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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:
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:

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:

MARTIN FRIEDE, Ph.D., Initiative for Vaccine
Research, World Health Organization

INDUSTRY PRESENTERS:

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:

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.
,,,,

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....
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. They had an upheaval with HIV.
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 troops serving in the middle east, now, should be tested. If they've
had any injections should be checked and nip in the bud before it gets 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 needleless jets specifically, they need to be
addressed appropriately. I know there are some modifications that have been made
like caps and disposable, they're working on things. But they really do need to make sure these guns 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 com