn\'t the way it was supposed to have been done.

MR. DAVID: I will go back to my first question that I\'m not sure that
the definition of low load and high users is appropriate.

MR. WATSON: I\'m sorry. We have some more information on that last
comment.

DR. BEZABEH: Just to clarify the MDR report. It did not document any
closed contamination. There was just misuse. So there was no documented
transmission or infectional cross-contamination.

MR. DAVID: My third question is about the effort that FDA put into
looking historically since it was noted here that the DoD has
significant amount of data use of MUNJIs, what are the effort the FDA
puts to review that source of data use of MUNJIs?

MR. WATSON: We primarily looked at what was out there in the literature
that the DoD had published.

We haven\'t actually received anything directly from DoD regarding
safety information about MUNJIs. Most of \-- well, whatever the DoD
wants people to know is out there in the published literature. Whatever
other information is available, may or may not be available to FDA
directly. So we\'ve primarily looked at what\'s in the public domain.

CHAIRMAN EDMISTON: Any other questions from the Panel members? Dr. Lin?

DR. LIN: If I may, just to add to FDA\'s comment. I think probably for
the Panel members probably need to be recognized that this is a 510(k)
device. It\'s close to 510(k) device and I think that the previous
presenter has mentioned that we are talking about substantial
equivalence; that means that you\'ll compare the new device with the
current market device. You can even compare with a pre-amendment that
earlier, like in 1950 something, those device. That\'s, as I mentioned
before, is still considered legally marketed device.

So now when we compare so called substantial equivalence, that means
that the manufacturer would have to establish that they are as safe, as
effective as those legally market device we call predicate device.

So that\'s the concept how we so call create this device for marketing.
And now that the question is what is considered the criteria to
establish a safe as effective, that\'s the issue. That\'s what we try to
address. Because the science changed when we review, like early in the
\'80s or \'90s as compared to now. The emphasis is quite different,
particularly for in person disease prevention control, quite different.
So that when you discuss the FDA\'s question, please keep that in mind.

And then second comment I wanted to help with that, I think Dr. Word,
you mentioned about the use and how FDA treats the users participating.
That\'s most of the time when we do reviewing, we will look at the
user\'s instruction or labeling. And that is also the area we would like
to hear your input, too. When we create a guidance document, what kind
of information we need to ask manufacturers to clearly indicate in their
labeling that we would appreciate your input in that regard.

Thank you.

CHAIRMAN EDMISTON: Now your statement about equivalence really relates
to the delivery of an effective vaccine dose or whatever you\'re
delivering. It\'s not addressing the concept of infectivity or safety
from that perspective, correct? But as the last surviving member of that
1999 Panel, it looks like we have a lot more data available to us for
consideration than we had six years ago. And the question that I rally
have is, you know Mr. Hooks\' presentation was compelling. However, it
was anecdotal to the point that we don\'t have any real evidence
relative to risk.

And I suspect my question is with the devices that are currently in
place, as any assessment been made in terms of the relative risk
associated with the use of these devices in acquiring an infective dose
of whether it\'s hepatitis C, hepatitis B or HIV?

MR. WATSON: Shewit, what do you think about this question? Is this a
question that you might be able to answer?

I just want to make sure I understand your question. Are you asking
about the effectiveness of actually delivering \--

CHAIRMAN EDMISTON: No, not at all.

MR. WATSON: Okay.

CHAIRMAN EDMISTON: What we\'re talking about now, because I think
that\'s the issue that we have to separate here. We\'re not really
concerned about to a great degree the effectiveness of delivering an
appropriate dose of the vaccine. What we\'re concerned with is how
effective is the device at preventing the transmission
cross-contamination of an infectious entity.

So my question is relative to \'99 when the committee requested a some
postmarket surveillance be done, has any consideration been given with
the devices currently in place what is the relative risk of acquiring an
infectious agent with the current device in place without realizing that
to a great degree the risk is associated with the compliance and how the
device is being used? So has any consideration been made of what this
relative risk might be?

MR. WATSON: I think Dr. Michaud might have an answer for us here on that
one?

DR. MICHAUD: Ginette Michaud, Deputy Division Director of DAGID.

I think it\'s very hard to answer your question. The reason we\'re here
today is to get advice from and recommendations from the panelists as to
how we should best assess the risk of cross-contamination due to MUNJI
devices, or that potential risk. And so it\'s very hard not knowing the
answer to that how would we determine the relative risk as compared to
the earlier designs of these devices.

CHAIRMAN EDMISTON: I appreciate that comment. And this goes back to my
first question to Dr. Lin. So therefore our deliberation will have a
profound effect on devices currently in place?

DR. LIN: Right.

CHAIRMAN EDMISTON: All right.

Yes, Dr. Word?

DR. WORD: Perhaps you stated this and maybe I don\'t recall. How many
devices are actually being utilized? Because when I looked at it, you
said that there were a number of \-- you know, CDC recommended it only
for risk, you weigh the risk and benefits. WHO doesn\'t utilize it. And
I\'m not really concerned about their use, because it doesn\'t effect
the United States right now. I know the impact that we have will
eventually have a global effect, whatever recommendations comes from
here.

How many devices are actually being utilized?

MR. LIPMAN: I can\'t speak precisely to the number of devices that are
being marketed. I can tell you what I\'m familiar with.

We have cleared two dental devices for delivering anesthetic during
dental procedures that are MUNJIs. We haver four cleared, at least four
cleared MUNJIs for mass immunization intended use. Of those four, there
are most likely I\'m thinking two that are probably \-- since there are
actually, you know, these WHO and CDC policies against using these
devices, the manufacturers have, obviously, had a very difficult time
marketing their devices within the United States and the world. So I
think Felton actually may be able to give you a better idea for how many
devices are actually being used and whether they\'ve been able to market
their device.

MR. WATSON: One thing to keep in mind is that even though these products
may not be widely used anymore, we\'re still getting submissions for
them. And to the extent that we have to evaluate them, we would like
some input on what you think we should be doing here. Because we\'re
still a clearinghouse for the world, the FDA. So even though they may
not be necessarily marketed here, companies will come to the FDA to get
clearance because the idea is get clearance and FDA and a lot of the
rest of the world will accept that. And we would like to be certain that
whatever we\'re clearing is something that we consider clinically
acceptable here, not just based on previous standards for clearing these
products.

So the actual number, we don\'t really know that. We don\'t really have
records for that here. But we do know we get asked to clear them. So
that\'s sort of one of our concerns.

CHAIRMAN EDMISTON: Dr. Butcher, do you have a question?

DR. BUTCHER: It\'s been answered.

CHAIRMAN EDMISTON: Are there any further questions by any members of the
Committee?

I think we\'ll move on to our next presentation from Dr. Martin Friede
from the World Health Organization.

DR. FRIEDE: Well, thank you very much for inviting me to attend this.
And I would like to reiterate something that was said a few moments ago.
The recommendations from this Panel will have a global effect.

So, first, I\'d like to apologize. I have modified my slides slightly
compared to what you received. And this is because I learned last night
that Dr. Weniger was not able to attend. So I have added some more
background slides. So I hope this does not effect what you have too
much, but there is some more data.

So if we\'d please go into the first slide.

So we\'ve already heard quite a lot of background about the early
history of safety concerns. And, unfortunately, my eyes are getting
worse and worse with age. I can hardly read that myself. But let\'s go
through this.

If we begin around about 1959 there was already an evaluation done using
precipitin test for human serum. And this really showed up negative. And
this group in 1959 were also unable to transfer hog cholera from one
viremic pig to another. So this was really the beginning of the
evaluation of safety.

In 1962, though, Eli Lilly & Company, I\'ll show you this in a moment,
but on their inference of product insert, that bleeding could occur and
that this would carry a risk of hepatitis, and that it recommended to
the doctor that if blood was observed, then resterilization should be
done.

1970 bleeding was noted on the nozzles, on the skin and blood on the
nozzles. And it was hypothesized that disease transmission could occur.

And in another 1970 paper there was an increased detection of albumin on
nozzles.

And 1981 there was a study done, this time negative, no hepatitis B
surface antigen detected by radioimmunoassay after injection of just two
volunteers, both of whom were hepatitis B carrier patients.

Next slide, please.

So I certainly can\'t read this, but I know what\'s written there. This
is the product insert from the 1962 package from Eli Lilly and it states
somewhere there under red lined that if bleeding does occur, and
bleeding does occur sometimes with jet injection, then the nozzle should
be resterilized. So there was recognition then that hepatitis B
transmission could take place.

Next slide, please.

Well, I think the change to the world jet injection took place in 1985.
And in 1985 suddenly we had evidence of risk. This was the very well
known case of the weight loss clinic in California where a hepatitis B
outbreak took place. But I would like to emphasize, this is a fairly
unique situation. These were people coming back time after time. I
believe it was 15 to 30 times over a two months period. Back to the same
clinic where they were being injected in the same small population where
there must have been one high titer carrier that was there who could
reinfect this population. Also, one this one single device and was this
device being properly used. So this opens up a lot of questions of how
to ensure that devices that may appear to be safe, how do we ensure that
they are being properly used and how do we ensure that they are
retaining their safety over time and in the hands of everybody?

Next slide, please.

This is some data taken from that California study. Printed in the
*Morbidity Weekly Report*. And this shows that when the jet injector was
no longer being used in that clinic, we began to see a decline over the
next several weeks of hepatitis B onset. So this was really the proof.
But we must recognize that this is not quite the same situation as
immunization where you typically go and get one injection, maybe once
per year.

Next slide, please.

So after 1985 the world changed slightly, and suddenly people really
began to look at what were the risks of using these. And, again, I\'m
stretching my eyes to see this.

1985 there was a demonstration done that the LDH virus, this is a mouse
lactic dehydrogenase virus, could be transmitted experimentally between
mice using a jet injector. Again, a comment here. How does the thickness
of the skin of a mouse represent a model for human beings? And if you
were to give a mouse a jet injection with an injected aim to give
intramuscular injections, this would probably cause a tremendous damage
to the mouse.

1980 hepatitis B was found on the skin on the site of injection, however
it was not found on the nozzles of the injection.

1994 this was a study by Mr. Brito. Blood detection in the ejectates. So
the volunteers were injected and then the next shot was p ut into a
tube. And they were using the forensic occult blood detection stripes
which measure about 2,000 picoliters as limit of detection. And in
roughly one percent of the ejectates, blood was detected.

Now this introduces the concept of picoliters. We\'ve already heard
brought up this concept 10 picoliters is the minimum level of blood that
can transmit infection. I hope that in my presentation I will show you
that this is not a scientifically sound observation, but we will see how
we can address this.

So already at 2,000 picoliters, one percent of the ejectates did have
blood in them.

1997 a VEE virus was transmitted between animals using three Russian jet
injectors, one of which I understand is the originator of the Felton
device which has subsequently been prior approved.

1997 a very interesting paper published from Bulgaria, Dimache, et.al.,
this was in *Vaccine*. Now this is interesting because no hepatitis B
transmission was observed in population. So this is a field study.
38,000 intradermal injections were given with a disposable spacer, which
they claim was something like a protection cap. And this is very
interesting. We\'ll discuss this in a moment as to what this does not
mean.

2001, this has already been mentioned, a meta analysis of hepatitis B in
Brazil showed that people who had received the yellow fever vaccine via
a jet injector were much more likely to have also been infected by
hepatitis B.

Then two studies that I will briefly discuss have already been
discussed. 2001 the calf model, serum albumin was detected in the
ejectates, and that\'s an unpublished data already discussed about a
clinical model.

Next slide, please.

So in the calf model what was done here is that four different injectors
were used and saline was injected into the calves and then injected into
a tube. And using a calf or a bovine serum albumin assay looking to see
what was taking place. What is important out of this is that you see
that there are a lot of samples that have between 10 and 50 picoliters
and quite a lot that have between 50 and 1,000 picoliters of serum
albumin. So this shows that all four of the old model jet injectors were
transmitting quite often quite a significant amount of blood. Certainly
what we would consider to be an infectious level of blood.

Next slide, please.

Now this is unpublished data. Again, coming from Brazil using, again,
old model injectors. And when I refer to \"old model injectors,\" I am
comparing this against improved injectors that may be available soon.

What was done here saline was injected into the volunteers and then
three injections were made sequentially into a tube. And using a human
serum albumin study looked at how much blood was there. Now this study
had, apparently, a limit of detection of 10 picoliters. So wherever you
see something positive, it simply means greater than 10 picoliters.

And what we\'re seeing here is whether it was wiping with the nozzle or
wiping without the nozzle, we had between 7 and 11 percent of the
ejectates were contaminated with blood. However, what was also done in
this study was injecting saline into the tubes before injecting people.
And you see there are positives there. So this really begins to question
this assay. We were getting false positives here. And I will discuss
this later. But the reliability of this assay is doubtful.

Next slide, please.

So what has been the reaction of the public health organizations? First
of all, we\'ve had over 2 billion immunizations given worldwide from
1952 to 1990. We\'ve had warnings on the risk of blood transmission.
We\'ve had the hepatitis B outbreak. So in 1987 WHO recommended
restricted use of these devices. And finally in 1996 we actually
recommended against the use of these devices.

And from 2000 to now there has been the development of new generation
devices aimed at overcoming these safety concerns.

Next slide, please.

So I\'d like to summarize and the rest of the meeting summarizing a
meeting that we had in March 2004 which was aimed specifically at
determining the safety of these new generation devices. And by \"new
generation devices\" I mean devices that are aimed at overcoming these
safety concerns; that have a built in safety device.

The questions are how infectious is blood? How do we measure it? How do
you model the risk? What level of risk is acceptable? And our
conclusions.

Next slide, please.

So this is, I think, possibly my most important slide, is how infectious
can blood be? We\'ve already heard that hepatitis B is far more
infectious than hepatitis C, which is more infectious than HIV. And
there is a CDC reference for this. Now we\'ve heard the statement that
10 picoliters is able to transmit infection to a chimp. This comes from
the Bond, et.al. paper 1984. Ten picoliters could infect one picoliter
could not. However, this was one study on one sample. So it means for
that sample of serum had that type of viremia, 10 picoliters was able
to, one picoliter was not. And that\'s all that means.

So at the meeting last year we tried to answer the question of how
infected is hepatitis B. And you see over on the right hand side a graph
which is taken from the Lindh paper. And this shows two lines. The upper
line are people who are HBE positive with the HBE antigen. And it shows
their viremia in terms of genome equivalence per milliliter. The average
is around about 10 to the 9. It goes up to 10 to the 11. However, we
also heard at the meeting last year that in rare cases when people have
both HIV and hepatitis B, viremia can go up far, far higher; 10 to the
12, 10 to the 15 even.

So for the rest of this discussion I have just assumed that 10 to the 9
is an average amongst these HBE positive carriers. And we have done a
bit of modeling and assumed that hepatitis B carriers, of these 20
percent have high viremia, and this 10 to the 9.

And the conclusion of this is that a fraction of a picoliter can
transmit infection. So if you haver a viremia of 10 to the 9, this means
you have one genome equivalent per picoliter. But there\'s a
probability, of course, that you may have more than one genome
equivalent per picoliter because you never know how these things are
being distributed. And also you may run into somebody who has a viremia
of 10 to the 15, in which case one picoliter may have a very high number
of genome equivalence.

So the next slide, please.

Because of the recognition that we have to go below 10 picoliters, we
were looking at assays to measure blood contamination. Now the human
serum albumin assay had been developed as a surrogate marker. Since
human serum albumin is the main protein component within blood, it was
felt that this was a good target to be going for to measure how much
blood could be on the nozzle. This was developed by Kings College in
London.

And an improved assay was developed by them where they claimed they
could develop, approximately they could detect approximately three
picoliters. That was limited quantification, limited detection, about
one picoliter. However, as has been already mentioned, serum albumin is
everywhere. It\'s in our spittle, it\'s on our skin, it\'s in our hair.
And for example, dead skin may not have any probability of transmitting
infection, but it will give you a positive single. So this presents a
lot of problem using the human serum albumin assay as a surrogate marker
for blood.

Also, when WHO sent this assay out to two independent laboratories, we
discovered that you could not validate this assay and it was the
independent laboratories gave limited protection or limited
quantification between 15 and 30 picoliters. So it was therefore a
requirement for a more reliable and more sensitive assay.

Ideally, we need to be able to really measure infectivity. Measuring
blood volume, per se, doesn\'t tell you much. So we felt that a PCR
analysis of, for example, the hepatitis B virus from highly viremic
carriers, this gives you an idea of really how much, what\'s the
probability of getting infected.

Next slide, please.

Here this shows the comparisons. When the Eli Lilly product insert said
if you see visible blood, resterilize it, that\'s about 0.1 microliters.
There\'s a limit of what you can see. Chemical blood tests is about .01
microliters. Measuring surface antigen with an analyte is about .001
microliters. The albumin assay, 15 to 30 picoliters. And we believe that
using modern techniques you can detect hepatitis B virus at about 3
genome equivalents. So this would be about 3 picoliters of that high
titer serum.

So we then tried to \-- since we accept that you can get disease, you
can get disease transmission with less than 10 picoliters, the question
is how do you model this risk? We have to have an idea of what risk is
there with one picoliter. What risk is there with .1 picoliters? And
this begins off with the assumption that risk of getting hepatitis B
virus is proportionate to the endemicity. It\'s logical. If you are in a
room where 50 percent of the people in the room are hepatitis B carriers
and you will be receiving a jet injection subsequent to one of them, you
have a higher probability than if you\'re in a room where there is only
1 per 1,000 with this. So that\'s logical.

In the USA you have less than 2 percent carriers This is WHO figures. In
Africa, Sub-Sierra in Africa, there are between 8 to 20 percent of the
population that are hepatitis B carriers.

So let\'s go into some very rough modeling. This was presented at the
meeting last year. And I\'ve just tried to summarize this taking one or
two examples. If, this is a very big if, if each injection transmitted
.5 picoliters, now this would be safe by our PCR assay that I just
discussed which is measuring about 3 genome equivalents. So .5
picoliters would pick up nothing. We would say safe.

If 2 percent of the population were carriers and if 20 percent of these
were HBE antigen positive, in other words high titer carriers, then also
if one ID50 was 10 genome equivalence \-- I should mentioned that WHO
tried to find out from hepatitis B experts what is the ID50. How many
genome equivalents does it take to transmit infection?

We heard from Bob Purcell, not at the meeting. This was by oral
communication he gave us. That 10 genome equivalence may do it. We heard
other experts said maybe a 100 genome equivalence do it. So we don\'t
really know. But we\'re taking a worse case scenario and say 10 genome
equivalence could transmit infection.

Now, we can do some mathematics on this. And this would say that on a
population with 10 to the 9 genome equivalence per millimeter, which is
your high titer carrier, one ID5 would be 10 picoliters. But what
happens if you are giving less than 10 picoliters? So we worked out a
mathematical formula which tries to express the fact that this is not a
linear decrease, but we expressed the probability that N ID50s give you
an infection as being one minus, not 25 to the N.

You could also get roughly the same number by just dividing the number
of microliters or picoliters that are being given by the 10 picoliter
sample, which contains your ID50.

In this case the probability of infection on receiving .5 picoliters
from a higher viremic carrier is .034. And then to calculate the
probability of infection, you have to work out what is your probability
of this person being in line in front of you, which is the probability
of having your hepatitis B carrier there and the probability that that
hepatitis B carrier is a highly viremic carrier times by the probability
of the .5 picoliters carrying an infectious dose. And this comes to \--
you\'ve got the numbers written there. .000132, which means that they
could be up to \-- and I emphasize up to 132 infections taking place per
million injections.

However \-- next slide, please \-- I\'d like to really show the caveats
of this. First of all, the ID50 that I took there was 10 genome
equivalents. This is the most infectious that we\'ve heard from. Other
scientists have said it\'s more like a 100. So this would bring us down
to 12 infections per million.

Now, first of all, the studies that have been done including the Bond
study in 1984, the serum was injected intravenously. Now when we give
jet injectors, this is not intravenously. So it could be that by giving
nonintravenous delivery, we are also going to decrease the infectivity
by not getting to the blood, not getting to the liver. So this could
drop this down even further.

Also, there may be other factors such as drying. The numbers that we get
there, this is the worst, worst, worst situation, the worst case
scenario possible. It assumes a linear risk. It could very well be that
below a certain viral load the risk may be infinitesimally small. And it
also assumes that every ejectate is contaminated. So that is the caveat
for this and it gives us a number.

Now let\'s look at risk assessment in field trials. I already discussed
briefly this Dimache study 1997. This was a slightly new generation
injector. It had a disposable spacer. It was not really a protector cap.
38,000 injections were given in adults. This was in Bulgaria where the
hepatitis B endemicity is 5 percent. And these volunteers were followed
up for six months to determine how many cases of hepatitis B virus
infectivity took place subsequent to the immunization, which could be
ascribed to cross contamination. And absolutely none took place. No
observed hepatitis B infection in vaccinees. However, this was a low
volume injector. It was delivering .1 to .2 mls intradermally. This is
not the same as the studies we talked about previously which were
typically intramuscular or subcutaneous with 0.5 ml. Intradermally one
could imagine a lower splash back.

Zero out of 38,000 observed infections. The upper 95 percent interval of
this is 4 per 38,000. So we could be having a risk of really 1 per
10,000, risk of infection and still observe zero to 38,000 in a field
trial.

So the field trials to prove safety would require very careful design to
give power. And I think this is one of the real difficult questions
here. When we\'re dealing with such low figures of shall we say 10 per
million or a 100 per million infectivity as being the possible risk of a
device, how do you see this signal above the background noise?

If you go to Sub-Sierra in Africa where you have a background and a high
rate of infectivity taking place, you have a high noise. So how would
you see your relatively big signal. If you do this in the USA where you
have a relatively low background, you will also have a very relatively
low signal.

Determining your signal to noise ration in a field evaluation is going
to be exceptionally difficult.

Next slide, please.

So the conclusions of the WHO meeting were that sub picoliter levels of
blood can transmit disease. Ten picoliters is not a scientifically valid
number.

Available blood markers, which were the serum albumin, are inadequate as
surrogate markers of safety. However, PCR detection of hepatitis B from
highly viremic carriers is much better.

It is feasible to evaluate safety for a small sample size by PCR.
However, how does one take into account device aging and device
misfunction? And I\'d like to bring up a question here for your
consideration, which is how do you determine the reliability of the
safety mechanism? You may prove that your device is safe in a small
trial of a 100 people, but how do you determine that the device is
reliable over a long term? This would probably require ex vivo and in
vitro studies, but this will have to be considered.

We also concluded that it would be very complex to evaluate safety for a
large sample size. So, first of all, going from this small field study
using highly viremic carriers to the population which you\'re actually
using the device in the population, we could not determine the ethical
pathway to get there.

Next slide, please.

So, WHO position. The determination of the safety of MUNJIs is the
responsibility of national regulatory agencies. WHO will not determine
the safety. This is the responsibility of the national regulatory
agencies.

Secondly, if used property needle injection is safe. Now this is a big
if. We know that the injections are not always done properly and we know
that disposal is not always done properly. However, if done properly it
is safe.

To the WHO is not acceptable to replace injection by a technology for
which the safety is questionable. So while we have questions on the
safety, it is not acceptable to replace needle and syringe.

Needle-free vaccine delivery is desirable. We recognize this. If we can
get rid of needles from the immunization program, this would be
fantastic. Given for the moment the questions on the safety of MUNJIs,
we believe that disposable cartridge injectors where there is no
reusable path or appropriately safe alternatives, whether or not
they\'re cost effective is another issue. We are evaluating the use of
these for vaccine delivery.

Now, I\'d like to finish. Next slide, please. With two slides. First of
all, these are the points for consideration.

We\'ve already heard about the advantages: There\'s no sharps, there\'s
no waste, it\'s fast and it is low cost, very low cost per injection.
The comment to this is that there may be a risk. Whether the risk is a
real risk, whether it is a risk that is perceived by the population,
this could really be inhibitory of these devices.

Daily cleaning and sterilization of the fluid part is required and there
may be a risk if this is not properly performed. We know that ensuring
the use of syringes properly is difficult ensuring safe cleaning of
these multiuse devices may be complex. And we also face the problem of
the cost per device.

Under what circumstances is high speed injection required? It\'s
required really where you have a low ratio of health care worker to
population or where you have centralized, not dispersed health care.

And finally, what level of risk is acceptable? So I think we really have
to balance the risk benefit here. Needles injection is not always
performed safely. Needle stick injuries do occur. Needle disposal is not
always performed safely. However, for the individual, an individual
receiving an injection from a sterile needle and syringe runs no risk.
So we have to look a the risk to the individual compared to the risk to
the population, and I think that is a question for the Panel.

Thank you very much.

CHAIRMAN EDMISTON: Thank you very much for traveling to Washington and
making this presentation.

At this time this presentation is open for any consideration. Do any
members of the Panel have any questions for Dr. Friede? Yes, Dr. David?

MR. DAVID: I have two questions. One is relating to the comment you made
about the disposal cartridge. What do the study looked at when they
looked at this puzzle card as far as volumes and so on?

DR. FRIEDE: There has not yet been a study. We are beginning to evaluate
these.

MR. DAVID: So your statement about it is an alternative safe is based
on?

DR. FRIEDE: It\'s simply because there is no reuse of the fluid part,
there is no reuse of the nozzle. There cannot be transmission of blood
from a nozzle because the nozzle is not reused.

The definition of a MUNJI was given previously, earlier on this morning,
as being one where the fluid part is reused. In the disposal cartridge
the entire fluid path, the entire \-- the whole fluid path, the whole
nozzle is used once and cannot be reused.

MR. DAVID: I see. So the whole fluid path is replaceable then, that\'s
the point?

DR. FRIEDE: Completely.

MR. DAVID: Okay. And if we can go back to your risk model slide. Where
was it.

DR. FRIEDE: Next one. That\'s right.

MR. DAVID: Can you just take me again through the ID50 argument.

DR. FRIEDE: Okay. The one figure that we received from Bob Purcell
suggested 10 genome equivalents is an ID50. So let\'s just take that as
a starting point. Other people have said 100.

Now, if you have 10 to the 9 genome equivalence per milliliter, this
means you have one ID50 in 10 picoliters. In other words, if you receive
10 picoliters, you have a 50 percent probability of becoming infected by
definition of the ID50.

So the question is if you receive less than ten picoliters, if you
receive one picoliter, what is the probability in one picoliter that you
are going to have ten genome equivalents? So this is our applying the
statistical laws.

You have a random distribution of your ten genome equivalents per \--
I\'m sorry, your 10 to 9 per milliliter. What is the probability that 10
genome equivalents are going to be found in one picoliter?

MR. DAVID: Okay.

DR. FRIEDE: The way to do this is to use that formula. Okay. This is an
expediential formula. So the probability that you will find an ID50 in
one picoliter is going to be 1 minus now .5 to \-- it\'s going to be one
divided by 10.

MR. DAVID: So you\'re making actually two arguments. One is the volume
of the injected and the other one is the site intramuscular or
intravascular as two mechanisms?

DR. FRIEDE: The caveat is this concept of 10 genome equivalents, this
comes really from intravenous studies. And it could very well be. I\'m
putting this as a caveat, as a scientist, that when we deliver this
intramuscular and it doesn\'t get straight into the capillaries or into
intravenous system and go to the liver, it might take a far number of
genome equivalents. This is a worst case scenario if you take all
available data that we have. So we\'re really looking at what the worst
number could be.

MR. DAVID: Okay.

DR. FRIEDE: And with that number, you see that your signal is quite
small and it really opens up the question of how would you see this in a
population.

DR. ARDUINO: But when we get to risk, because I\'m doing some stuff with
biodefense stuff, an ID50 may not be acceptable. What happens when if
you shift the curve and want to look at an ID10 or an ID1? Well, your
number gets how many \-- you know, it gets a lot smaller, doesn\'t it?

DR. FRIEDE: It does. I put this really as a method of looking at it. Now
those numbers there are not validated numbers. These were numbers that
we put up as a method of approaching this to enable you to accept the
fact that 10 picoliters is not a number, is not suddenly that below 10
picoliters nothing happens. Things can happen below 10 picoliters. We
need to determine what is the worst probability that something will
happen?

CHAIRMAN EDMISTON: Any other questions from the Panel members? Dr.
Layton?

DR. LAYTON: Yes. I have a question on the risk assessment, the Rumanian
study where you talked about the lower splash back risk than 0.5 ml
intramuscular and you had a question mark. Would you care to elaborate
on that relative to this intradermal versus intramuscular and any of
your observations or knowledge relative to the knowledge relative to the
level or degree of splash back?

DR. FRIEDE: That I put up \-- we have it on the slide.

This is, as a scientists, I just imagined that if you inject .1 ml
intradermally, you\'re going to have a much lower risk of forcing body
fluids back up onto the nozzle than if you inject a larger volume
deeper. Intradermal probably shouldn\'t really be giving you any blood,
and there\'s not much going in. The volume coming back is probably going
to be a function of the volume going in, and also the elasticity of the
tissue that it\'s going into.

So I think looking at this study it\'s an interesting study, but as I
said there are two caveats here. One is it\'s intradermal and low
volume. And what I really wanted to bring this up for is that seeing
zero in this population doesn\'t tell you a lot.

DR. LAYTON: Thank you.

CHAIRMAN EDMISTON: Any other questions?

I have a question. From your perspective what troubles you about these
devices? Is it their design or the hydraulics? Because obviously these
devices are not going to go away, especially in a circumstance where we
need mass immunizations.

DR. FRIEDE: Okay. There\'s two things that worry us. And I give you the
official point of view here.

The first one actually is to do with the maintenance of these. That in
the populations which are our responsibility to reintroduce a cleaning
procedure which has to be done, and the maintenance, this is a very big
problem for us.

The second problem is that while there is concern of safety, any
concern, for us to impose on countries to use this device just carries
an enormous risk that until we get really clear evidence or a clear
consensus that this is safe, it is going to be difficult for us to
recommend to countries to use this. Because any incident that took place
would come back and we would struggle to say we confident that that
incident, your infection, did not occur because of the device. So until
then we are standing by our policy, which is that immunizations will be
given with auto-disabled syringes. And that the auto-disabled syringes
will be provided with sharps disposal boxes to try to ensure that sharps
disposal is done correctly.

CHAIRMAN EDMISTON: If the devices are used in a compliant manner the way
they\'re meant to be used, do you think the devices are safe?

DR. FRIEDE: The devices that we have seen without a protection cap, we
have data from the calves and the data from the Hoffman study in Brazil
to show that frequent contamination of the ejected did take place. And
that contamination was clearly of a level of blood that we are convinced
can carry disease. So the devices which do not have a protection cap
which are to be used for giving intramuscular injection we are convinced
that these carry a significant risk.

CHAIRMAN EDMISTON: Okay. Any other questions by members of the Panel?

Well, thank you very much for your time.

I\'ve been informed that we can do lunch. Actually, we\'re about half an
hour ahead, which is terrific.

I\'d like to invite you all to lunch, and we\'ll meet back in one hour.

Is industry going to be making their presentation? Is 12:00 fine for
industry presentation? Is everybody here. Okay. Well the plan at this
time is to reconvene at 12:00 and begin our industry presentations.

Thank you.

(Whereupon, at 10:58 a.m. the meeting was adjourned, to reconvene this
same day at 12:00 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

12:05 p.m.

CHAIRMAN EDMISTON: I would like to now call the meeting back to order.

I\'d like to remind the public observers in the audience that while this
portion of the meeting is open to observation, public attendees may not
participate unless specifically requested to do so by the Chair.

We will now continue with industry\'s presentation related to today\'s
topic. And we have Mr. Darin Lee Zehrung, did I pronounce your name
correctly?

DR. ZEHRUNG: That\'s correct.

CHAIRMAN EDMISTON: He will be addressing Program for Appropriate
Technology and Health.

DR. ZEHRUNG: Thank you.

Do I have to make a conflict of interest statement at this time?

CHAIRMAN EDMISTON: Yes, we would appreciate that.

DR. ZEHRUNG: Well, PATH is a nonprofit organization, nongovernmental. It
is focused on improving health in the developing world. And we\'re
actually working with a couple of different needle-free injector
developers, one of which is Felton International, and that\'s the
technology that I\'ll talk about today. It\'s a collaboration with
different developers that includes a development portion as well as
clinical testing. But we do not receive any funds from these
manufacturers, and actually we\'re self-funded by different donors.

Next slide, please.

So, as I said, PATH is a nonprofit organization. And this is our
mission: To improve the health of people around the world by advancing
technologies, strengthening systems and encouraging healthy behaviors.

Actually, I\'ll hold there.

We\'ve actually been involved in the development of safe injection
technologies for the past 20 years, either disabled syringes, Uniject
which is a prefilled injection device, sharps disposal technologies all
focused on improving immunization safety in the developing world. And I
work within a program called Technology Solution within PATH, which is
that is our prime mission.

Next slide, please.

So we talked about this earlier today. What\'s the technology need for a
high speed needle-free injector? There\'s the application for mass
immunization campaigns. In the developing world examples are measles,
yellow fever, meningitis and there are other examples. There are also
emerging vaccines that in the development pipeline that could also be a
good application for high speed, high throughput, high numbers of
injections for those in the developing world such as meninge which is
focused on West Africa, malaria vaccines and also human papilloma virus
vaccines.

Pandemic outbreak is also another key application for this technology.
Influenza, you know we\'ve read these recent articles about avian flu
and the potential for outbreak.

There\'s really not a technology that exists that could provide high
throughput, mass immunization to those vulnerable populations, either in
the developing world or in the United States or Europe, for that matter.

Bioterrorism response is also another important application. And I think
that I\'d actually like to hear from others that represent perhaps that
perspective to see if this technology or what their plans would be to
respond to an outbreak or even a bioterrorism attack.

And then there\'s the military application. Although we heard about
earlier issues with devices, the first generation MUNJI devices, so to
speak, there could perhaps still be a need for a high speed injector in
the military.

Next slide.

So this is actually a slide that I received from Dr. Bruce Weniger, and
unfortunately he could not be here today. He\'s actually Mr. Needle-Free
Injector at CDC. And I think he has a very prominent position in the
needle-free injector community. And he\'s done a lot of work on looking
at the efficacy of needle-free injectors in delivering multiple
antigens. So this is a list. And I think we saw an earlier version of
this in a presentation this morning where there is great historical
evidence, over decades of use, needle-free injectors delivering
different vaccines. Perhaps with the new combination vaccines and newer
vaccines in development there is not this clinical history, but it\'s
clear that needle-free injectors are effective in delivering vaccines.

Next slide.

So this is a technology that we are collaborating with in terms of
Felton International. They\'re the manufacturer. And, actually, if there
are more specific questions about the technology, I would defer to my
colleague Dr. Anatoly Loskutov from Felton International who could
perhaps provide more in depth answers.

I\'d like to point out that we see this technology as a design hybrid.
It\'s really not a MUNJI. There is a reusable fluid path, yes, but
there\'s not direct nozzle to skin contact.

The key feature of this technology is that it utilizes a protector cap
as a disposable shield. And actually I\'ve passed around samples of this
protector cap to the Committee members. This shield is intended to
prevent cross-contamination. And we\'ve been involved in collaborating
with Felton over the last several years, a combination of in vitro and
in vivo testing to build the safety profile for this technology to
demonstrate that it does, indeed, prevent cross-contamination.

The current spec for the device is that it has a fixed half cc dose.
It\'s intended for subcu delivery, which most of the developing country
mass immunization campaigns deliver a half cc subcu dose. But with
different orifice sizes you could either achieve an intradermal dose or
intramuscular. We focused on subcu for the current specs for the
technology.

And it\'s hydraulically powered. It does not require electrical power.
It utilizes a foot pedal and hydraulics which compressed a spring within
the hand piece. That provides the energy then to provide the injection.

And we\'ve targeted in terms of the spec six injections a minute. Now,
it\'s not as quick as the earlier first generation MUNJI devices, but
it\'s more rapid than needle and syringe delivery. So, therefore, still
we would consider it a high workload device.

It also requires steam sterilization of a reusable path. Let me point
this out here.

So this is the hand piece here. This is the fluid path portion. So
that\'s detached from the hand piece, cleaned and then steam sterilized.

And actually, I think Jason Lipman mentioned this, there are few
technologies, MUNJI devices that have received 510(k) clearance
post-amendment era. And this technology is one of them. Well, actually
last year in 2004 this particular design received a special 510(k)
clearance based upon an earlier 510(k) clearance for a device called the
BI-3M, which was originally a Russian design. Dr. Loskutov comes from
the original design group, and perhaps he could talk about that for
those that are interested.

Next slide.

So unfortunately, I had a video demonstrating the technology. It
doesn\'t work. So what I\'d like to offer is for the Committee members
that are interested \-- okay. Well, for the Committee members, I\'d like
to offer I could bring my laptop to show you the operation of the
technology. And then, again, anyone from the public observing, if you
have questions please feel to contact me or Dr. Loskutov and then we\'ll
demonstrate the technology.

But basically the protector cap is placed on the nozzle face. Let me go
to the next slide. It incorporates a space between the nozzle and the
injection site. The injection stream passes through a thin polyethylene
film. And once the injection stream penetrates that film, that enters
into the tissue. And any splash back, any contamination is then
contained within the protective cap. And for the next injection, the
protector cap is discarded and a new sterile protector cap is placed on
the nozzle face.

Another key feature about this protector cap is that it\'s
auto-disabled. Once you eject it from the nozzle face, it\'s disabled so
that if you were to put it back on the injector, you could not provide
an injection through that spent protector cap.

One key features and perhaps Anatoly could speak to this that\'s
development now and it will be available for the next design iteration,
is an interlock which would require placement of a protector cap on the
nozzle face for the device to operate. So perhaps, Jason, you\'ll see
that in a subsequent submission.

So in terms of the benefits of the technology, a key feature: Prevents
cross-contamination. It uses a protector cap. And I think that the PATH
position is that we believe that this technology can be demonstrated to
be safe. We could talk about the safety design, we can talk about sample
size, but we have the confidence that this technology could have great
application and would be a safe technology eliminating needles from use
in mass campaign scenarios.

It\'s also high speed, as we talked about. It allows for rapid response.

One key feature and one feature benefit that we see is that it protects
health care workers. There\'s no risk to needle stick injuries. And in a
mass campaign when you\'re dealing with large numbers of individuals, at
least in the developing world, we have mountains of sharps waste that
you need to discard it. And Dr. Friede had mentioned that the current
policy is to bundle safe injection boxes, sharps waste boxes, with those
auto-disabled syringes. But there\'s still the potential for health care
worker needle stick or for community needle stick injury in terms of the
general public.

Many times these syringes are buried in a pit behind a health care
center or there\'s an attempt to incinerate them or burn them. Many
times unsuccessful. So that there is a general need, an acute need, for
a needle-free technology.

Next slide.

So, are main focus in this project has been to conduct safety testing of
the protector cap injector, the Felton device. This project has been
funded by the Bill and Melinda Gates Foundation. He\'s very interested
in this technology for mass immunization.

And there have been a number of in vitro and in vivo studies that we\'ve
conducted. What I\'m going to present are our recent studies. There are
studies that we have conducted over the last several years that I won\'t
discuss today, but if you\'re interested I could provide that
information after the meeting.

So fluorescein testing as a simple model. I think earlier we talked
about the challenges of identifying an appropriate animal model. Our
focus has been to focus on a bench test model using a very sensitive
assay and marker to demonstrate that there\'s cross-contamination that
does not exist.

And then the focus our human safety testing has been hepatitis B virus
detection. You know, from the WHO meeting that was held last year, we
took that input and we focused on a method, identifying a method that
could be used to detect hepatitis B virus in subsequent injections.

Next slide.

So for the fluorescein safety testing we use a very highly concentrated
fluorescein dye, and that\'s a surrogate for high titer HBV infection.
And the detection limit of this current approach is .04 picoliter.

I think that we\'ve talked about picoliters and volumes of infectivity
throughout the meeting. And I think that for some it might be a little
unclear, but really what it means is that it\'s about 100 fold more
sensitive than available PCR methods.

The original design of this fluorescein test focused on the 10 picoliter
threshold. But given the input last year at the WHO meeting, we put that
aside and just focused on if anything could be detected with the method,
then that would be the definition of contamination. So I think that the
current results that I can show you demonstrate that with the protector
cap injector there\'s no cross-contamination in comparison to predicate
devices such as earlier MUNJI devices there is demonstrated
cross-contamination.

The samples that are generated in the PATH laboratory are sent to a
third party laboratory, MDS Pharma in the base outside of Seattle,
Washington. And they use their equipment to analyze samples.

Next slide.

So thanks Dr. Friede, he gave me this slide earlier today. So I would
like to stress my appreciation for this.

What I want to point out is that in comparison to the other
contamination assays that Dr. Friede had presented, the fluorescein
assay really exceeds the PCR methods in terms of a detection limit. So
it\'s very sensitive, it\'s very specific in terms of an assay. And we
believe a good surrogate aside from human testing to demonstrate
cross-contamination safety.

Next slide, please.

So you may not be able to see these pictures. This is a first generation
MUNJI device. I think that those are familiar with these technologies
know what that device would be called. And you can see after injection
into the test fixture, there is contamination at the injection site.
There\'s a combination of splash back as well as contact contamination
during the injection process. You see that it\'s contaminated with the
fluorescein dye.

The same is true for the protector cap injector. This is the protector
cap on the nozzle face itself. It\'s hard to see in this photo, but this
protector cap post injection into the test fixture is also contaminated.
But the down stream sample collected after injection into the text
fixture is demonstrated to be free of cross-contamination.

Next slide.

So this is a slide showing the comparison of first generation MUNJI
testing with this method versus a protector cap injector. These are the
number of samples. So for a 100 samples with the first generation MUNJI
device, all were contaminated, a 100 percent with an average
contamination rate of 268 picoliters. In comparison with the protector
cap injector for 300 samples, all samples were free of
cross-contamination.

So the conclusion is that the protector cap prevents fluorescein
contamination of the fluid path. And, again, we believe that this is a
very useful and powerful method to demonstrate contamination risk with
the earlier devices and then lack of that risk with the new generation
protector injector.

Next slide.

So for human safety testing, as I said, we\'ve been focusing on
detection of hepatitis B virus. And given the recommendations from the
WHO Committee from last year, we focused on recruiting high titer
individuals that have greater than a million copies per ml and injecting
them with buffered saline, and then collecting the next dose and
assaying that for presence for Hep B and A.

Currently we\'re implementing a pilot study in Pasadena, California at
the Huntington Medical Research Institute, the Liver Center there.
Working with Dr. Myron Tong.

We\'re focusing on recruiting high titer volunteers, as I said, but also
to HBV negative volunteers as controls. And one key feature of this
study is that it\'s a nonsignificant risk study by our definition, that
the fluid path is sterilized between use with different volunteers. And
so there\'s no chance of cross-contamination.

We\'re using an assay that was developed and actually licensed for use
in terms of blood screening products in the United States by National
Genetics Institute. It\'s called Ultraqual. And it\'s also a NAT assay.
It\'s a nucleic acid test. So it\'s a very sensitive test. And I have
results from a validation study that was conducted last year prior to
initiating the safety study which was started September of last year to
demonstrate the sensitivity and the limited detection for that
particular test.

This did receive both PATH IRB as well as Huntington IRB approval. And
we\'re currently continuing to recruit volunteers for this study.

Next slide, please.

So, the study endpoints primarily is to determine if there\'s HBV
contamination in down stream doses. But secondarily, we\'re also
assessing the pain of the injection site and any injection site
reaction. So that\'s also collected in terms of the study, the
information from volunteers.

As I mentioned, there\'s two sterile saline injections per subject, one
in each deltoid. So after injection into the deltoid, the NET is
collected. And then that\'s sent off to NGI for testing.

There\'s also four negative control samples per volunteer that are being
collected. Two injector samples prior to injection into the deltoid that
are collected to demonstrate that the injector is free of
cross-contamination, but also to determine if there is any background
contamination of HBV in the examination room where the injections are
taking place. Also two air samples are collected. These are test tubes
that are left open in the test tube rack right adjacent to where the
injections are taking place in volunteers. Once the injections are
completed, then those are stoppered and the whole group of samples are
sent to NGI.

Additionally, another blood sample is collected the day of injections to
reconfirm titer levels. So for initial enrollment there is a blood test
that\'s conducted to determine titer level, and that\'s a condition for
enrollment into the study. And then the day of injections there\'s
another blood draw to demonstrate that there is still high titer viremia
in the particular volunteer.

Next slide.

So in terms of the assay itself, this is used for blood product
screening in the United States. And it\'s also uniquely used by the
Liver Center for HBV titer level determinations. It\'s part of their
clinical diagnoses screening. And HMRI has a close relationship with
NGI, and that influenced our decision to work with both HMR as well as
NGI.

It was validated for use in the pilot safety study last July.

And the mean sensitivity was determined to be 1.589 internationally in
its per ml, which is about 5.4 viral copies.

The 95 percent detection limit is determined to be 6.316 international
units, which is equivalent of 21.73 copies. So what it means in terms of
a half cc volume, it\'s about 10 viral copies that is reliably
detectable with this method.

Next slide.

So this may be a little hard to see. To date we have recruited five
volunteers. I have to say that it\'s been challenging to identify and
recruit and gain consent from volunteers.

You know, we\'ve talked about 10 to the 9th as an average in terms of
viral load, but in terms of this Liver Center and the majority if not
all the patients are hepatitis B infected, it\'s very difficult to
identify those that are greater than a million copies per ml. We have
identified several that have consented to be in the study; actually
three to date. And as I said, we\'re continuing to enroll subjects.
We\'ve also recruited our negative volunteers. So these volunteers 002,
004 and 005, those are hepatitis B infected individuals. You can see
that there\'s a range of 10 to the 6th, 10 to the 8th in terms of viral
load. All the down stream samples from the left and right deltoids have
been negative for presence of hepatitis B DNA.

So we believe that this is a very powerful method to demonstrate
cross-contamination safety with human volunteers focusing on the
infection of interest, hepatitis B infection and using a very sensitive
method for that detection.

Next slide.

So from that pilot study our plans are to then proceed to a larger scale
study that would be conducted in China. The reason for that is that in
China there is a very high prevalence of hepatitis B infected
individuals, more so than in the United States. There\'s also a higher
prevalence of higher titer individuals. And so we think that it\'ll be
much easier to recruit those individuals and then add to the safety
profile for the technology.

The current study design is focusing on recruiting 300 high titer
volunteers. Each volunteer would receive two injections. So it would
have a similar design to the pilot study. We\'re using the same assay,
and so the jet injector down stream samples that are generated in China
will be shipped to NGI for analysis.

The location will be in the Beijing area. And there are three sites,
three hospitals that are focused on hepatitis treatment that have agreed
to participate in the study.

And we\'re working with a clinical research organization. It\'s an MDS
Pharma office based in Beijing who help manage and coordinate the study
working together with PATH and Felton International.

And I\'d like to close by saying that the data that\'s generated, we
plan to submit that in a submission to a national regulatory authority,
perhaps it\'s the FDA, perhaps it\'s the Chinese SFDA. And we were very
supportive of the FDA\'s efforts to determine a pathway to demonstrate
safety of the technology. And we offer our assistance to help work with
your group to determine a way forward. And we firmly believe that there
can be a way forward to demonstrate that the technology can be safe.

With that, I\'d like to introduce Dr. Mark Kane, who is my colleague at
PATH. And I would say that he is a hepatitis B expert. He would like to
make some comments regarding earlier points that were made this morning.

Thank you.

DR. KANE: Thank you.

These are more observations of things I\'ve heard today and don\'t
represent in anyway any kind of official industry stance, but just some
comments that I had. I didn\'t know where else in the program to be able
to insert them.

I think in 1984 by necessity, because of the level of technology and
understanding, the issue of transmission was defined as a volume \--

CHAIRMAN EDMISTON: Excuse me. You\'re not on the list that we had here.
But I appreciate your being here. But could you make some statement in
terms of possible conflict of interest?

DR. KANE: Okay. My name is Mark Kane. I work at PATH, so I have exactly
the same conflict of interest profile as Dr. Zehrung. Also worked for 20
years in the hepatitis branch of the Centers for Disease Control, the
last ten of which at the World Health Organization.

CHAIRMAN EDMISTON: Thank you.

DR. KANE: Okay. I\'m sorry.

As I said in 1984 the issue is framed as a volume issue in terms of
picoliters of blood that may or may not be infectious, but we\'re way
beyond that now in our understanding of how many genomes and viral
particles might be in a ejectate. And so I think it is possible to ask
questions like given any level of detection in a test system what is the
probability that there\'s one infection dose in that ejectate. And it
seems to me that the sensitivity and specificity of some of the tests
that we\'ve seen discussed this morning would make that an answerable
question in the real world.

The second issue is that I haven\'t heard any reference to the
experience with blood screening using the ELISA test, which is approved
by FDA for use in screening all blood. I understand that certainly there
are many differences between the problem of preventing post transfusion
in hepatitis, but there are also are some interesting similarities. And
certainly infusing an entire unit of blood versus the volume of an
ejectate is relevant, too.

And basically, using an ELISA which has a sensitivity of hundreds to
thousands of picoliters equivalents has essentially eliminated post
transfusion hepatitis B in the United States. I think the latest
estimate that I\'ve seen from NAHs that residual and we may be getting
down into compliance error problems is about 1 transmission for 220,000
blood transfusion.

And so we have a test of orders of magnitude less sensitivity than the
current tests that are available that have essentially done in a public
health sense a very valid job in reducing the transmission of disease.

The next point has to do with the model that Martin presented. And when
you present a model, when you multiple the worst case scenarios for
every variable in your model, in this case probably ten, and present
that as the results of your modeling, I wonder whether a better way of
presenting a model is to take your best case estimates for every
variable, multiple them together, present that as the outcome of your
model. And then you can use the worst case scenario and even best case
scenario estimates as a sort of confidence interval. Because it seems
that the greater probability is that the amount of transmission that
would occur using our best knowledge of what those variables are would
be very, very much lower than the model that was presented to the
Committee by Martin.

And the position of WHO puzzled me. In a sense we were told that there
are 12 to 16 billion injections given int he world. That 50 percent of
them were estimated to be unsafe. Immunization injections account for
less than 5 percent of those 16 billion injections. And they\'re pretty
much the only ones that use AD syringes. The other 95 percent of the 16
billion injections rarely use any AD syringes, yet the WHO position is
that they cannot recommend the device with any theoretical risk of
transmission because if all needle injections were given compliantly,
there wouldn\'t be any risk. To me this seems really a lot like the
perfect being the enemy of the good. And I wonder if this Committee
would, you know, consider the realism of that.

And that\'s really all I have to say.

I think that there is a way forward, given our knowledge of the
infectivity of hepatitis B and the current sensitivity and specificity
of some of the tests that had been presented this morning. And I think
that as I imagine a scenario and a very bad weekend when 300 million
Americans need to be injected, and doing that with 300 million single
dose vials of vaccine with needles and syringes seems to me a very
unlikely scenario. So I think that there is a potential in this country
for a useful high load jet injector device. And definitely for mass
campaigns in the developing world.

So I would thank the Committee very much for the opportunity to address
you. Thank you.

CHAIRMAN EDMISTON: Thank you. At this time I think that there are other
public speakers, other speakers from industry who would like to comment.
But because these two individuals that have represented a single entity,
I\'d like to take a few moments now to ask the Panel if they would have
any specific questions for these two gentlemen. Yes, Dr. Butcher?

DR. BUTCHER: Yes. I just wanted to make sure when the presentation was
being made and I understand we didn\'t see the video, but is what
happens this is what you passed to us, this is taken off each time and
is this disposed or is this sterilized and then a new one put on with
every injection? Is that \--

DR. ZEHRUNG: Yes. Once the injection is provided into the patient, then
the device is reset. So the device ejects that spent protector cap, and
then that\'s discarded. And then a new sterile cap is placed on the
nozzle face.

And you can see in the packaging, actually the packaging comes in a tray
of 25 protector caps that can be broken into rows of five protector
caps. And so I passed some of the pathing examples around.

You would present or open one tray or one protector cap at a time, place
it on the nozzle face of the injector, provide the injection, eject that
spent protector cap and then open a new sterile protector cap and place
that on the nozzle face again and proceed with injections.

So for that, you know the process actually explains why the rate is
lower than the 900 an hour or whatnot that we\'ve heard with the earlier
MUNJI devices.

Does that answer your question?

DR. BUTCHER: Yes.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: I think I have two questions, and I think I just need
clarification.

From an industry perspective, and I think you partially answered it,
when I looked at where you\'ve done your mass campaigns, you\'ve been
administering things such as meningococcal vaccine, yellow fever and
polio. Polio is eradicated here. We don\'t have meningococcal, we\'re
not in the meningococcal belt. And we don\'t have yellow fever. So
essentially what the message I\'m hearing right now, because in the
beginning I wasn\'t sure what the question was and it sounds as if this
isn\'t something that you want for use in the United States, but you\'re
looking for use outside. So then my question really is what is it that
you\'re asking this Panel to do? Because why wouldn\'t it be for their
regulatory agencies of that specific country?

You\'ve alluded to the fact that oh we might go to China. We\'re
interested in hepatitis B, etcetera. What question do you have, and I\'m
not quite sure. Are we here just to provide advice? Because everything
that you\'ve said I don\'t see where this is going to be utilized here.

DR. ZEHRUNG: Right. Well, actually, I think that \-- let me clarify
again. I work for a nonprofit organization, so I\'m not an industry
representative in terms of being a representative for the manufacturer.
Our focus is health in a developing world. And so when I listed those
mass immunization campaigns, those are examples of applications for this
technology, at least as we see it. But there is also the potential
application for bioterrorism response or pandemic response in the United
States. That\'s something that we are interested in, but as PATH as an
organization that\'s not our focus. That\'s not the constituents that we
focus on.

But going back to the FDA meeting that was held last year, I think one
of the recommendations from that Committee was that WHO deferred to
national regulatory authorities in terms of determining the level of
risk and safety of the technology. So at least for the United States
it\'s the FDA.

For China, for instance, and we have already initiated discussions with
Chinese CDC and a specific program, immunization program representatives
of China. We\'ll work with their NRA to license this technology in
country working with the manufacturer. So we will be doing that
individual country NRA submission and interaction. But at least for the
United States, the question is as the Panel has laid out, is it safe for
the United States, what are the methods that could be used to
demonstrate safety. And, again, we defer to the FDA and the Panel to
determine that, at least for the United States. The United States is an
example around the world in terms of national regulatory authorities.
And many regulatory authorities would follow the FDA lead in terms of
demonstrating the safety of the technology, and there are many examples
of that.

So I think there is a connection, although as you say the focus for the
FDA is consumer protection in the United States.

So I hope that answers\--

DR. WORD: I guess, too, in all fairness for the FDA is it fair to have
them review and do all the work and not be compensated for it, for
something that\'s going to be utilized in another country? That\'s why
I\'m saying it may meet \-- like there are standards that will be set
for our government, but it may not be the same for the others. And
that\'s why I\'m saying is it not appropriate that you go to their
regulatory agencies and find out what\'s appropriate and acceptable for
that particular country? I mean, it sounds like you want them to do the
work and not get compensated.

DR. ZEHRUNG: No. I think that it\'s a combination of two approaches. I
think that direct country level interaction, which there\'s a different
risk benefit profile that they\'ll evaluate versus application of this
technology in the United States. So if the FDA can determine what that
risk benefit profile is and if it is appropriate for use in the United
States, that is information that would feed into a decision for a local
or like a country level NRA. Perhaps they won\'t agree with that.
Perhaps they would agree with a different risk profile calculation.

So it\'s a combination of the two approaches, I think.

CHAIRMAN EDMISTON: Ms. Petersen, do you have any questions?

MS. PETERSEN: Yes, I had a couple of questions.

First, with regard to the information about speed. The presentation
notes that the injector will do six injections per minute. Does that
include the time to eject the used cap, to \--

DR. ZEHRUNG: Yes.

MS. PETERSEN: \-- open another new one to put it on?

DR. ZEHRUNG: Yes. We\'ve conducted time studies in terms of using the
device. And with a proficient user, someone that\'s trained, they can
achieve the six injections a minute rate. So it includes placing the
protector cap on, filling of the dose, provide the injection, rejecting
the spent protector cap, opening the package.

MS. PETERSEN: And will the unit operate without a cap?

DR. ZEHRUNG: The current design \-- well, actually the design that was
cleared for market last year did not include an interlock feature. The
current design that will be actually used in the China safety study will
have an interlock. And so that it will require placement of the
protector cap on the nozzle face for the device to operate.

And it was part of this sort of the development pathway that felt, and
then perhaps Dr. Loskutov could speak to this, first demonstrating
safety in a small pilot study and then having that converge with the
design development effort to include more specific safety features such
as this interlock prior to actual market introduction.

And I should say that these technology is not being sold. It\'s not
being used in the world. We\'re actually working with the manufacturer
to build the safety profile. And we\'re looking for NRA approval and
also public health agency approval for use of the technology. So it\'s
not really being used. It\'s not delivering vaccines at the current
time. We\'re conducting safety testing.

Is that \--

MS. PETERSEN: And will the newer version with the prevention
capabilities so that a ap has to be used, will that be fairly easy for
an individual to modify so that caps are not necessary? I guess what
I\'m saying is can someone buy it and then get the safety mechanism off
the gun so they can use it without caps?

DR. ZEHRUNG: Well, I think the focus of the design effort has been to
implement an interlock feature that\'s very durable that would be very
difficult to disable. Now, with tools or whatnot, it perhaps may be
possible. But we\'ve been focusing on and working with the manufacturer
to develop a feature that would be as durable and as effective as
possible.

And if you\'d like to learn more, we could perhaps demo the device for
you. But that\'s been the focus. And actually that was a concern earlier
on pre-WHO safety meeting last year working with Dr. Bruce Weniger and
also Dr. Mark Friede at WHO that an interlock feature was an absolute.
If this device was going to be used in the developing world for mass
immunization campaigns, it needed an interlock. So we\'ve been focusing
on that as an effort.

CHAIRMAN EDMISTON: Dr. Word?

MS. PETERSEN: Do you have any sense of the cost of the caps? Say the
device approved and sent out for use, what the caps would cost?

DR. ZEHRUNG: That\'s a good question. The spec has been that the cost
per injection needed to be much less than the cost of an auto-disabled
needle and syringe, at least in the developing world. So the cost of
auto-disabled syringe is, perhaps, down to .04 cents, more likely .05 to
.06 cents range. It\'s been projected that the cost per injection for
this device with the disposable protector cap would perhaps be .01 to
.02 cents. So that\'s another benefit of the technology; that it\'s
extremely low cost. And not only is it needle-free, but it\'s comparable
to \-- well, actually it exceeds the auto-disable syringe costs, but
it\'s comparable to reusable syringe costs. So that was another spec
that we focused on.

MS. PETERSEN: And how does that cost compare with prior MUNJIs, the cost
of use?

DR. ZEHRUNG: Well, prior MUNJIs did not have a disposable component.
There were some components that needed to be replaced in terms of O
rings and whatnot, but those devices \-- and I can think of an example
of like the Ped-O-Jet, which was perhaps \$2,000; the per injection cost
amortized over the life of the device was very low, fraction of it
essentially. So it is more expensive than those earlier devices, but the
reason for that is that there is a disposable component, which is a
recurring cost per injection.

MS. PETERSEN: Sure. But in developing countries would not the
practitioners be comparing the cost of the previous device with the
lower cost to this new one that has the additional cost associated with
the cap?

DR. ZEHRUNG: That\'s a good question. Interestingly enough, given the
stop of using this technology in the developing world, there\'s been a
turnover with those health care workers, many of which are not familiar
with jet injectors. Those health care workers have either retired or
they\'ve gone on to different parts of their life. And so when we\'ve
interacted with health care workers in the developing world, you know
their first question is where is the needle. So that\'s part of also our
challenge is really reeducating in terms of the benefits for needle-free
injectors, be it this device or disposable cartridge injectors, as Dr.
Friede had talked about. And so there isn\'t that comparison.

Actually, the health care workers that we\'ve talked to, and also
program managers, their question is safety. They want to know that it\'s
a safe technology. They\'re concerned about speed, they\'re concerned
about using the device in terms of the logistics of cleaning and
sterilization. They focus more on that.

Many times it\'s not those health care workers or program managers that
control the money. It\'s actually further up the chain. So there\'s a
difference there. So there isn\'t that comparison that\'s being made.

CHAIRMAN EDMISTON: Dr. Layton?

DR. LAYTON: Yes, I have several questions. One relates to the bullet
point where you say prevents cross-contamination.

DR. ZEHRUNG: Yes.

DR. LAYTON: And can you say that it prevents splash back?

DR. ZEHRUNG: That is prevents splash back? Splash back occurs, the
protector contains that splash back and then that\'s discarded. So
splash back does occur during in the injection into tissue, but that
protector cap contains it. So the splash back does not contact the
nozzle face and then thus the fluid path.

DR. LAYTON: So it prevents splash back to the fluid path way in the
nozzle?

DR. ZEHRUNG: Right. So there is a reusable fluid path and the nozzle
orifice that generates the high velocity narrow injection stream, that
stream passes through the protector cap and into tissue. So the
injection site splash back or reflux is contained within the protector
cap.

DR. LAYTON: All right. Next question, is this \-- you\'ve only presented
information on subcutaneous. Do you have anything on intramuscular?

DR. ZEHRUNG: That\'s a good question.

Our focus has been as a design spec given the prevalence of subcu or
vaccines that are delivered subcu for mass immunization campaigns, we
would consider testing with an IM specific nozzle if that were
requested. But I do not have data on IM delivery.

DR. LAYTON: All right. Thank you.

The final question is either you or the FDA, possibly. You said you have
a special 510(k) and the label says that it\'s an IDE. Why? Why was \--

DR. ZEHRUNG: It\'s IEE.

DR. LAYTON: Why, if says an investigational device, limited by U.S. And
you said it was a special \--

DR. ZEHRUNG: Oh, the packaging for the protector cap. These are actually
samples that I passed out. So I\'d have to defer to Dr. Loskutov and
Felton International in terms of describing their current labeling and
instructions for use. But I just passed those out as samples.

DR. LAYTON: There was a 510(k) \--

DR. ZEHRUNG: Yes.

DR. LAYTON: \-- for this protector cap.

DR. ZEHRUNG: Actually, there is an original 510(k) for a device called
the BI-3M, which is precursor to this technology. It utilized a
different protector cap. And actually, the Russians over the last 15
years had identified this as a needed and started with very crude
protector cap designs, and it\'s been refined over the years.

So that original 510(k) was the basis for the special 510(k) that was
cleared last year.

DR. LAYTON: All right.

DR. ZEHRUNG: For this new device iteration.

DR. LAYTON: All right. Thank you.

CHAIRMAN EDMISTON: Any other questions from panel members? Dr. Word?

DR. WORD: Just a question about this cap here. You said it can\'t work
without it, correct? What happens if someone just forgets to take it off
and change it between the patients? I mean, is it designed that it only
can work one time?

DR. ZEHRUNG: Yes. The interlock feature requires that the user follow
all the steps for filling and ejecting the spent protector cap. So you
could not use the cap or use the injector again with a spent protector
cap. It would force the user to eject that spent cap.

CHAIRMAN EDMISTON: Dr. David?

MR. DAVID: Thank you. I have a couple of questions.

One, is you design associated with specific volume that the cap is
protecting or it\'s a general statement you have on your product?

DR. ZEHRUNG: Volume in terms of splash back or \--

MR. DAVID: In the injector?

DR. ZEHRUNG: Oh, you mean the fixed dose? Again, that\'s a spec that was
determined by the volume that\'s delivered in mass immunization
campaigns, which is basically \-- I mean that\'s a fixed dose that\'s
used in immunization programs as well as in immunization campaigns. So
other than perhaps BCG, all vaccines are delivered a half cc.

MR. DAVID: You mentioned sensitivity and specificity. I didn\'t
information relating to specificity.

DR. ZEHRUNG: Of the Hep B DNA tests or \--

MR. DAVID: On the fluorescein.

DR. ZEHRUNG: The fluorescein test? Well, actually, it\'s a very specific
test. And we have a report that we put together that I could provide to
you and the other Panel Committee members that goes into greater detail
describing that test.

MR. DAVID: My last question relating to user skills. And I think you\'ve
described it as logistics; things that involve with cleaning,
sterilization and maintenance of the device. The cleaning and
sterilization, your study included that just as part of a validating
study particle or that\'s a requirement?

DR. ZEHRUNG: It\'s a requirement. It was a requirement, actually, from
the IRBs that review the study protocol. And we conducted a test to
demonstrate that the fluid path can be effectively steam sterilized.
Through a third party laboratory we conducted bioburden testing
introducing bacterial contamination into the fluid path, following the
cleaning procedure in this and then also the sterilization procedure to
demonstrate that the fluid path post steam sterilization is sterile.

So not only is it a product requirement in terms of maintenance and
demonstrating the device, the fluid path can be sterile, but it was also
an IRB requirement to allow for approval of the study.

MR. DAVID: And how often would you recommend to do that?

DR. ZEHRUNG: It really depends on the usage, and actually that\'s
another design development effort that we\'re undertaking determining
what the maintenance life and cycle life would be for the technology. I
think that earlier devices there was this recommendation for daily
sterilization. We are determining study designs to demonstrate if after
using a particular vaccine, such as measles vaccine, for several hours
would the user have to replace that fluid path and use a new sterile
fluid path.

And actually I didn\'t mention this, but the idea is that with one
injector hand piece and foot pedal there would be multiple fluid paths.
So in a centralized facility, you would sterilize perhaps five, six,
half a dozen or more fluid paths and then that would be packed with the
injector and then sent out for injections on site.

So if a fluid path, either there was a malfunction or if by our study
results we demonstrate that it needs to be replaced more than daily,
then the user would then take the old fluid path off, put a new sterile
one on. And those sterile fluid paths, the intent is that they would be
packaged within a tyvek pouch, so then they would be sterile to the
point of use. Once the user is ready to use that fluid path, they would
open the pouch up, install it on the injector, prime the fluid path and
then proceed with injections.

MR. DAVID: Your mechanism, the interlock that you mentioned, so do you
have any estimate on a life cycle, how many uses?

DR. ZEHRUNG: Well, our target in terms of durability of the device has
been a quarter million injections. We have conducted some initial life
cycle testing, and that will be part of the design verification work
that will occur with the latest design iteration to verify that the
design does meet that design requirement prior to any introduction in
the marketplace.

MR. DAVID: Thank you.

CHAIRMAN EDMISTON: Any further questions by the Panel?

Thank you very much.

DR. ZEHRUNG: Thank you.

I understand we may have one or two other presentations from industry
representatives. Do we have any further industry representatives in the
audience? Raise your hand, please.

We have two? Could one of you come forward first and identify yourself?
And, again, briefly describe any potential conflict of interest?

MS. D\'ANTONIO: Yes. My name is Linda D\'Antonio. The name of my company
is DCI. And in terms of conflict of interest we\'re a needle-free jet
injector manufacturer. Not manufacturer, developer. We are working on
disposable cartridge needle-free jet injector.

And, actually, I wasn\'t planning to speak today but I just wanted to
address one point. This morning I think it was during Martin Friede\'s
presentation, there was a question that came up about high speed devices
and the multiuse nozzle jet injectors. And I just wanted to make sure,
to make clear that there are other high speed needle-free jet injectors,
those being the disposable cartridge type, which is the type that we\'re
developing.

Our company is developing a high speed disposable cartridge jet
injectors for mass immunization type use, for use in the military for
bioterrorism, preparedness kinds of things response. And so I didn\'t
have really more to say than that, other than just to simply make it
clear to the panel that there are alternative injection systems to the
multiuse nozzle jet injectors.

And I don\'t know if my colleague has more.

So if there are any questions on that, I would be happy to answer them.
But just my clarification.

CHAIRMAN EDMISTON: Thank you.

Yes. Come forward and please identify yourself. Again, identify any
conflicts of interest.

MS. CALLENDER: I\'m Kathleen Callender from Genesis Medical
Technologies. And we developed the Pharma-Jet injector and our
disposable vial.

I am President of the company, so I do have an economic interest in it.
Our family owns the majority of the stock.

And it\'s kind of been my mission to do this. I\'ve been working on it
for probably eight years.

Mine is completely disposable, and it\'s a one time use plastic
polypropylene vial. So our concept is to prefill it and to booster pack
it for ease in use in third world countries as well as in our grocery
stores and our flu vaccine clinics.

And we have been marching through the FDA, and got a long way to go.
We\'re cleared as a Class II medical device, but now I understand I have
to go through the Office of Combination Products.

So I just also wanted to let you know that there\'s some other people
out there that are trying to solve the problem of disease transmission
and trying to get rid of some of the needles in the world.

Thank you.

CHAIRMAN EDMISTON: Thank you.

Are there any further comments from industry? If that\'s the case,
let\'s move on.

I would now like the FDA to present the questions to the Panel. I\'d
like the questions presented in total, and then we\'ll go back and
discuss each question individually.

MR. LIPMAN: The first question is: Identify the scientific questions
that need to be addressed to demonstrate whether MUNJI devices are safe
for multiple patient use in the United States.

Second, discuss the adequacy and feasibility of the currently available
methods to assess the potential for cross-contamination and the risk of
disease transmission by MUNJI devices.

And finally, Feinman, et.al. in 1984 suggested that a volume of blood as
small as 10 picoliters can transmit hepatitis B virus in chimpanzees.
However, this finding is based on a single animal study. Considering the
potential public health benefit of MUNJIs is there a threshold of volume
of blood contamination that presents an acceptable risk? If so, what
threshold would be considered acceptable?

CHAIRMAN EDMISTON: Okay. Could we go back to question number one. And
let me comment before I open this to the Panel that the issue at hand is
really the issue of safety and cross-contamination. We\'re going to
address the issue of whether or not these devices are safe. And if we
have an issue regarding the safety of these devices in terms of
cross-contamination, then what the technologies or the tests that must
be applied to validate their efficacy?

Again, the first question: Identify the scientific questions that need
to be addressed to demonstrate whether MUNJI devices are safe for
multiple patient use in the United States.

And this time I\'d like to open this up to the Committee, the Panel for
any commentary. Yes, sir, Dr. Butcher?

MR. DAVID: Mr. Chairman, the thing that I would like to ask is that we
have a definition of the MUNJI devices now. We\'ve been presented with a
few hybrids or alterations or advances and all like that. Is all of that
going to come under the MUNJI device or we just sticking with MUNJI?

CHAIRMAN EDMISTON: We\'re focusing on multiple use devices.

MR. DAVID: Okay.

DR. ARDUINO: Well, I might as well start.

I think if you look at most of the studies, we\'re looking at a poor
surrogate of blood contamination. So instead of focusing on blood
contamination with the testing that is available now, supposedly
molecular testing for DNA, we should be actually doing more studies to
look at to see if we actually have virus carry over in your injections
or cross-contamination that way. Because I have problems with using
serum albumin. It\'s just too much of it could be leaked to too many
false positives. And if you look at some of the studies, even their
negative control \-- you know, some of the negative controls were
positive with those as using that. Or we have to find some other
indicator of blood contamination there.

So I think we should be looking at the infectious agent.

CHAIRMAN EDMISTON: Any further comments?

DR. BUTCHER: Well, again, my comment if to follow along with what was
just said, is that it seems as though all of the studies that we
listened to were previous studies and none of them seemed to be updated
and so forth. So it looks as though we\'re going to really need to have
some concurrent studies as to what\'s going on.

CHAIRMAN EDMISTON: Dr. Layton?

DR. LAYTON: Yes. In terms of scientific or engineering questions, I
think you definitely have to put some definition in to the three
different intended uses. And what I\'m saying that is intramuscular or
intradermal or subcutaneous may all require different volume ranges,
different pressure ranges. And these are going to play a role on the
amount of splash back and also the amount of potential contamination. So
definition needs to be established relative to what those performance
criteria are for those three different applications intended use.

CHAIRMAN EDMISTON: Let me ask this question and toss it out to the
Panel: Do you think that there is sufficient risk in the use of these
devices that warrant consideration of whether or not these are safe
devices as they currently exist?

MS. PETERSEN: I think it may be that if we provide recommendations, we
want to create recommendations that take into account different
scenarios under which they might be used in the United States. You know,
we keep hearing about the bioterrorism, and if you had to vaccinate
3,000 people or 300 million in a weekend how would you do that? And
that\'s certainly one scenario. And at that point we would be willing to
accept some level of risk that I suspect is very, very different for
wanting to vaccinate the 1500 first graders in some given town. And
it\'s handy to do it one day and kind of have it over with, but that\'s
not a pressing need. You know, if Junior can\'t be there Tuesday
afternoon between 1:00 and 4:00, it\'s not going to be a problem if
he\'s there Friday morning or next Wednesday.

What would be okay I think is very different in those two scenarios. And
there\'s also the question of how the military component fits in as
well. Because, presumably, that\'s not quite the same thing as the
bioterrorism scenario.

CHAIRMAN EDMISTON: So what I\'m hearing from the Panel members based on
not only the information that was presented but the information that
wasn\'t presented, is that there is a relative level of risk of
cross-contamination with these devices. And that either through increase
in technology or through possibly considering alternatives from these
devices, this is the direction we should be moving in. Is that correct?
Is that a fair assessment?

MS. PETERSEN: Can we quantify the risk associated with the various types
of MUNJIs and compare that to other possible devices and tie that into
how it can be used?

CHAIRMAN EDMISTON: Well, I think you brought up a very good point. And
where I\'m uncomfortable is that in looking at how these devices are
being used is to assess the risk, the true risk associated with the use
of these devices. And while I\'ve heard some compelling information
based on both personal and laboratory experiences, I\'m not really sure
from the epidemiologic perspective. I have a good handle in terms of
what the true risk is in the use of these multiple use devices.

I would personally like to see some additional data developed looking at
the epidemiologic nature. And I think that data is available in a
retrospective perspective to determine what the relative risk is.

Now, that\'s a sort of a personal perspective working in the area of
hospital infection control. But does the rest of the panel sort of have
a similar concern?

DR. ARDUINO: Well, some of the EPI study, or there\'s potential EPI
studies to actually go \-- if we look at, say, the VA and the data they
have with their elevated anti-HCV rates. If we were able to go back and
look back to see okay, now what were the exposures, are there other
compounding factors involved. And actually do some sort of formalized
study that actually then will put okay, we have these risks associated
with these \-- well, is there a risk with a certain type of device or is
it just the categories itself or are there other compounders in there?

CHAIRMAN EDMISTON: The reason I bring that up is that in every device
which is approved by the FDA is a package insert. And that package
insert has a practice in terms of how that device should be used. And
every device has potential for being abused.

And I think we\'ve had commentary from some members of the audience has
suggest, this should be fail safe device. I don\'t see that occurring
with the current pre-amended devices that are currently in the market.

So I think what I would like to see personally from my perspective is
some sort of epidemiologic data to really give me a sense of what the
true risk is within both U.S. populations and the populations that are
Dr. Friede is dealing with from the World Health Organization.

Dr. Lin, is that a reasonable question to ask?

DR. LIN: Well, that\'s your call.

CHAIRMAN EDMISTON: Well, you have to do the work, all right.

The other issue, this is sort of \-- Dr. Word?

DR. WORD: I\'m sorry. As you started to begin to break down the various
scenarios, which I think is very important, I\'m still not quite sure if
we utilize these same \-- you use these MUNJIs in adults versus
pediatrics, do I take a 2,000 gram infant versus a 50 kilogram adult, I
mean \-- I don\'t know if you\'ve looked at them in that population. I
assume you have. But I would like to see something in terms of pediatric
versus adults and break it down. Because most children are immunized by
\-- they receive the majority of their immunizations in the first two
years of life when they\'re receiving them. So if you\'re saying \-- it
sounds as if we\'re utilizing in the United States, it would be during a
situation where we would have to have a rapid mass campaign, and that
would really be limited to some type of bioterrorism type of thing.
Because if we had a pandemic with influenza, we wouldn\'t have the flu
vaccine available. It wouldn\'t be made anyway, so you couldn\'t
administer it. No one could make it that quickly. So you\'re looking at
something different.

But I also like your comment about why not test it not to look about see
if you isolate viruses. So I would second that and also just looking at
the route that it\'s administered.

CHAIRMAN EDMISTON: I think your comment would become appropriate as we
move down to the second and third question.

DR. WORD: Oh, I\'m sorry.

CHAIRMAN EDMISTON: The issue that you raise is the relative safety of
these devices, these multiple use devices in pediatrics versus adult
population.

If there is an issue of safety, and we\'re talking about
cross-contamination now when we use the word \"safety,\" then I suspect
what I would want to know is there technology available which would
allow you to retrofit, for instance, the pre-amended devices? I think
this is a compelling argument for using multiple use devices, but again
it doesn\'t address the pre-amended component. And I think that\'s an
issue we have to lay on the table because there are probably thousands,
if not hundreds of thousands of these devices still out there.

So is it possible to develop technology either similar to this or
parallel to this that would make these pre-amended devices safe? What\'s
the thoughts on that?

MR. DAVID: I agree with you, Mr. Chairman. I also would like to add to
the scientific and Terry said correctly the engineering question is also
looking at the life cycle. If we\'re talking about high pressure, high
flow devices it will be appropriate to look at benefit risk ratio when
the device is used for 100 thousand injection as compared to the first
or the second injection. And what is the performance effect of that? And
that question does not have an answer today.

CHAIRMAN EDMISTON: And does the risk decrease or increase with longevity
of the device?

MR. DAVID: Right. Correct.

CHAIRMAN EDMISTON: Are there any other comments relative to that first
question? Let me review that again; is there data available on the
relative risk of these devices within both U.S. and world population?
That would be important information to have from a scientific
perspective.

Number two, what data exists looking at the safety or the potential for
cross-contamination of these devices between both the pediatric and the
adult patient population?

Number three, if there is indeed a risk, what technology is available
that either is in place on new devices prior to approval or in devices
that could be retrofitted to the devices already that have been approved
through pre-amendment?

And the fourth, which is an interesting consideration, is that as these
devices age is there any data to validate the safety component of these
devices as they move through their life expectancy of 100,000 or 200,000
injections?

Dr. Lin, is the FDA satisfied with the response for that first question?

DR. LIN: Well, you want to put me on the spot.

CHAIRMAN EDMISTON: You\'re sitting at the table.

DR. LIN: Yes. I think this is probably is a very course of this and then
the recommendation.

CHAIRMAN EDMISTON: Having gone through this once before, what we\'ve
been presented with today at least in my mind has given me a better
concept of how we can crystalize some of these answers that we couldn\'t
do six years ago.

DR. LIN: Yes. But you looked \-- the bottom line of our question
essentially that, for example, today or tomorrow a manufacturer present,
such as one we have, but any new generation device come to us, then you
remind when we talk about fond memories, what type of an issue we should
ask the manufacturer to address other than, you know, we know that this
is some potential, whether it\'s perceived or it\'s real or a close
combination. But what type of question we should ask. I think you point
out \-- that\'s probably beyond what the pre-market review we can do.
But if somebody come to us, as I say, either today or tomorrow or in the
next few months, what type of questions, scientifical question we should
ask in view of those potential cross-contamination. You can help with,
that would be assuming \--

CHAIRMAN EDMISTON: Any more comments on that first question? Let\'s move
on to the second question.

DR. WORD: I know you\'ve asked about cross-contamination. Are you asking
us to specify what specific agents that we\'re looking for?

DR. LIN: No. I think it\'s scientific equation for some part right now.

DR. WORD: Okay.

DR. ARDUINO: Or the type of testing? Are you kind of aimed at, you know
\-- we know that splash back is a problem. What type of testing have you
done to show that the device does not get contaminated.

DR. LIN: Right.

CHAIRMAN EDMISTON: And this is from the manufacturer\'s point of view.

DR. ARDUINO: From the manufacturers.

CHAIRMAN EDMISTON: Because they\'re going to be responsible for
conducting these tests.

DR. ARDUINO: Yes.

DR. LAYTON: That\'s the questions that the FDA asks.

DR. WORD: Okay.

DR. LAYTON: Because they\'re asking those questions relative to
industry. And a lot of them is how much splash back does your new device
have and how does that compare to the predicate device.

DR. ARDUINO: And if there is splash back, what engineering controls have
you included your design to prevent contamination of the fluid pathway.
Kind of wind that up.

CHAIRMAN EDMISTON: Yes. That works well for the new devices coming.

DR. LIN: New devices, yes.

CHAIRMAN EDMISTON: But it doesn\'t address the pre-amendment devices.
And I suppose we could take a position right here that these multiple
injection devices are totally unsafe and they shouldn\'t be used at all.
But I haven\'t seen the data that compels me, at least from my
perspective, to agree with that. I mean, how do you feel about this as a
Panel?

MR. DAVID: I feel that you definitely raised the correct question, and
that\'s not only we looked at \-- reassociated with data that was
presented, but data that was not presented concerning. And my feeling is
that definitely we need to send a message of cautious \--

CHAIRMAN EDMISTON: It may very well be that based on these initial
questions that we proposed, especially the first question, is that the
risk is significantly high in selected patient populations. And based on
that, then possibly these multiple use devices may not be safe. But I
don\'t think we have that information at hand to make the decision, or
even to make that recommendation to the FDA.

DR. LAYTON: No. I agree. We don\'t have. But it\'s suspect.

DR. WORD: So would you consider any \-- say if you cultured, you did a
viral culture or PCR, whatever, and you isolated any virus, would that
be considered unacceptable? Because if I \-- you know, if it\'s 1 in a
million cases that it happens, if you\'re that one it becomes important.
But then, too, I may be willing to take 1 in a million, just like with a
lot of vaccines that have adverse effects, you have to do a million
people in order to see it to protect the good. So then if you limit it
back to the scenario that you would utilize it in the United States,
then you might say, you know this is worth it.

CHAIRMAN EDMISTON: You make an excellent point. Because it always comes
down to risk versus benefit. And it may very well be the vaccine itself
has greater risk associated than actually the injection component. So,
there\'s a lot of data we don\'t have here and hopefully we can develop
some of this data over the next couple of years.

DR. LIN: Well, but you know we probably cannot wait for another couple
of years. But, as I said, if the device come in, then what \-- for
example, present some of their test data. For example, they have a study
or have a full test, unfortunate that data is not available yet. But now
that the question \-- the submission come to us and not \-- like today
or tomorrow, then in your mind that as our FDA Advisory member, what
would you advise the FDA, what type of scientifical question would you
ask?

For example, as Dr. Wood point that maybe you have limited to certain
patient population or those type of questions. That\'s what we are
looking for, your recommendation.

CHAIRMAN EDMISTON: Yes?

MR. WATSON: I just wanted you to put yourself in the reviewer\'s
position. You\'re sitting at a desk, somebody drops this on your desk
and says, you know, evaluate this. What question would you ask of that
manufacturer. And I think you were going that route. I think I heard
some of the comments were heading now scientific testing, that kind of
thing. That\'s really what we want to know. Because we\'re in the
situation where we will see more, probably. And we want to make sure
we\'re at least asking the right question, realizing that maybe we
don\'t have quite yet the cut off levels, if you will. Maybe that will
come later. But having some appropriate questions to be asked will give
us a good starting point. And I think you started down that road. So I
just wanted to encourage that.

CHAIRMAN EDMISTON: Well, we know splash back occurs. We know it occurs.
And we know that there\'s a risk associated with that. We don\'t know
how significant that risk is. One tack you might take is that devices
that are being submitted have to have the ability to reduce the risk of
splash back. And that would be a reasonable expectation understanding
that splash back is a risk. So that fits into that technology component;
what technology is in place or can be placed, input in place with that
device, these devices that are coming along to reduce that risk of
splash back.

DR. LAYTON: But it has to be expanded to the extent that the splash back
is also over the performance characteristics of the device. The pressure
variation that the device sees, the shelf life or the number of uses.
Also the volume that it injects.

So splash back has to be looked under all of these conditions. splash
back leads to contamination.

CHAIRMAN EDMISTON: So in devices presented to the FDA, whether it\'s ID
subcu or intramuscular, that there has to be some performance criteria
to demonstrate that there is a reduction in splash back?

DR. LAYTON: Yes.

MR. DAVID: I\'m a little bit hesitant with the word \"reduction.\"
Reduction from 1,000 to 999.

DR. WORD: You have to define.

DR. LAYTON: Reduction from the predicate device, for one aspect of it.
If you have a predicate device to demonstrate, to be able to compare it
to. But the other aspect is, you know, just having the information on
splash back and relating into our next questions that we\'re addressing
provides a tremendous amount of information for them to help make a
decision.

CHAIRMAN EDMISTON: Any further comments.

DR. WORD: I guess I, too, am a little concerned about that word
\"reduction.\" Because it\'s non specific. I mean, they could down by
one percent, it would be reduced. So I don\'t know how \-- I mean, quite
honestly maybe I missed it or I don\'t recall anyone quantifying how
much splash back if you had. If they quantify how much splash back that
you\'re getting now from the one that you have \-- you know, I don\'t
know if someone picks an arbitrary letter \-- I mean, amount. I mean, do
you go down by 15 percent, do you go down by 25 percent? I mean, you\'re
setting a goal for something. Or something realistic.

CHAIRMAN EDMISTON: Well, let me do this: Let me bring Dr. Friede, can
you stand up by the podium. And I could I bring in the gentleman from
PATH, could you stand up next to him, please?

Here\'s the question. I\'m going to ask the question from the gentleman
from PATH. When you designed the system what was the percent reduction
in splash back within your system?

DR. ZEHRUNG: The goal was complete elimination of splash back in terms
of the contamination of the nozzle and the fluid path. In comparison to
predicate devices such as the Ped-O-Jet device and the earlier design.
Like, for instance, the fluorescein test, we used a threshold of 10
picoliters, anything below 10 picoliters was considered not
contaminated, anything above was contaminated. And the tests that we
conducted in comparison with the predicate device was to demonstrate
that at that definition of contamination, the device was free of
contamination.

CHAIRMAN EDMISTON: So you achieved greater than 95 percent reduction?

DR. ZEHRUNG: Yes. Yes.

CHAIRMAN EDMISTON: Dr. Friede, let me ask you a question. With that
expectation what\'s your thoughts on a multiple use device or a criteria
for the development of a new multiple use device that would assume a 95
percent reduction in splash back, be it IM, ID, substitute, subcu?

DR. FRIEDE: I think seeing the fluorescein data, this is the first time
that we have seen a test that appears to be repeatable, reliable, to the
extent that this does not require very, very complex technology that can
only be performed in one laboratory on earth.

So as a benchmark I would say this is beginning to look like a very good
benchmark.

The only concern that I would have as a scientist, and this a personal
view, is that we do not yet know how the in vitro splash back is
comparable an in vivo splash back. But I think this is the first time
that we have seen a test which shows really significant reduction.

Now to put numbers onto it, I don\'t know. But when you look at theirs,
it is zero contamination using the most sensitive measurement that we
have ever seen. So this appears to be a very good benchmark.

CHAIRMAN EDMISTON: Well, let\'s hold that assay component thought for a
moment when we get to our next questions. But in terms of a percent
reduction, this Panel has been asked to make recommendations to the FDA.
Do you feel that a greater 95 percent reduction in splash back is a
reasonable expectation given the current level of technology that\'s
emerging with these devices?

DR. FRIEDE: The data that was presented by Darin suggests a 100 percent
reduction in splash back.

CHAIRMAN EDMISTON: So you\'re recommending that we suggest to the FDA
that there should be a 100 percent reduction in splash back with this
device?

DR. FRIEDE: There is a test. It is relevance may be called into
question, but there is a test which achieved 100 percent reduction in
splash back.

I bring you back to the statement that was made, everything must be
viewed in risk benefit.

CHAIRMAN EDMISTON: It may very well be that a 50 percent reduction gives
you the risk benefit ratio that you need. That\'s the issue that\'s sort
of before us.

DR. FRIEDE: For each different scenario of acceptable risk.

CHAIRMAN EDMISTON: Yes.

DR. FRIEDE: When we\'ve heard it is completely different to be giving
little Johnny his measle shot or to be giving the whole population an
antiterrorism shot.

CHAIRMAN EDMISTON: So it would seem to me that in your population, the
population that the World Health Organization is dealing with, there may
be an intrinsically higher risk in some of those subset populations
compared to what we see in our own population. Is that correct?

DR. FRIEDE: I would say so.

CHAIRMAN EDMISTON: Therefore, the performance characteristics, because
obviously these devices are going to be submitted to the FDA and other
nations throughout the world will be using these devices, the
performance characteristics really should be applicable to not just the
populations here, but obviously the populations abroad, which will be at
a higher risk category?

DR. FRIEDE: Exactly.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: I guess I may not necessarily\-- I would suggest that we are
not here to approve or make recommendations for other countries. I think
they have their own licensing organizations. And that we, I think, as a
Panel for the FDA, that we should set the standard for what is
acceptable for the use in the United States. And then we say this is
what we will find acceptable here. If you choose a different scenario
outside in another country, then you go to \-- you\'re going to go to
their licensing agency. I think that\'s fair. But I think if we try to
break it down for every single \-- well, not every single country, but
for different regions of the world, I mean you could have a PI that\'s
so long or even just when they submit an application, it\'d be so long.
Plus, I go back to I don\'t know if necessarily fair that U.S. reviewers
have to do it for the rest of the world and not get compensated for it.

MS. PETERSEN: Perhaps one way to address that issue as well as to look
at the issue of risk and relative risk and what\'s acceptable when is
for the FDA to look very seriously at tying the use and restricting use
to specific scenario and saying for this purpose we\'ll look at this
way.

One concern that I have is that we go forward with this because of the
issues of injection in other countries and the genuine need in other
places to have such a system and our concern about bioterrorism, the
device gets approved and then suddenly it\'s being used in ways where
that risk is not really appropriate for the situation. Mass vaccination
of school children, for example, or pneumonia vaccine for older people
who may already be somewhat immunosuppressed or have other risk factors.
Where what we think is, ah, kind of, sort of, usually fairly negligible
for most of us is really much more significant of a risk. You know, to
tighten those approvals for use in particular scenarios and rule out
other uses so that we don\'t see the drift of risk into places where
it\'s not really appropriate.

CHAIRMAN EDMISTON: You know, in scenarios such as this is very, very
difficult to define a relative risk. And I\'m really uncomfortable from
my own perspective to recommend a percent reduction, not having all the
information at hand. I really believe we need to have a more sound
epidemiologic model that tells us what the relative risk is going to be
for these devices, and then base \-- base the performance criteria of
new devices coming forward, again, on that risk within those patient
populations.

MR. DAVID: Mr. Chairman, I agree with your comment. However, it seems
like that we are presented with technological options that we suggest
that we can at least as a benchmark achieve a tremendous reduction into
the 90, even 200 percent of the contamination due to splash back. So as
a Panel member, I would like to recommend that we will ask the FDA to
achieve this type of benchmarking in their consideration of the product.

CHAIRMAN EDMISTON: In terms of that assay, has that assay been repeated
by other investigators or is that a single observation from your group?

DR. ZEHRUNG: It has not been repeated. It\'s only been in-house work at
PATH over the last several years.

CHAIRMAN EDMISTON: You know, this really fits more into the assay
component. But I think we really need to validate that assay. And I
think the FDA needs to validate that assay either from other independent
investigators or in-house contractual sources.

But again, relating to the first question, are there any other issues
here within this first question that need to be \-- yes, sir?

DR. LIN: If you allow me, can I ask PATH presenter a question about \--

CHAIRMAN EDMISTON: Yes.

DR. LIN: Do you mind that I ask you question?

DR. ZEHRUNG: No, sir.

DR. LIN: And in your \-- I did not have a chance to hear that your
product called, but I have a question. The fluorescein dye that you use
is water-soluble or is it viscous?

DR. ZEHRUNG: It\'s water-soluble, yes.

DR. LIN: It\'s water-soluble. But how much of that would meet actual
blood condition, you know the blood is kind of viscous. And did you see
any difference, have you \--

DR. ZEHRUNG: That\'s a good question, and it goes to this issue of in
vitro and sort of replicating the tissue response. The resulting dye
concentration is very viscous, but in terms of comparison to blood, I
think that\'s an interesting point to pursue.

We\'ve focused on the test as a means to induce contamination of the
fluid path and using a marker that\'s actually very inexpensive and very
innocuous in terms of safety, and that could be easily detected. But in
terms of the protocol and the reports that we put together, we\'d be
more than willing to share with you.

DR. LIN: Okay. Thank you.

CHAIRMAN EDMISTON: I think in terms of this reduction issue, because my
colleagues really brought to my attention that reduction is not a very
finite terminology, but one of the other considerations is possibly a
significant reduction. A significant reduction in splash back compared
to predicated devices. And I think that would address some of the safety
aspects of this device.

I want to thank Dr. David for bringing that to my attention.

Yes, Dr. Friede?

DR. FRIEDE: Could I just make a comment on that? Imagine we have two
devices out there. And take the example of the device that was presented
where we have absolutely no contamination of the fluorescein, not
whatsoever. And then we have another device that\'s called X. And this
has a contamination of \-- it\'s significantly better than it was 30
years ago, but we are seeing that 1 out of every 10 shots is getting
contaminated, and it is getting contaminated with, let\'s say, 20
picoliters of what would be liquid. So let\'s say 20 picoliters of
blood.

So would you really consider allowing that device to be used when there
is a safer device available?

From my point of view and public health sector, I would be giving
recommendations to using the device that has the safer profile, even if
it was only safety in terms of theoretical safety.

MR. DAVID: If I can jump in. As a Panel member I\'m not convinced that
there is 100 percent safe device. This is a short description of a slide
that has not been validated. So I would love to believe that this the
mainstream rather the extreme, but we don\'t have data to say this is
the benchmark.

So I support your view and I would definitely look at the possibility of
looking at 100 percent reduction as the answer to the first scientific
engineering question. But I realize that we do not have sufficient data
today to ask for that. And by suggesting significant reduction with a p
value that is small, that\'s getting close to that.

CHAIRMAN EDMISTON: I think there\'s an underlying issue here that I\'m
uncomfortable to address, and I\'ll bring it up again, is that your
point is valid. And I think that as the technology improves, we\'re
going to see devices that have a significant impact on reducing splash
back. But what the predicated devices, the devices that are already in
the field? What can we do about those devices? And I think that\'s the
troubling component. Because as you remember asked Mr. Lin are we
talking about guidance for new devices or are we also considering those
devices that are currently in the field.

And my question that comes up is that I\'m not convinced that these
devices are totally unsafe from a cross-contamination perspective. I
think that when we look at the relative risk, and that\'s where I have a
problem. If I had really compelling numbers, and I\'ve seen some data
that suggests there might be a safety issue. But they\'re limited
studies; animal studies. And also possibly with the application of this
new technology, we may be able to get better data on whether or not
these devices represent a significant risk for cross-contamination.

It would be difficult for me to say at this time to the FDA, though
there are probably people in the audience who would love for us to say
this, that these multiple use devices are unsafe and should not be used
under any circumstance. You might be happy for us to say that, too. But
I\'m just not comfortable personally making that comment or unless my
Panel members feel overwhelming that this is the case and these devices
aren\'t unsafe.

DR. BUTCHER: Mr. Chairman, what I would say is that the standard should
be set and the preexisting devices should be brought up to that standard
for us to say okay.

So I don\'t see it as a difference. I agree with your point of view. But
if we\'re saying a significant reduction, that means any pre-device
should have a significant reduction also.

CHAIRMAN EDMISTON: And it may be entirely possible to retrofit these
devices if that\'s the vendor\'s wish.

DR. BUTCHER: Yes.

CHAIRMAN EDMISTON: And the vendor wishes not to do that, then these
devices may actually go away.

Any other comments? Okay. I think we can move on to question two.
Discuss the adequacy and feasibility of the current available methods to
assess the potential for cross-contamination and risk of disease
transmission by MUNJI devices. And I think we\'ve probably come close to
answering that.

DR. ARDUINO: Yes. And basically this is detecting the viral agent in
ejectate from a device following its use on a none posit. And you can
that now. With the NAT testing and PCR testing that\'s available, we
could probably do that. And actually figure how many copies.

CHAIRMAN EDMISTON: Any other comments?

Do you think there should be a biological and a physical test in
parallel when testing these devices? For instance, the fluorescein would
not be a biological test, per se. Would you consider that a biological
test or a chemical test, correct? A chemical/physical test?

What does the Panel feel? Does the Panel feel there should be a higher
threshold here, not just a single test but at least two tests to
validate the ability of these devices to reduce splash back?

MS. PETERSEN: Well, I think if you could do a physical or a chemical
type test in a human population, you would certainly be getting a better
picture of what actually happens in the clinical setting in the field.
And you\'re looking at the physiological barrier that we\'re dealing
with, human skin as opposed to calf skin, mice which has some different
mechanics and physics associated with it.

CHAIRMAN EDMISTON: I understand this a new technology, this assay. Do
you feel it\'ll be possible to correlate this assay with biological
assays?

DR. ZEHRUNG: The fluorescein test?

CHAIRMAN EDMISTON: Yes.

DR. ZEHRUNG: I would recommend that it be a combination of a fluorescein
or a chemical test, plus a human test with a mark. And that\'s why
we\'ve focused on hepatitis B and conducting clinical trials as such.

I think that these questions of correlating the in vitro tests to an in
vivo sort of model will always be there. And regardless of how thorough
you would be in terms of trying to model that, it would just be easier
to graduate right to an in vivo model, such as a human being.

CHAIRMAN EDMISTON: Well, there\'s other models out there for other types
of devices in which they look at both bench type data and also like
clinical trial type data. So I think that\'s a valid approach if these
devices are going to come forward and we\'re going to demonstrate their
efficacy and safety, then the use of a two or more test to validate
their safety and the prevention of cross-contamination is probably
warranted.

MS. PETERSEN: I mean, at least in that circumstance you would have a
more balanced picture of the risk and you could, I think, more easily
consider that risk benefit equation that we keep coming back to from all
directions.

CHAIRMAN EDMISTON: Dr. Lin, I think we\'ve been presented data both on
the bench and in animal studies and some limited clinical data which
suggests that there are assays out there at varying levels of
sensitivity. And I would suggest that the choice be made to choose the
most sensitive assay to validate the safety of these devices.

Any comment on that from Dr. Layton?

DR. LAYTON: Don\'t forget, you\'re going to have multivariant data also
relative to the splash back. Just splash back alone without your
biological or your human. But your laboratory your bench top is going to
give you a tremendous amount of data showing what that is for the level
and degree of splash back.

So that\'s a major part of it also.

CHAIRMAN EDMISTON: From a guidance document perspective in terms of the
manufacturer should the FDA then recommend that two or more assays be
used to validate the safety of these devices?

DR. LAYTON: I don\'t have a problem with that.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: I don\'t know should we say one has to in vivo, one because
\-- I mean you\'re talking about \-- maybe not. You were suggesting like
with the fluorescein, that was \-- and I don\'t know if we necessarily
have to use fluorescein. They may be able to use something else, just to
see if they\'re getting something back to pick that up, but something
that\'s done in a human. But I think your point was well taken. You want
to know if there\'s actually virus isolated.

DR. ARDUINO: Because if there\'s no virus isolated and we\'re not
getting virus \--

DR. WORD: It\'s a moot point.

DR. ARDUINO: Then it\'s a moot point.

CHAIRMAN EDMISTON: Dr. Lin?

DR. LIN: I think the easy road to travel that we have been faced right
now as this morning, now FDA has present from our own laboratory, CBER
and some people present, although there\'s some potential\-- potentially
this is some \-- the FDA can recommend to the manufacturer to do some
kind of a testing to see whether this splash back or any residential
blood remaining after its injection. But the current suggests no any \--
that can be directly applied to a MUNJI device. And that is one of the
problems we are facing.

I know that Dr. Friede from \-- last year he convened a panel of expert
to address this issue. I know whether, Dr. Friede, you care to comment
to see those methods could be used with it to be applied to a MUNJI
device.

DR. FRIEDE: Could you remind me what this assay was I \--

DR. LIN: I thought that last year you convened a panel of experts to
replace the \--

DR. FRIEDE: Yes. The meeting that we had in March last year, we looked
at the albumin assay and we decided that this was inappropriate because
to actually measure as a surrogate of safety. Because you get albumin
and dead skin. And dead skin has no value. You get albumin on the hair.

So at that time we thought that the measurement of hepatitis B as an
example of a live virus, which has been suggested here, appeared at the
time to be the most appropriate in vivo assay. And my gut feeling is
that that concept of having both in vivo with an in vitro, the in vitro
we\'ve been able to get much larger numbers to give you more confidence
so that the two together \-- but I think there\'s many ways to do the in
vitro as well; enzymes, fluorescein, other things, coloring agents.

DR. LIN: But in your mind, if you don\'t mind I can ask.

CHAIRMAN EDMISTON: Of course.

DR. LIN: In your mind it is still currently there\'s any test method
that can be applied to the MUNJI device so that FDA want, FDA reviews
some of the summation then we say well this is the test you should do to
hear that this device is safe for multiple use?

DR. FRIEDE: There is no validated assay yet. I think the assays that we
heard about today, if validated when we see the data, I think we\'ll be
able to look at the data and assess whether these are applicable. It
looks promising.

DR. LIN: But it\'s not ready yet \--

DR. FRIEDE: The committee did not see all the data last year that we saw
today. And all the committee recommended last year was that the
evaluation virus was more relevant than evaluating human albumin.

CHAIRMAN EDMISTON: Could Dr. Daya come up to the podium?

Dr. Friede, could you stay there. I just like listening to you.

One of the issues is feasibility. And there will be a burden placed upon
the vendor, the manufacturer if the FDA requires testing.

Lt me ask you a question. You described very, very well the technology
that you\'re familiar with that you\'ve had the ability of performing in
your laboratory. Does that represent feasible technology from a
manufacturing test perspective?

DR. RANAMUKHA: Before that I would like to comment on, this \-- I laid
out all the methods available. I wasn\'t aware of the fluorescein
method, but the published methods. Out of these published methods the
best we can get is 100 copies, 100 genome equivalents per milliliter of
blood. With that, you know there comes what is our detection limit we
need. We don\'t know what the limit is. So with that, we cannot say the
method in that case. Because that\'s the lowest we can go down. So
that\'s the question that we are dealing with.

CHAIRMAN EDMISTON: This is a difficult question.

DR. RANAMUKHA: Yes.

CHAIRMAN EDMISTON: Because there\'s a similar question that comes up
with TSE, as you realize.

DR. RANAMUKHA: Yes.

CHAIRMAN EDMISTON: You know, what is the level of infectivity in terms
of the prion.

DR. RANAMUKHA: Yes.

CHAIRMAN EDMISTON: And that varies widely. And I think what you
described and what\'s been brought to my attention that I wasn\'t aware
of is that the infectivity is going to be highly variable depending on
where the inoculation is being given.

DR. RANAMUKHA: Absolutely.

CHAIRMAN EDMISTON: So I think that to place an unrealistic burden upon
industry to perform at such a high level with probably a very expensive
test at this point, it may not be prudent, nor may it be fair unless we
have some sound statistical data showing the efficacy of this procedure.

DR. RANAMUKHA: Yes. In that sense, actually, and like I said, there are
two methods. One is the HBV-NAT assays and the second is the Taqman
assay. Taqman use broader range and also it is feasible because it does
not involve a lot of expensive equipment. So it is a feasible assay and
then it can be used under diagnostic setting, I would say.

CHAIRMAN EDMISTON: My understanding with the FDA in the past when
they\'ve had a situation such as this, they looked at available
technology and then the vendor, the industry, the manufacturers have the
option to submit data involving one or more of those technologies,
correct?

DR. RANAMUKHA: Right. And that\'s correct.

CHAIRMAN EDMISTON: All right. I think the other issue that comes up, and
I think this \-- and let me get that fellow that PATH again. You stand
up there. All three of you guys stand together, all right. A Kodak
moment here.

As a methodology, is that fluorescein a feasible methodology from
industry\'s perspective if it could be used by a variety of vendors?

DR. ZEHRUNG: I would believe so. And it\'s not only feasible, it\'s
extremely low cost. And the comparison in terms of the assay that\'s
being for the FE testing, it\'s very expensive. It\'s \$185 a sample to
test. So that would actually represent a financial burden to a
manufacturer. And we\'ve adopted that or we\'ve accepted that sort of
responsibility in terms of our collaboration with the manufacturer. But
it\'s an expensive test.

CHAIRMAN EDMISTON: But I know there\'s no gold standard. But that
probably could be perceived as a possible gold standard if you looked at
the rest of the methodologies out there.

I think the fluorescein assay has great promise, but the concern I have
is that I\'ve only seen the data presented from your institution. And
we\'d need to see more data with a variety of devices.

So I suspect what I would consider to present to the panel is that we
have methodology available that the FDA could require the vendor to
submit performance data using a number of those current methodologies.
If the fluorescein assay appears a successful assay, then I would also
encourage the FDA to consider that as one of the surrogate tests. But I
think at this time I\'m not sure if we could recommend that assay
because we don\'t have the kind of laboratory experience with that as we
do with the other methodologies.

Any comments from the Panel on this? You guys agree or disagree or \--

MR. DAVID: I agree, yes.

CHAIRMAN EDMISTON: Okay. So I believe in terms of question two, the
methodology that should be applied should be feasible and should be
adequate. And we currently have presented published \-- published
methodologies which are accepted by the scientific community to detect
biological particles in samples, both blood and other body fluids. Is
that a reasonable consideration.

DR. LIN: I wanted to ask PATH, is your method is going to be published
in an open literature?

DR. ZEHRUNG: That\'s a good question. We\'ve discussed that and I think
we\'ve just focused on supporting any sort of regulatory submission for
the data. But I think we would be open to doing that.

CHAIRMAN EDMISTON: Would you accept their data from a regulatory
perspective if it\'s not peer reviewed methodology?

DR. LIN: Well, as long as it\'s scientifically sound, then we don\'t
have a problem whether it\'s published or not.

CHAIRMAN EDMISTON: Okay.

DR. LIN: But my question is that to be aware to other manufacturing, if
the method is published, and then somebody could use their method to
compare \--

CHAIRMAN EDMISTON: Is this a proprietary methodology?

DR. ZEHRUNG: No. I mean, we haven\'t designed any sort of patent, you
know, applications for it. So I think our position would be it would be
free to industry to use.

CHAIRMAN EDMISTON: So you don\'t consider it proprietary? Does that
fellow back there consider it proprietary or \--

DR. ZEHRUNG: From Felton? No.

CHAIRMAN EDMISTON: The gentleman who was with you?

DR. ZEHRUNG: Dr. Loskutov?

DR. LOSKUTOV: No.

CHAIRMAN EDMISTON: No? Well, I think it would be in the best interest of
the industry as a whole if we had that data available to us in a
published form.

DR. ZEHRUNG: And as I said earlier, PATH is more than willing to
collaborate and share this information with these technologies.

CHAIRMAN EDMISTON: Are there any other comments on question two?

MS. PETERSEN: Has PATH made any effort to seek some kind of grant or
collaborative funding to assist with the higher cost of some of these
assays to get the validation?

DR. ZEHRUNG: Well, that\'s part of the funding from the Bill and Melinda
Gates Foundation is to conduct the safety testing for the protector cap
injector. And so that would be \--

CHAIRMAN EDMISTON: Dr. Friede, do you have any final comment on this
issue here?

DR. FRIEDE: No. As I said, this is the best we\'ve seen.

CHAIRMAN EDMISTON: Excuse me. You pronounce your Friede?

DR. FRIEDE: Friede.

CHAIRMAN EDMISTON: Friede?

DR. FRIEDE: Yes.

CHAIRMAN EDMISTON: All right. I had that totally screwed up, didn\'t I.

DR. FRIEDE: I think that from what I \-- my personal view is that this
has set for the moment a benchmark. This is the most sensitive we\'ve
seen. It is a 100 fold more sensitive than anything else we\'ve seen.
And I think from my perspective we\'re going to try to go for as safe as
possible.

CHAIRMAN EDMISTON: We\'re talking about the fluorescein assay?

DR. FRIEDE: The fluorescein assay.

CHAIRMAN EDMISTON: But as a scientist also you would want to see that be
submitted for peer review?

DR. FRIEDE: I would want to see it permitted for peer review. I would
also somewhere along the line like to see somebody try and if possible,
look at this and say how does this correlate with real life situation.
Because we are talking about an in vitro situation. And so if this is
possible somewhere the line. But I do like the fact that it can probably
be repeated in many laboratories, easily done and we can probably even
have these kinds of things standardized.

CHAIRMAN EDMISTON: And I think that\'s an excellent point, but I\'m not
sure that\'s the purview of the FDA. I mean, that\'s something that\'s
going to probably conducted independently, or at least within their
laboratories if they have an interest in this.

Any other questions in terms of \-- any comments?

DR. LIN: I tell, you would echo Dr. Friede \--

CHAIRMAN EDMISTON: Friede.

DR. LIN: His comment. Can correlate those and test results with their
ongoing current study. That will be wonderful. It will be an excellent
correlation for that. So data can be compared.

CHAIRMAN EDMISTON: Any further comments on question two?

Did you understand our response in question two, that there currently
are feasible and adequate assays available which the manufacturers could
use to benchmark their device.

DR. LIN: Okay.

CHAIRMAN EDMISTON: Number three, Feinman, et.al. suggested a volume of
blood as small as 10 picoliters can transmit hepatitis B virus in
chimpanzees. However, this finding is based on a single animal study.
Considering the potential public health benefit of MUNJIs is there a
threshold volume of blood contamination that presents an acceptable
risk? If so, what threshold would be considered acceptable? Any comments
by the Panel?

DR. ARDUINO: I think we\'re focused on the wrong thing because it all
depends on what the viral load is on the person \-- you know. I mean,
this is a single animal. I mean, it\'s not a population. I mean, we have
no idea what real infectious dose is based on what, an N of what? And
it\'s kind of out of context. Because this wasn\'t in vaccine
development. This was more looking at a test development for detection
of virus.

So, you know, I\'m kind of \-- you know, 10 picoliters, how we going to
measure 10 picoliters? It\'s also based our serum albumin studies which
is probably a lousy test to begin with. So, you know, how accurate is
that really when you look at the other assays they\'re using to measure
that?

I would still look at reduction of the infectious agent or you can
demonstrate that there\'s no infectious agent or to whatever the limit
of detection of the tests are.

CHAIRMAN EDMISTON: From biological perspective?

DR. ARDUINO: From a biological perspective.

CHAIRMAN EDMISTON: How about the concept of a genome equivalent?

DR. ARDUINO: Well \--

CHAIRMAN EDMISTON: That\'s the same thing?

DR. ARDUINO: That\'s a copy.

CHAIRMAN EDMISTON: Okay.

DR. WORD: I\'m sorry.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: I would probably go with the lowest level detectable. Because
generally if it\'s not detectable, we say it\'s negative if you\'re
looking at copies of something.

I\'m not comfortable with that 10 picoliters at all.

DR. ARDUINO: And we\'re using hepatitis B as a marker, you know it\'s
great \-- transmission requires \-- it\'s great \-- you know, has more
potential transmission than the other viruses.

CHAIRMAN EDMISTON: Dr. David, any comment?

MR. DAVID: I thought I have an idea until I heard the comments. Now I\'m
not concerned. It sounds to me like you\'re saying 10 picoliter is a
number you\'re not comfortable for several reasons loading N on one \--

DR. ARDUINO: It\'s all based back on the virus. You know, you really
don\'t know what the \-- and the viral load depending on, you know,
whether you\'re HBV, HIV infected, HBV and HCV infected or HBV alone, or
HBV with e antigen. It\'s going to be different.

So I would rather focus on, you know, the lowest detectable amounts of
virus.

CHAIRMAN EDMISTON: Dr. Word?

DR. WORD: I guess my other question is do we have to include other
viruses that we\'ve known are blood born, not just \-- I mean, I know
hepatitis B is the most easily transmitted. But just like when we screen
for blood, we screen across the board for hepatitis A, B and C and
we\'ll also look at HIV. Do we have to set a limit for all of those, not
just hepatitis B? I think I\'d feel more comfortable, because why not
treat it the same way if you\'re telling me there may be some back
splash in their blood there. I don\'t know how other people feel about
it, though.

CHAIRMAN EDMISTON: Well, we\'ve been shown methodologies that exist that
detect anywhere from one to 0.4 picoliters of fluid contamination. You
don\'t feel that going down to the \-- one to 0.4 picoliters would be a
sufficient threshold?

DR. ARDUINO: No, it\'s hard.

CHAIRMAN EDMISTON: Dr. Layton?

DR. LAYTON: Well, I think from an industry perspective you want to try
and put a limit on it. And it goes back and relates there to the
question one also. Now whether it\'s 10 picoliters or what is it, 0.4 or
.4 picoliters. And we\'re looking at total reduction of splash back. And
you put a limit on it today, you don\'t know, you know next year we may
have another blood born disease that plays an issue relative to it. So
that\'s why the best from an industry standpoint and from my
recommendation, you try to put a limit on it relative to a volume.

CHAIRMAN EDMISTON: What is the FDA\'s perspective on threshold.

DR. LIN: Well, that\'s the question that we try to ask of our panels to
help us. You look at this morning\'s presentation, this is potential
public health need that somebody probably already present. And whether I
say in this country or in other country or in other third world country,
this is a potential public health need. On the other hand, this also has
potential risk of blood cross-contaminations.

Now if from looking at the risk benefits consideration, our question to
you is that in your mind we should not allow any risk or threats of risk
or we should allow for certain level of risk. That\'s the question that
if you can help to address that, it would be very helpful.

CHAIRMAN EDMISTON: Well, what you\'re saying is that we get back to that
100 percent issue of reduction in splash back?

DR. LIN: Right. Right. Yes.

CHAIRMAN EDMISTON: And I think if that\'s the case, then we can take it
one step further, that\'s no detectable viral particle or detectable
blood \--

DR. ARDUINO: Except we really don\'t have, other the fluorescein, which
is a surrogate, we really have no way of actually measuring that level
of blood.

DR. LIN: I think that that\'s why you have to look at question number
two, which is also the current available method.

CHAIRMAN EDMISTON: Right.

DR. LIN: Is there any way you can really direct to the level. And if
not, then what kind of level you can recommend to FDA that would be
appropriate for the reviews of this type of device.

CHAIRMAN EDMISTON: Well, if you review the published assays, especially
HBV assays, hepatitis B virus assays, you\'re limit of detection varies
anywhere from .1 nanograms to 10 to the 9th, depending again on the
methodology. And if you go 10 to the 9th, we\'re talking about a
threshold that we initially discussed early on, anywhere between 1 and
10 picoliters, correct?

So we really need some consensus here in terms of what the Panel
believes to be a threshold value. And I think Dr. Friede suggested that
10 picoliters was much too high, correct?

DR. FRIEDE: I think just looking at the numbers, we know that 10
picoliters can transmit infection and less than 10 picoliters will
therefore be able to on some occasions.

CHAIRMAN EDMISTON: So on a risk benefit basis more than likely what
we\'re talking about is a device that has the capability of reducing \--
reducing exposure to below 10 microliters \-- 10 picoliters? Correct?

DR. WORD: Excuse me, Dr. Edmiston. What is the acceptable level that we
use in blood when we transfuse someone? I mean, I don\'t know what the
exact number is. I don\'t know if anyone here might know?

CHAIRMAN EDMISTON: Dr. Michaud?

DR. LIN: She\'s a hematologist, so she\'ll be \--

DR. MICHAUD: Ginette Michaud, Deputy Director of DAGID.

I would suggest in fact the question may not be entirely relevant to
this discussion. Because I believe that the acceptable limits are driven
by the available technologies. And the tests are applied to blood
products which are lifesaving biological products. So it\'s really, I
think it\'s a very different thought process that goes into that.

And as you look at the history of screening of blood products, the limit
of detection on the acceptable assays has been driven down as the
technology is able to offer a lower limit of detection.

CHAIRMAN EDMISTON: So we\'re actually back to the risk benefit component
again in the sense that the technologies that we have in front of us
here have variable specificities or variable units of detection. And I
think that Dr. Friede\'s comment is that if we\'re going to try and
achieve maximum reduction, maximum risk with overall benefit of the
device, then we need to look at that value less than 10 picoliters.
Would you agree with that?

DR. BUTCHER: Mr. Chairman, I don\'t think that we\'re going to be able
to put a number on it, but I think that going to your previous thing
that significantly reduce it down and that would get it. I mean, we know
that the ten is too high. We don\'t have enough evidence with those that
are less yet.

CHAIRMAN EDMISTON: Yes, sir?

MR. WATSON: I\'d like to put a little perspective on the numbers. I know
that it\'s a little bit of a challenge to actually pin it down.

When we look at substantial equivalents, which right now what we\'re
actually proposing to do is set an actually kind of a bar, which is a
little bit of a challenge in the 510(k) process, but it can be done when
we have safety concerns. If we can get a number \-- realizing that that
is a challenge, if we can get some kind of a bar to start with. Because
we can always make that bar higher as we know more about the developing
technologies.

Right now we don\'t \-- I mean 10 picoliters has come up or 10
picoliters has come up and we don\'t really know what to do with that.

CHAIRMAN EDMISTON: Right.

MR. WATSON: As you mentioned, you know, less than 10 picoliters, at
least if the Panel \-- and I\'m not suggesting that they should \-- but
if the Panel would give us that as a starting point, that would help us
tremendously. But other than that, it\'s sort of a touchy situation for
us because then we don\'t have a goal in place without that.

So I would encourage any valuable numbers that you think based on what
you\'ve seen today, if you can give us some guidance in that area, that
would be much appreciated.

CHAIRMAN EDMISTON: The NAT technology, can the NAT technology detect
down to 10 picoliters? NAT? I\'m not sure it can.

DR. RANAMUKHA: NAT technology detected DNA copy numbers. So it does not
go with the volume. And so it comes down to how many copies you find in
the \--

CHAIRMAN EDMISTON: Gotcha. Gotcha.

DR. ARDUINO: That\'s why I almost saying that ten is irrelevant if
you\'re looking at how many genomic equivalence are present.

DR. WORD: I was going to say I like presence \--

CHAIRMAN EDMISTON: Well, the issue is is that copies or genomic
equivalents is a nice ideal number. But the issue is also in terms of
volume of detection. And I\'m a bit perplexed by this number issue, you
know.

MR. DAVID: And the number is what I\'m left today after seeing the data,
is that 10 picoliter is transmittable volume and would give a
significant concern if we are supposed to judge risk to benefit as the
safety issue is not addressed.

So definitely I\'m looking for a volume that is below that numbers,
because then I showing this number is unsafe.

CHAIRMAN EDMISTON: And realizing, too, that number, 10 picoliters, was
based on a single study, correct? A single study.

DR. ARDUINO: In one animal.

CHAIRMAN EDMISTON: In one animal. But it does represent a starting
point.

Does the Committee have any concerns with making a recommendation of
less than 10 picoliters as a bar?

DR. ARDUINO: As a start.

CHAIRMAN EDMISTON: Start.

DR. ARDUINO: No.

DR. WORD: Can you put the caveat that they will revisit it?

CHAIRMAN EDMISTON: Oh, they\'ll revisit it, there\'s no doubt about
that.

DR. WORD: No. But if you tell them.

CHAIRMAN EDMISTON: This is a moving target. Am I correct in
understanding that this is a moving target, correct?

DR. LIN: Well, when you set the benchmark, then I\'m sure that industry
can \-- but once you set the benchmark, the industry would develop a
tendency to meet that goal. Hopefully.

CHAIRMAN EDMISTON: You represent sort of the pragmatic perspective here,
Dr. Friede. You\'re out there in the field. If industry met that
benchmark of less than 10 picoliters, would that give you a sense of
assurance that we\'re moving in the right direction, especially if we
evaluate the risk versus benefit component.

DR. FRIEDE: Okay. Let\'s just imagine the situation. We have a device,
again this famous device X, and it\'s actually transmitting 5 picoliters
per injection. That\'s less than 10. And we know that we\'re in a room
with 50 percent chronic carriers, and they\'re all looking very yellow.
And we all have to stand up and we have to inject the person standing
next to us and then inject ourselves. How many people here are going to
do that, especially if there was another device that was undetectable
using the most sensitive assay, absolutely undetectable?

So for me putting a number and saying five or less than ten, this is not
relevant. It must be undetectable using the most sensitive assays that
we have. Because if you can detect blood on it, then there is a risk.
That risk might be, as Dr. Kane mentioned, you know I presented the
worst case scenario and we should also be looking at the best case
scenario. But we are going to have a recommendation to people to use a
device. And if we know that that device, we say oh yes, use it, it does
transmit blood but not a lot. Don\'t worry about it. I\'m not
comfortable with that. I think we have to say there is no detectable \--

CHAIRMAN EDMISTON: So in essence we would raise the bar to a level we
don\'t even raise with TSE?

DR. FRIEDE: Yes. I don\'t know what you do for TSE, but it does appear
to me that we have seen this morning data which suggests that there is
something that does not have any transmission. It appears to me that
this is a benchmark and one could not allow anything which is worse than
that.

CHAIRMAN EDMISTON: What\'s the Committee\'s perspective on Dr. Friede\'s
comment that no detectable \-- let me get a vote here. How many feel
that the Committee\'s recommendation for this question should be that
there is no detectable entity?

Everyone who feels there should be no detectable entity. One, two,
three, four. Four to two or four to three. So it would appear that the
Panel would recommend that there would be no detectable entity.

I think that that\'s a very difficult thing to achieve, but that\'s the
Panel\'s recommendation.

Any comments from the FDA in terms of that recommendation?

DR. LIN: Well, we can live with.

CHAIRMAN EDMISTON: You can deal with it?

DR. LIN: We can, yes.

CHAIRMAN EDMISTON: Okay.

All right. What we\'re going to do at this time is take a brief break or
do you want to continue on. Well, I\'ll tell you what, let\'s have a
very quick break. Let\'s have a five to ten minute break and we\'ll come
back, and at that time we\'ll finish up with a final public comments.

(Whereupon, at 2:17 p.m. a recess until 2:29 p.m.)

CHAIRMAN EDMISTON: I\'d like to call this meeting back to order. We will
now hold our second half hour open public hearing. If there any
individuals wishing to address the Panel, please raise your hand,
identify yourself at the time. Also at the time you identify yourself,
please indicate again any proprietary interests or conflicts of
interest. Please.

DR. KANE: Yes, my name is Mark Kane. I work for PATH. I spoke before and
I have the same conflict of interest profile as the other PATH speaker.

I think the point I\'d like to make is that is a perspective that comes
from a little bit of the history of the development of some of these
assays.

The original intent in developing the serum albumin assay, at least at a
certain point, was that we would in parallel develop a physical chemical
test like the serum albumin assay in parallel with a biological test
looking at the actual etiologic agent that we were most concerned about,
which is hepatitis B. Then because although the hepatitis B testing is
sensitive, specific and available, it is not an easy task for a
manufacturer to go out and go to China and get 300 hepatitis B carriers
and undertake the kind of study that is being proposed by PATH.

So the idea was to use the hepatitis B testing as sort of a gold
standard, correlate that with the physical chemical test like serum
albumin. And in the future it would be possible for manufacturers just
to use the simpler test.

Now, that did not work out because the serum albumin test was not
acceptable because of contamination from the environment, because we
live in a sea of the stuff. But the principle that you have a biological
assay available that measures exactly what you\'re worried about, the
highest titer pathogen hepatitis B and the major pathogen, you\'re
actually lucky to have that available to you. But if that could be
correlated with an assay, a much simpler assay like the fluorescein in
the future, then it might be possible at a certain point when all the
tests have been validated, to move over to a much simpler and cheaper
test. But conceptually I would think the gold standard would actually be
the hepatitis B model, because you\'re measuring exactly what you\'re
worried about.

And the second point I\'d like to make is that I totally agree with the
Panel\'s recommendation that they should basically accept zero
detectable level of contamination. My concern is that that doesn\'t go
quite far enough to answer all the questions that need to be answered.
Because there exist out there a number of detection systems with
different outputs and with different levels of sensitivity and
specificity.

So, for example, the fluorescein test which the panel seemed to be
interested in gives you a readout in terms of volume. Some of the DNA
tests for the hepatitis B virus give you an output in terms of genome
copies. All of these can potentially be useful. So some kind of
guidance, I would imagine Dr. Lin, you know which one of those might be
\-- some direction, some guidance to the FDA might be very helpful to
them.

For example, there\'s been a history of different levels of sensitivity
and specificity. In the \'60s it was visible blood. Then it was a blood
dip stick. Then it was an ELISA test of the sensitivity and specificity
of blood ELISAs. Then it was PCR, and now it\'s fluorescein. And
certainly it\'s a moving target. But basically if someone said well
there was no visible blood on the head, would that be acceptable? No.
Would a dip stick be acceptable? Probably no. Would the fluorescein and
PCRB and the best we have for those two lines be acceptable? It\'s the
best we can do right now.

So, you know, some sort of guidance along those lines I would guess
might be helpful as well to the FDA.

Thank you very much.

CHAIRMAN EDMISTON: Does the panel have any questions for the speaker?
Yes, Dr. Word?

DR. WORD: I don\'t have a question. But when he started talking about
the hepatitis B and how many copies, I think if you\'re looking for FDA
for the guidance, you\'re looking at license test that your agency
itself has licensed. And if you get down to the lower limit of
detectable, whether it\'s 200 copies or 150 copies, if it\'s 200 copies
then it comes in at 199, then but it\'s nondetectable.

But I guess what I\'m saying is when he was suggesting that you have to
use a test because there\'s so many, you know which ones you\'ve
licensed. So I don\'t know, do we say it has to be one that\'s licensed
in the United States because that\'s the only one you\'re going to look
at?

DR. LIN: You\'re asking me to comment? Well, the one that licensed, from
our sister center, Center for Biologics and CBER, these centers their
licensing for blood donation, blood donor. But here the one that we\'re
talking about to assay the procedure biocopy; that you don\'t have to
use that kind of blood licensing because that\'s totally different
method.

But here I think that probably one of the challenges is how you assay
those virus remain on those top or any fluid pathway. That is probably
most of the challenge that the manufacturer is facing. How you excerpt
those virus out to assay for those copying.

CHAIRMAN EDMISTON: Dr. David?

MR. DAVID: Thank you, Mr. Chairman.

Just to clarify in my mind what the Panel voted on is a question to the
FDA is the capability that you have if you have \-- you kept asking
would should FDA do if they have an application submitted tomorrow. And
in this kind of time frame is the FDA capable of reproducing tests to a
level that the Panel has recommended?

DR. LIN: I shouldn\'t have used the term \"tomorrow.\" I don\'t mean
right away. I mean just in the near future we get a submission. But the
Panel\'s recommendation that will help us to prepare a guidance document
to the industry. That\'s essentially what I mean.

MR. DAVID: Okay.

CHAIRMAN EDMISTON: Do we have any further speakers from the public?

Dr. Zehrung, could I call you to the podium for a moment?

DR. ZEHRUNG: Yes.

CHAIRMAN EDMISTON: This is more from a reviewer perspective, all right.
This device that you have that fits on the end of your injector?

DR. ZEHRUNG: Yes.

CHAIRMAN EDMISTON: The splash back that may occur is contained within
the bottom chamber, is that correct? Is this positioned the right way on
the device with the \--

DR. ZEHRUNG: Yes, sir. The flat portion is the skin side.

CHAIRMAN EDMISTON: The flat portion is the skin side.

DR. ZEHRUNG: So that outer flange would then contact the skin.

CHAIRMAN EDMISTON: Yes.

DR. ZEHRUNG: And then the tail end of it, actually, comes into close
proximity to the nozzle of the \--

CHAIRMAN EDMISTON: Okay. This part right here. Okay.

DR. ZEHRUNG: Yes.

CHAIRMAN EDMISTON: Like that?

DR. ZEHRUNG: Right.

CHAIRMAN EDMISTON: Like a flying saucer, correct? Okay. And so any
potential splash back is contained within this bottom chamber, is that
correct?

DR. ZEHRUNG: Both chambers.

CHAIRMAN EDMISTON: Both chambers?

DR. ZEHRUNG: Yes.

CHAIRMAN EDMISTON: So let me ask you a question. It\'s contained in both
chambers. Is there a membrane that is above this?

DR. ZEHRUNG: There is membrane.

CHAIRMAN EDMISTON: There\'s a membrane?

DR. ZEHRUNG: That\'s \--right. So on the side that\'s in close proximity
to the nozzle \--

CHAIRMAN EDMISTON: Yes.

DR. ZEHRUNG: \-- there is a thin polyethylene film that the injection
stream pierces on its way through the protector cap and then into the
tissue.

CHAIRMAN EDMISTON: Is that also a replaceable membrane or is that a
permanent membrane?

DR. ZEHRUNG: It\'s permanent. It\'s actually welded onto the backside of
the protector cap during the fabrication process.

CHAIRMAN EDMISTON: Okay. And that membrane prevents the splash back from
getting back into the nozzle component of the device?

DR. ZEHRUNG: So far studies have indicated that that that\'s the case.

CHAIRMAN EDMISTON: Okay. And basically what you\'ve seen to date is
there is no \-- when you remove this membrane and you look at the \--
there obviously is some residual material on the membrane in the top,
correct?

DR. ZEHRUNG: Sometimes.

CHAIRMAN EDMISTON: Sometimes.

DR. ZEHRUNG: Especially with the fluorescein test which is an
exaggerated sort of test.

CHAIRMAN EDMISTON: Okay. But it greatly reduces to a significant extent
\--

DR. ZEHRUNG: Definitely.

CHAIRMAN EDMISTON: \-- the infiltration of that splash back into the
nozzles?

DR. ZEHRUNG: That\'s true.

CHAIRMAN EDMISTON: Does that answer questions out there? Okay. Very
good. Thank you so much.

Do we have any further comments or questions?

At this time, I believe I have to turn it over to my Executive Secretary
to read a statement.

EXECUTIVE SECRETARY COLBURN: Well, before we adjourn for the day, I just
want to remind the Panel members that all the material that you have
received for preparation and review for this Panel is not considered
proprietary, and you do not need to destroy this as if it was a PMA
panel or something like that. So you are free to keep the material that
you have received.

And I just want to extend my thanks and gratitude for all the Panel
members, and invited consultants from other panels who have helped us
out in conveying for today. And we appreciate all your very informative
comments.

And I would also like to extend my thanks to Dr. Friede from WHO coming
and presenting to the Panel, as well as the industry representatives
that have helped us out in guiding the discussions today and helping us
come to at least a consensus and direction where we can forward in
developing of these devices.

Thank you.

I\'ll return this back to Dr. Edmiston for any final comments.

CHAIRMAN EDMISTON: And I also want to express my sincere thanks to the
members of this Panel for this diligence and interest and effort in
today\'s activities. And the members of the public, especially Mr. Hooks
for his presentation. And also the members of industry for really a very
interesting presenting of what could be some new emerging technology.

If there is no further business, I would like to adjourn this meeting of
the General Hospital and Personal Use Device Panel.

Thank you very much.

(Whereupon, the meeting was adjourned at 2:41 p.m.)