UNITED STATES OF AMERICA

 

MEDICAL DEVICES ADVISORY COMMITTEE

 

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GENERAL AND PLASTIC SURGERY DEVICES PANEL

 

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MEETING

 

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THURSDAY, AUGUST 25, 2005

 

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            The Panel met in Salons A, B, and C of the Hilton Washington, D.C. North, 620 Perry Parkway, Gaithersburg, Maryland, at 8:00 a.m., Joseph LoCicero, III, M.D., Panel Chairman, Presiding.

 

PRESENT:

 

JOSEPH LOCICERO, III, M.D., ACTING PANEL CHAIRMAN

DAVID KRAUSE, Ph.D., EXECUTIVE SECRETARY

GRACE T. BARTOO, Ph.D., RAC, INDUSTRY REPRESENTATIVE

BRENT BLUMENSTEIN, Ph.D., VOTING MEMBER

LEELEE DOYLE, Ph.D., CONSUMER REPRESENTATIVE

CHERYL A. EWING, M.D.,  VOTING MEMBER

ANN MARILYN LEITCH, M.D., VOTING MEMBER

FRANK R. LEWIS JR., M.D., TEMPORARY VOTING MEMBER

MARK MELKERSON, FDA

MICHAEL J. MILLER, M.D., VOTING MEMBER

AMY NEWBURGER, M.D., VOTING MEMBER

MICHAEL J. YASZEMSKI, M.D., Ph.D., TEMPORARY VOTING

      MEMBER

 

 

 

 

 

 

PRESENTERS:

 

SOUSAN S. ALTAIE, Ph.D., OFFICE OF IN VITRO

      DIAGNOSTIC DEVICE EVALUATION AND SAFETY

CHARLES N. DURFOR, Ph.D., OFFICE OF DEVICE

      EVALUATION

SUSAN N. GARDNER, Ph.D., OFFICE OF SURVEILLANCE AND

      BIOMETRICS

RICHARD KRONENTHAL, Ph.D., ORTHOCON, INC.

CDR STEPHEN P. RHODES, OFFICE OF DEVICE EVALUIATION  MARJORIE G. SHULMAN, OFFICE OF DEVICE EVALUATION

TAD WELLISZ, M.D., UNIVERSITY OF SOUTHERN CALIFORNIA

 


                     I-N-D-E-X

 

Conflict of Interest Statement ................. 6

 

Appointment to Temporary Voting Status ......... 9

 

Introductions ................................. 12

 

General and Plastic Surgery Devices Update,

      Stephen Rhodes .......................... 14

 

FDA's Critical Path Initiative, Sousan Altaie . 17

 

CDRH Changes re Condition of Approval Studies,

      Dr. Susan Gardner ....................... 24

 

Overview of Device Classification, Marjorie

      Shulman ................................. 32

Bone Wax

Presentation of Richard Kronenthal, Ph.D. ..... 38

 

FDA Presentation David Krause, PhD

FDA Panel Discussion .......................... 43

 

Panel Deliberations ........................... 63

 

Public Comment:

 

      Tad Wellisz, M.D. ....................... 92

      Dr. Del Stagg .......................... 116

 

Classification Questionnaire and Supplemental

      Data Sheet ............................. 116

 

Medical Maggots

 

FDA Presentation, Dr. Charles N. Durfor ...... 143

 

Panel Deliberation ........................... 156

 

Classification Questionnaire and Supplemental

      Data Sheet ............................. 179

 

 

 

                     I N D E X

 

                                              PAGE

Medicinal Leeches

 

FDA Presentation, Dr. Charles N. Durfor ...... 204

 

Panel Deliberation ........................... 212

 

Discussion of FDA Questions .................. 224

 

Classification Questionnaire and Supplemental

      Data Sheet ............................. 235

 

 

 

 

 

 

 

 


               P-R-O-C-E-E-D-I-N-G-S

                                       (8:08 a.m.)

            DR. KRAUSE:  Good morning, everyone.  We are ready to begin this meeting of the General and Plastic Surgery Devices Panel.

            My name is David Krause.  I'm the Executive Secretary of this panel, and I'm also a reviewer in the Plastic and Reconstructive Surgery Devices Branch in the Division of General Restorative and Neurological Devices.

            I'd like to remind everyone that you are requested to sign in on the attendance sheets which are available at the tables by the doors.  You may also pick up an agenda, a meeting roster, and information about today's meeting at the table.  The information includes how to find out about future meeting dates through the Advisory Panel phone line and how to obtain meeting minutes or transcripts.  This and other panel meeting information, including panel meeting summaries and transcripts are now available on the World Wide Web.  Advisory Panel meeting activities are available by clicking on the CDRH home page from the FDA Website, which is www.fda.gov.

            Before I turn the meeting over to Dr. LoCicero, we're required to read two statements into the record.  One is the conflict of interest statement, and the other is the deputization to voting status.

            Jenny Slaughter will read the conflict of interest statement at this time.

            MS. SLAUGHTER:  Thank you, Dr. Krause.

            Good morning.  The Food and Drug Administration is convening today's meeting of the General Hospital and Personal Use Devices Panel of the Medical Devices Advisory Committee under the authority of the Federal Advisory Committee 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 subject to federal conflict of interest laws and regulations.

            FDA has determined that members and consultants of this panel are in compliance with the federal conflict of interest laws, including but not limited to 18 USC 208 and 21 USC 355(n)(4).  Under 18 USC, Section 208, applicable to all government agencies, and 21 USC 355, applicable to FDA, Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it's determined that the agency's need for a particular individual's services outweighs his or her potential 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 employer, spouse or minor child related to the discussion of today's meeting.  These interests may include investments, consulting, expert witness testimony, contracts, grants, cooperative research and development agreements, teaching, speaking, writing, patents and royalties, and primary employment.

            The agenda on August 25 involves a discussion of the classification of three pre-amendment medical devices, bone wax, medical maggots, and medicinal leeches.  The agenda on August 26th involves a discussion of the classification of two pre-amendments, tissue expanders and wound dressing with a drug.

            In accordance with 18 USC 208, a waiver has been granted to Dr. Amy Newburger.  A copy of the written conflict of interest waiver statement may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

            In addition, Dr. Grace Bartoo is participating as the industry representative acting on behalf of all related industry and is employed by Decus Biomedical.

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

            Thank you.

            DR. KRAUSE:  Thank you.

            Okay.  I would like to now read the appointment to temporary voting status.

            Pursuant to the authority granted under the Medical Devices Advisory Committee Charter, dated October 27th, 1990, and as amended August 18th, 1999 and November 16th, 1999, I appoint Frank R. Lewis, M.D., and Michael J. Yaszemski, M.D., as voting members of the General and Plastic Surgery Devices Panel for this meeting on August 25th, 2005.

            For the record, these individuals are special government employees and consultants to this panel or other panels under the Medical Device Advisory Committee.  They have undergone the customary conflict of interest review and have reviewed the material to be considered at this meeting.

            Also, I would like to note that Dr. Joseph LoCicero, III, has consented to serve as the Chairperson for the duration of this meeting, and it's signed by Dr. Daniel Schultz, Director, Center for Devices and Radiological Health.

            Also, before I turn the meeting over to Dr. LoCicero, I'd like to acknowledge a few members of the panel.  This panel meeting will be the last panel meeting for a number of members, and I would just like to acknowledge that.  One of the members was unable to come today, which was the Chairman, Dr. Choti.  He's cycling off the panel at the end of this month.

            The other two individuals who are cycling off are Dr. Miller and our consumer representative, Dr. Doyle. Sheila  Walcoff, Esquire, the Associate Commissioner for External Relations, has sent the following letter, and this is both for Dr. Miller and Dr. Doyle.

            "I would like to express my deepest appreciation for your efforts and guidance during your term as a member of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.  The success of this committee's work reinforces our conviction that responsible regulation of consumer products depends greatly on the experience, knowledge and varied backgrounds and viewpoints that are represented on the committee.  In recognition of your distinguished services to the Food and Drug Administration, I am pleased to present you with the enclosed plaque."

            This is what the plaque looks like, and I have one for Dr. Doyle and one for Dr. Miller.

            Thank you.

            At this time I'd like to turn the meeting over to Dr. LoCicero.

            PANEL CHAIR LoCICERO:  Good morning.  My name is Joseph LoCicero, III, and I am the Acting Chairperson for the General and Plastic Surgery Devices Panel.

            Today the panel will be making recommendations to the Food and Drug Administration on the classification of bone wax, medical maggots, and medicinal leeches, which are all presently unclassified, pre-amendment medical devices.

            Before we begin the meeting, I would like to ask our distinguished panel members who graciously give their time to help the FDA in the matter being discussed today and other FDA staff seated at the table to introduce themselves.

            I'll begin with myself.  I'm Joseph LoCicero, III.  I am a thoracic surgeon.  I'm currently the chair of surgery at the University of South Alabama in Mobile, Alabama.

            Let's go clockwise.

            DR. DOYLE:  I'm Dr. Leelee Doyle.  I am the Assistant Dean for Faculty Affairs and Professor Emeritus of Obstetrics and Gynecology at the University of Arkansas, at the Medical Sciences College of Medicine.

            DR. BLUMENSTEIN:  I'm Brent Blumenstein, statistician, working in private practice in Seattle.

            DR. BARTOO:  I'm Grace Bartoo.  I'm the industry rep. and nonvoting member, and I'm general manager of Decus Biomedical, and my expertise is in medical device product development and clinical trials.

            DR. YASZEMSKI:  Hi.  I'm Michael Yaszemski.  I'm an orthopedic surgeon, and I work at Mayo Clinic in Rochester, Minnesota.  I chair the Spine Surgery Division and direct the Polymeric Biomaterials Laboratory.

            MR. MELKERSON:  I'm Mark Melkerson.  I'm the Acting Division Director for the Division of General Restorative and Neurological Devices.

            DR. LEITCH:  I'm Marilyn Leitch.  I'm a surgical oncologist at UT Southwestern in Dallas, and a Professor of Surgery, voting member.

            DR. MILLER:  I'm Michael Miller.  I'm a Professor of Plastic Surgery at the University of Texas in the Anderson Cancer Center.  I'm a voting member.

            DR. NEWBURGER:  I'm Amy Newburger.  I'm a clinical dermatologist in private practice in Scarsdale, New York.  I teach at St. Luke's Roosevelt Hospital Medical Consortium.  I'm a voting member.

            DR. LEWIS:  Frank Lewis.  I'm a general and a trauma surgeon, currently Administrator at the American Board of Surgery where I'm the Executive Director.

            DR. EWING:  My name is Cheryl Ewing.  I'm a surgical oncologist.  I am a faculty member at the University of California at San Francisco, and I'm a voting member.

            DR. KRAUSE:  Oh, I'm David Krause.

            PANEL CHAIR LoCICERO:  Before we continue with the classification hearing, we were scheduled to hear a number of presentations.  First we have Mr. Stephen Rhodes, the Branch Chief of Plastic and Reconstructive Surgery Devices Branch who will provide an update on general and plastic surgery device activities since the last meeting.

            Mr. Rhodes.

            CDR. RHODES:  Thank you, Dr. LoCicero.

            For the record, I am Commander Stephen Rhodes.  I am Chief of the Plastic and Reconstructive Surgery Devices Branch.

            Welcome, members of the General and Plastic Surgery Classification Panel.

            In April this town made recommendations to FDA on two pre-market approval applications for silicone gel filled breast implants, one from Inamed and one from Mentor Corporation.

            Earlier this summer, FDA determined that Mentor Corporation's pre-market approval application was approvable subject to a number of conditions.

            The FDA continues to work with both sponsors on their best implant applications. 

            I also want to update you on two personnel changes in the Division of General Restorative and Neurological Devices since our last meeting.  As you know, Mark Melkerson is the Acting Director of the division; also Dr. Barbara Buch, an orthopedic surgeon, is an Acting Deputy Director, and her responsibilities include the General Surgery and the Plastic and Reconstructive Surgery Branches.

            Today and tomorrow you will make recommendations on the appropriate regulatory classification for five types of general and plastic surgery devices.  Since 1976, this panel has made recommendations and FDA has classified approximately 70 types of general and plastic surgery devices.  Surgeon's gloves, gauze, chin prostheses, lasers, surgical mesh, absorbable gut sutures, and cryosurgical devices are just a few examples of the diverse devices that have been classified.

            Device classification is important because it determines the appropriate types of controls that are needed to insure the devices are safe and effective, and a recommendation from a classification panel such as this one is a necessary step towards device classification.

            The devices you will be considering have been regulated by the Center for Devices and Radiological Health as unclassified medical devices.  In 1997, Congress reminded us of our obligation to appropriately classify all remaining unclassified device types.  For each of the devices that you will consider, the agency is proposing that Class II is the appropriate classification level to assure their safety and effectiveness.

            I want to thank the members of this panel for their time and participation in this important process.  I also want to thanks the members of the Plastic and Reconstructive Surgery Devices Branch who have prepared presentations for you on these device types.

            And lastly, I also want to thank the sponsors and members of the public who are here today for their interest and in some cases presentations to this classification panel.

            Thank you.

            PANEL CHAIR LoCICERO:  Thank you, Mr. Rhodes.

            At this time, I would like to introduce Dr. Sousan Altaie, who will give us a presentation on the FDA's critical path initiative in medical devices.

            DR. ALTAIE:  Good morning,  I'm Sousan Altaie, and I'm Scientific Policy Advisor at the Office of In Vitro Diagnostics, and as one of my responsibilities I do a liaisoning for CDRH to the critical path initiative of the FDA.

            And today I will try to tell you what is the FDA critical path initiative and why is FDA interested in the critical path and what are the critical path tools that we talk about in this initiative and what are medical devices areas of interest under critical path.

            And then I'll go ahead and tell you about what medical devices critical path projects are currently at the center, and then I will ask you to participate, and I will tell you how to participate.

            So critical path is a serious attempt to make product development more predictable and less costly, and if you look at the cycle of device development from basic research to prototyping, preclinical and clinical development and finally FDA application and marketing, critical path is a journey from medical product candidates that ranges from prototyping to marketing.  It does not cover the basic research area of the product development.

            And you might wonder why we are interested in it.  We're interested because we realize the significant benefit of bringing innovative products to the public faster.  We're interested because we have unique perspective on product development.  We see successes, failures, and missed opportunities because the critical path will help us to develop guidance and standards that foster innovations.

            So what do we want to do?  We want to work together with industry, academia, and patient care advocates to modernize, develop, and disseminate solutions.  These are tools to address scientific hurdles in device developments.

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

            And these are some of the critical path tools that we think of in the FDA when we talk about critical path tools.  We think of biomarkers, Baysean statistics, animal model biomarkers, clinical trial designs, computer simulations, quality assessment protocols, post market reporting, and we're also open to any suggestions you might have that we could add to this list.

            So if you look at medical device opportunities in the center, there are a lot of them.  We regulate in CDRH anywhere from Bandaids to stethoscopes, to hand held glucose monitors, to PET scans and heart valves and all sorts of other equipment in between.  So there are a lot of possibilities in looking for tools in development of these devices.

            However, we're different than the drugs in this critical path initiative because we deal with complex components, biocompatibility.  We deal with durable equipment, rapid product cycles on these devices.  We deal with device malfunctions, user errors, and we also put a heavy weight on bench testing as well as clinical studies.  And we are regulated also differently than the drugs we are under quality system regs. in ISO 9000.

            So we're quite different in that matter from the drugs and our issues are different.  So these are kind of medical device areas of interest under this critical path, and for device safety tools, we think of biocompatibility databases, effect of products on diseased or injured tissues.

            Under effectiveness tools we think about surrogate endpoints of cardiovascular device trials.  We think of computer simulated modeling for implanted devices, and under industrialization, we'll look at the practice guidelines for follow-up of implanted devices and also validated training tools for devices within known learning curve.

            These are a series of projects that currently are being carried in CDRH, and I'll explain some of them.  For validation of biomarkers, we're looking to generate blood panels to assess sensitivity and specificity.  For peripheral vascular stents, we are working with Stanford University to develop computer models of human physiology to test and predict failure before going into animal and human studies.

            For interpartum fetal diagnostic devices we're working with NIH to develop clear regulatory path with consensus from the obstetric community.

            We also are collaborating with NIH on pharmacokinetics and image guided interventions.  We are working with CDC and Johns Hopkins to develop a well defined serum panel to test the sensitivity and specificity of the hepatitis assays.  We are working on pathways for statistical validation of surrogate markers, especially in the area of cardiovascular devices, and we are working with medical specialty organizations to develop practice guidelines for appropriate monitoring or permanently implanted devices.

            We are also determining the extent of neurotoxicity testing for neuro-tissue contacting materials, and this is how you could get involved in case you are interested in critical path initiative.  You can send comments to a docket on the FDA critical path white paper and identify areas that benefit from research and development of critical path evaluation tools.

            You also can add the national critical path opportunities list that we are compiling, and we're almost there, and this is where you can find the docket that you could put in your commends on the paper, and the CDRF Webpage under news and events you can find links to the critical path paper as well.

            So at the end, I want to leave you with this thought that at CDRH we believe that insuring the health of the public through the total product life cycle is everyone's business.  So we strongly suggest that you participate in critical path and have some input in that where we go with that with this crucial initiative.

            With that I am open to questions.

            PANEL CHAIR LoCICERO:  Does anyone have any questions for Dr. Altaie?

            (No response.)

            DR. ALTAIE:  All right.  Thank you.

            PANEL CHAIR LoCICERO:  Now, I would like to introduce Dr. Susan Gardner to give us a presentation on recent CDRH changes regarding condition of approval studies.

            DR. GARDNER:  Good morning.  In this particular case the wonders of technology have not overcome an error on my part.  So I'm going to have my slides handed out on hard copy and ask if you would follow along or look up here or something else, and I apologize for that.  We thought we could get them sent in  through wireless technology, and we haven't been able to do it.

            So what I'm going to tell you about this morning is a significant programmatic change in CDRH, and the essence of the change is the move of the condition of approval studies program from the Office of Device Evaluation into the Office of Surveillance and Biometrics, of which I am the Director.

            Briefly, the Office of Surveillance and Biometrics, I think we're often seen as the post market office, but, in fact, we play a large and significant supporting role in the pre-market also.  The statisticians who you often hear from in the panels and the epidemiologists whom you may be hearing from more in the future are in my office.

            We're also responsible for adverse event signal detection by virtue of the fact the we receive all of the adverse event information in terms of about 160,000 adverse event reports a year into the office, along with having some other post market surveillance strategies.

            We're responsible for taking the lead in characterizing risk by looking through our adverse event information and coordinating the center response when it goes out to health care professionals, and we're also responsible for interpretation of the MDR regulation.

            In terms of the regulation, under condition of approval studies, it says that post approval requirements can include the continuing evaluation and periodic reporting on the safety, effectiveness and reliability of the device for its intended use.

            So a couple of years ago, some folks in my office decided to take a hard look at the quality of our condition of approval study program, and they looked at all of the PMAs that were approved from 1998 through the year 2000.  It was 127 PMAs, and of those we had ordered condition of approval studies for 45 of those PMAs.

            Unfortunately we were never able to really get to the quality part because we found that we really weren't able to locate and evaluate many of those studies, and what we found is we didn't have any standardized tracking program within the office to be able to track these studies, and as you might expect, many of the people who had been lead reviewers and responsible had moved on to other positions, as happens in any organization.

            And the additional problem was that in the pre-market side these folks really didn't have the resources to do the job that the center thought, that everybody thought we needed to do in keeping a good handle on these important studies.

            So we came up with the strategy for change, and the strategy, the goal, of course, is because we think it's extremely important, is to make sure that we obtain this important post market information as the device enters the market to assure the continued safety and effectiveness of the device.

            And that's sort of the moment of real world use, which of course is often quite different from the clinical trial use.  And this, of course, will allow us to better characterize the characteristics of the device and help us make better scientific decisions.

            So the change has been implemented.  As of January 1st, the program officially transferred from ODE to OSB, although this was on the heels of a two-year pilot where we worked out a lot of the procedures before it happened, and we tested sort of the key parts of the program.

            We have developed an automated tracking system, and of course, we'll be acknowledging the receipt of study requirements and giving feedback to industry and doing follow-up on these studies.

            Another key part of the change has been to add an epidemiologist to the PMA review team when we suspect that there's going to be a condition of approval study.  The epi folks are responsible for taking the lead in the development of post market monitoring plan during the pre-market review, and in developing -- and this is the key piece here -- in developing really well formulated post market questions.

            They're going to have the lead in the design of the condition of approval study protocol and in the evaluation of the results of the studies after the product has been approved and the studies are ongoing.

            And of course, we're going to keep the team together.  They're going to continue to work with the folks on the pre-market side and everybody else who's been involved in the product approval.

            Why do we think this will work better?  I mean, one is certainly that we're giving it our full attention and we've gotten a lot of cooperation from industry because they also agree that this is really an important part of the program.

            A key part really is the development of the post market questions and the study design.  We have to really ask the right questions, and we have to believe that the study design that we're proposing is important because if we really want industry to follow up and we're going to evaluate this, we want to be in a position where, again, we understand that we're asking the really important key questions.  If those questions change over time during the study, then we come back to the table and we change what we're saying, but again, that's really a critical piece.

            The acknowledgement of the study reports as they come in, the feedback on the study reports we believe will keep everybody more motivated to continue to participate in this, both, again, on the industry side and certainly on the FDA side also.

            We are going to be posting the study status of condition of approval studies on a Website, which we hope we'll be motivating also, and we do have the ability under something called Section 522 to mandate post market studies once a product is on the market, and there are penalties for failure to comply with that. 

            We would hope never to be there.  I mean, I think if we all do a good job in designing these studies and understanding what the questions are, again, there will be a lot of motivation to move forward, but we can do that.

            So what does this mean to you folks on the advisory panel?  I think it may not be quite as important today, but other times I think it will come into play in your role as the advisory panel, and certainly during the approval process.  I think post market questions, first of all, they come up naturally and sometimes they're going to come up very deliberately.

            And as always, we're going to look to you for your advice on what the important issues are and your concerns are post market and at times even ask you for possible approaches to post market and ask for your consideration on those approaches.

            And we're also committed then to coming back to you either with presentations from industry or from FDA so that you will get some feedback on follow-up on what happens to these products after you approve them and find out what we've done as the study design for condition of approval and what those results are.

            Questions?

            PANEL CHAIR LoCICERO:  Thank you, Dr. Gardner.

            Are there any questions?  

            What is the effective date of this change?

            DR. GARDNER:  January 1st.  It is ongoing.  We are currently monitoring and involved in the condition of approval studies.

            PANEL CHAIR LoCICERO:  January 1st, 2006?

            DR. GARDNER:  2005.  I'm sorry.  2005.

            PANEL CHAIR LoCICERO:  2005.

            DR. GARDNER:  Yes, we're there.

            PANEL CHAIR LoCICERO:  Thank you, Dr. Gardner.

            DR. GARDNER:  Okay.  Thanks.

            I'll now ask Ms. Marjorie Shulman of the Office of Device Evaluation to give us a brief overview of device classification.

            MS. SHULMAN:  We're just setting up the overhead.  My PowerPoint didn't work either.

            Thank you all very much.  My name is Marjorie Shulman.  I am with the Program Operations Staff in the Office of Device Evaluation and also the Classification/Reclassification Coordinator.

            I'm just going to give a brief overview of the classification and reclassification process that we're going to follow in the next two days.

            The act divided the devices into two distinct categories:  pre-amendment versus post amendment devices, and that only is a regulatory term that helps differentiate what procedures we follow when we classify or reclassify a device.  So it depends when the devices were introduced into commercial distribution.

            Classification of pre-amendment devices, which is why we're here for these two days, are classified after FDA has received a recommendation from a device classification panel, published the panel's recommendation for comment along with the proposed regulation classifying the device, and then publish the final regulation classifying the device.

            Most of these were done in the late '70s, early '80s, but some were missed in the initial classification, and that's why we're here for these two days.

            For reclassification, we can reclassify a pre-amendment device in a proceeding that parallels the initial classification proceeding, and it's based upon new information developed as a result of the reevaluation of data before FDA originally classified the device or not presented or available at that time, but today we're just talking about classification.

            Post amendment devices are automatically classified into Class III and they remain in Class III and require pre-market approval unless and until the device is reclassified into Class I or II or FDA issues a substantially equivalent determination.

            For reclassification of a post amendment device, it can be initiated either by FDA or by industry, and FDA may for good cause shown refer the petition to a device classification panel, and the panel with recommendation to the FDA respecting the petition.

            So there are three device classes, and the device should be placed in the lowest class whose level of control will provide reasonable assurance of safety and effectiveness.  The three classes are Class I, which are general controls; Class II, special controls; and Class III, pre-market approval.  And now we'll just discuss those.

            Class I are for devices which any combination of the general controls are sufficient to provide reasonable assurance of the safety and effectiveness of the device.  General controls include prohibition against adult trade or misbranded devices; labeling adequate directions for use; pre-market notification if it's a reserve device.  Most Class I devices are exempt from 510(k).

            Ban devices, good manufacturing practices, registration of manufacturing facilities, listing of the devices, record keeping and repair and replacement and refund.

            Class II are for devices which cannot be classified into Class I because the general controls by themselves are insufficient to provide reasonable assurance of the safety and effectiveness, but there is sufficient information to establish special controls to provide the assurance.

            And the special controls include performance standards, discretionary, voluntary, national, international, or ones recognized by rulemaking; post market surveillance, either required or discretionary; patient registries, development and dissemination of guidelines or guidances, design controls, recommendations and other appropriate actions that the panel may recommend, tracking requirements.

            So it may be a combination of any or all of those, and in addition, for Class II, in addition to the Class I general controls.

            And Class III is for devices which insufficient information exists to determine that general controls and special controls are sufficient to provide the reasonable assurance of the safety and effectiveness of such device, and -- and?

            The devices are implants, life sustaining or life supporting, substantial importance in preventing impairment of human health or present a potential or unreasonable risk of illness or injury. 

            So those are the three classes, and that's what the panel will recommend today to classify the three today, two tomorrow pre-amendment devices.

            Are there any questions?

            PANEL CHAIR LoCICERO:  Does anyone have any questions for Ms. Shulman?

            (No response.)

            PANEL CHAIR LoCICERO:  Thank you.

            MS. SHULMAN:  Thank you.

            PANEL CHAIR LoCICERO:  We're about to begin our deliberations of the day, and I would like to note for the record that the voting members present constitute a quorum as required by 21 CFR Part 14.

            At this time we will begin a discussion of classification of bone wax.  We will start with a presentation by Dr. Richard Kronenthal, consultant to Orthocon.

            This will be followed by the FDA presentation.  Then we will have a general panel discussion of this topic followed by a more focused panel discussion aimed at answering FDA's questions.

            Following panel discussion, we will complete the reclassification work sheet and supplemental work sheet.  The vote on these work sheets will constitute the panel's recommendation to the FDA.  There will also be time for public comment before the vote.

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

            Let us begin with Dr. Kronenthal's presentation.

            DR. KRONENTHAL:  I won't use slide.  You can use tabs.

            Thank you for the opportunity to participate in this advisory meeting, and by way of introduction, my name is Dr. Richard Kronenthal.  I've been involved in the development of surgical products for almost 50 years.

            At the present time I hold the position of Vice President and Chief Scientific Officer of Orthocon, which is a new company, recently received 510(k) clearance to market a new bone hemostatic product.

            And this morning I would like to make a presentation on a brief history of bone wax from Horsley through to today.

            It all started following the microbial revelations of Pasteur.  The foundation for modern surgery was established by Joseph Lister who carbolized the operating room and its contents in an attempt to eliminate nosocomial infections.

            Shortly after this surgical revolution began Sir Victor Horsley, an English surgeon, concocted a mixture from beeswax, petrolatum and carbolic acid to control bleeding from bone and named it bone wax.  Interestingly, after a century of use, Horsley's innovation remains available to surgeons.

            A similar ancient preparation no longer in use was the Mosetig-Moorhof wax, recommended for filling bone cavities and comprised of spermaceti, sesame oil and iodoform.   I do not know if additional information concerning the origins of bone wax is relevant to this presentation, but for those interested a Google inquiry concerning bone wax will provide 791,000 references.

            Now, I must stop for a moment and explain I noticed that most of those references have nothing to do with the bone wax that is the subject of our meeting.  It has to do with waxes that have been used to waterproof raincoats and things of that sort, but I just wanted to see what was on the Internet in bone wax, and that's what came up.  Very little of that has to do with what we're going to be talking about today.

            So during the first half of the last century, aseptic surgery became a practice reality.  Newer sterilization methods and packaging systems made the addition of harsh chemical disinfectants to products such as bone wax much less common.  Thus, linolix (phonetic) and similar additives were eliminated together with their tissue toxicity consequences.

            Today the most widely used bone wax is a foil packaged radiation sterilized mixture of synthetic beeswax, not the natural, softened with isopropyl myristate, which is a fatty acid ester, to improve the handling properties of the material.  This product, Ethicon bone wax, has been virtually unchanged for more than 50 years, although the inconvenience about it is that it usually must be warmed and kneaded by the surgeon to soften the product before it is applied to the bleeding bone.

            There are no tissue interactive, biochemical clotting reactions associated with use of bone wax.  It is not an active hemostat.  It performs its hemostatic function solely by the physical mechanism of pressure tamponade as it is pressed into the pores of the cut bone surface.

            The number of orthopedic procedures is rapidly growing.  Surgeons are becoming increasingly attuned to the need to control bone bleeding, which for example in extensive decortication procedures can be so severe if uncontrolled that blood transfusion may be required.

            While all presently available bone waxes are certainly safe and effective if used in accordance with the surgical recommendations provided in a product package insert, the insert instruction that a minimal amount of product, just sufficient to provide hemostasis, should be used, and that excess, nonfunctional material should be removed.

            That may not be familiar to most surgeons.  Excessive amounts left in the wound may have adverse consequences.

            Speaking to that point, excessive amounts of nonabsorbable bone wax left in the wound occasionally may slow down or interfere with healing as well as act as a possible nidus for postoperative infection.

            In addition, intraoperative handling properties of available products, while long found to be acceptable, can be made even more optimal.  In a recent 510(k) clearance for bone waxes reflect the desire to improve some of these suboptimal characteristics of this type of product.

            In other words, it would be ideal to maintain the hemostatic safety and efficacy of the present products while improving less desirable, for example, handling characteristics.

            There is a long history of safety and efficacy reflected in the use of the present products.  In addition, modern technology has made available a broad selection of adequate and sensitive general control procedures.  These controls may involve both in vitro, such as chemical and physical characterization, and in vivo, such as tissue reaction testing, making the need for Class III regulatory requirements unnecessary.

            In my opinion, given the well established history of safe use and the available procedures for assuring safety and efficacy, it is entirely appropriate to classify hemostatic bone wax materials as Class II devices.

            Thank you.

            PANEL CHAIR LoCICERO:  Questions, comments?

            (No response.)

            PANEL CHAIR LoCICERO:  We will now have the FDA panel presentation.

            DR. KRAUSE:  Good morning.  I would like to extend my welcome to Dr. LoCicero, panel members, Mr. Melkerson, attendees from industry and the FDA, and all other attendees who have taken the time to attend this meeting of the General and Plastic Surgery Devices Panel.

            My name is David Krause.  I'm the Executive Secretary of this panel, but I'm also a reviewer in the Plastic and Reconstructive Surgery Devices Branch in the Division of General Restorative and Neurological Devices, and today I've been the branch member who has been selected to present the bone wax presentation to you.

            The FDA would like you to propose a recommendation for the classification of bone wax.  However, the agency would like to suggest that classification into Class II would be appropriate.

            During this presentation, I will focus on the following topics.  I will begin with what the FDA considers the definition of bone wax.  I'll go on to reasons why the agency believes that Class II is an appropriate classification for bone wax; give a brief history of the regulation of bone wax; go on to discuss what is in a special controls document; discuss updated risks and MDR reports; and finally give you a little bit about the FDA's thinking on the classification of bone wax.

            As Dr. Kronenthal pointed out, we consider bone wax to be a bone adherent material that's used to control bleeding from bone via the physical mechanism of tamponade.  We do not consider bone wax to have similar attributes as the absorbable hemostatic agents which in many cases interact with cells and allow the degranulation and clot formation due to a biochemical interaction with the blood.

            As far as the agency is concerned, bone wax acts only through the physical mechanism of tamponade.

            The major ingredient of most bone waxes or traditional bone waxes has been white beeswax.  Bone wax also includes softening agents, such as oils and palmitates.

            This is just a brief review of classification, and since Ms. Shulman did a fine job of covering this, I'm just going to skip over it.

            The FDA believes that classification into Class II would be appropriate because of the long history of use of bone wax and because classification into Class II would meet the FDA mandate which is to apply the least burdensome approach to regulating medical devices.

            Bone waxes have been used in orthopedic and other surgeries involving bone since approximately the 1880s, after Sir Horsley and also Rushton Parker introduced this product into the surgical armamentarium.

            The material proved effective in controlling bleeding from bone, but was also noted to interfere with some bone regrowth.  From the early 1900s until 1976 when President Ford signed the device amendments to the Food, Drug and Cosmetic Act, bone wax was not regulated.  After the signing of the device amendments, bone wax remained unclassified as it was overlooked and not recommended for classification by the original classification panels.

            Bone wax has been regulated via pre-market notification since 1979 when the pre-market status of bone wax was established.

            Since 1976, the Center for Devices and Radiological Health has cleared via the 510(k) process six additional bone waxes.  As far as I can tell, there were two pre-amendment bone waxes on the market in the United States.  One was Luken's bone wax, which has an established history that goes back to at least 1904 and also Ethicon bone wax, which also has a history that goes back to about 1942.

            Since then, we've cleared a number of other bone waxes as you can see on this slide.  The one by US Surgical has a glycolide base, which is absorbable.  Aesculap is white beeswax mostly.  CP Medical also white beeswax.  Ceremed, alkaline oxide copolymer based.  That one is also absorbable.  Surgical Specialties has a white beeswax that's actually they call that one Lukens.  They bought the rights to us the Lukens name, and a recent one that Dr. Kronenthal was talking about by Orthocon which has a base material of calcium stearate and is also absorbable.

            So you can see most of the waxes that we've presented here have a formula that contain white beeswax, which for the most part is considered nonabsorbable.  Some of the more recent ones have resulted in absorbable bone waxes with formulations including lactate, alkaline oxide copolymers and calcium stearate.

            The most common special control that it is used to date is a guidance document.  These are subject to updates and are not considered requirements.  However, these special control guidance documents give industry an idea of the types of information the agency would like to see provided in a pre-market notification application that is intended to support substantial equivalence.

            This is a general format for a guidance document.  It's by no means the only format.  Some of the sections will have different names, depending on what sections we feel are necessary to include, but anyway, this will give you an idea of what a special controls guidance for bone wax might look like.

            Keep in mind that we can update these as new information becomes available.

            Section 1 would include general information, including a brief explanation of why the guidance document has been written, the device for which the guidance document has been written, and references to the Federal Register, and it would also identify any previous guidance documents that are superseded by this new guidance document.

            The background section would state that the FDA believes that special controls, combined with the general controls that Ms. Shulman listed before, would be sufficient to provide reasonable assurance of safety and effectiveness. 

            The section also includes a brief summary of which sections contain the regulations and risks, et cetera.

            Also, this section identifies Websites and documents that give advice on the submission of the 510(k), including the rationale for the least burdensome approach.

            Section 3 contains standard language which discusses the content and format  of an abbreviated 510(k) submission where standards are cited in certain instances in lieu of providing actual data.

            Section 4 is the scope section and would provide things like product codes and definition of the device, et cetera.

            Section 5 discusses risks to health.  This section is where the FDA begins to provide information that's not standard to most guidance documents.  Here there are specific risks to health for bone wax would be identified and methods for amelioration of those risks.

            In a few slides we'll be putting up a table which addresses these risks.

            Section 6 would be the material and performance characterization.  It would provide an outline of the types of physical and chemical characterization that the 510(k) should include.

            Section 7 would discuss types of animal testing, such as determination of time to bone hemostasis, affect of bone wax on infections, et cetera, that would be necessary to make an assessment of safety and effectiveness.

            Clinical testing section may not be necessary, but we would include it here, and it would give the types of clinical testing that we would like to see if we felt that the bone wax product was a new material or something totally different and would require clinical data to establish safety and effectiveness.

            The sterility section contains standard language referring the reader to a Website and guidance documents that discuss the sterilization information recommended for submission in a 510(k).

            Biocompatibility section also contains standard language that refers the reader to the international standard ISO 10993, which the FDA follows for the most part for establishment of biocompatibility.

            And Section 11 would be a section that contains standard language about labeling which may include some suggestions that are specific to bone wax at the end.

            I went through the literature or actually I went through MDR reports at the FDA database and could only find four for bone wax, and two of those were infection.  One was granuloma, and the other one was paralysis.

            The reports weren't that specific, and I couldn't find out why there was paralysis, and it also didn't go on to say about whether or not that resolved itself.

            The MDR reporting system was voluntary from 1992 until 1996, at which time it became mandatory.  So this list is complete up until July of 2005.

            By searching the literature and looking at MDR reports and reading through the labeling of currently marketed bone waxes, I was able to identify the following risks and proposed methods for the mitigation of those risks.

            Of course, the first risk would be uncontrolled bleeding, and we feel that that can be addressed with animal studies and also clinical data, if necessary.

            Infection and fever, again, animal studies, device labeling, quality system review and bench testing for inflammation and edema.  Again, animal studies and labeling.

            The paralysis, we feel that proper labeling could avoid that. 

            Granuloma formation, again, animal studies and labeling.

            Failure to be absorbed for those that are intended to be absorbed, animal studies and bench testing could address that.

            Interference with methyl methacrylate adhesives could be addressed in the labeling.

            Product failure due to anticoagulation therapy and animal studies, and again, should be addressed in the labeling. 

            Interference with bone regeneration, we feel bench testing, animal studies, and again should also be addressed in the labeling.

            Based on the history of the use of bone waxes and the familiarity of the medical community with this product, the agency feels that a recommendation of Class II would be appropriate in order to effectively regulate this medical device.

            For listing in the 21 CFR, the following identification is one that the agency is proposing.  A bone wax is a bone adherent material used to control bleeding from bone via the physical mechanism of tamponade, and classification to Class II. 

            Please keep in mind that this would require a guidance document that has passed through the agency's good guidance practices review process.  The guidance document could be titled something like Class II special controls guidance document for bone wax, draft guidance for industry and FDA personnel.

            This ends my presentation.  These are the questions that we would ask you to please keep in mind when you discuss the FDA questions and hopefully by addressing these questions you'll then be able to fill out the questionnaire afterwards.

            Thank you.

            PANEL CHAIR LoCICERO:  Any questions for Dr. Krause?  Dr. Newburger.

            DR. NEWBURGER:  Dr. Krause, I just went down to the MAUDE database for bone wax, the more recent adverse event reporting system.  I found quite a few reactions reported with bone wax.  Could you clarify for me how you would look at MAUDE versus the MDR database, please?

            DR. KRAUSE:  I don't know.  I just looked at the one database that I usually look at.  If the MAUDE is better, maybe next time I'll look at that one.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  The handout that we received regarding the differences between the original bone wax formulations and the synthetic bone waxes make it apparent that there is a complete difference in the post application of those in that the synthetic bone waxes, which are artificial polymers apparently are fully absorbed by the clearance mechanisms of the body over some period of time, whereas the original bone wax formulations are not.  They're permanently implanted, and they're treated as a foreign body by macrophage and so forth.

            That's a huge difference in behavior of two products.  The fact that the products are intended for the same use does not make their behavior in the body the same, and so it's difficult for me to understand how those two products can have all of the same things apply to them.

            The second question is you haven't addressed any of the issues of efficacy in regard to the synthetic bone waxes versus the original bone waxes.  Is it accepted that they are equally efficacious in use and in hemostasis for the intended primary purpose of controlling bleeding?

            And then the third point is that there is one particular use of bone wax which leads to major morbidity and significant mortality, and that is in dividing the sternum for access to the heart for coronary bypass operations, bone wax is used liberally on the two edges of the sternum to control bleeding, and that's the only agent which is very effective for that.

            And when the coronary arteries are used for revascularization of the myocardium, which is quite frequent, then the incidence of dehiscence of the sternum becomes very, very significant.  If both coronary arteries are taken, the incidence of dehiscence may rise almost to double digits as a complication rate, and it certainly is in the range of two to five percent incidence.

            Once the sternum dehisces, very extended morbidity and significant mortality ensues.  If truly the newer formulations of bone wax are fully absorbed and the possibility of the foreign body reaction is eliminated, then it could have very significant impact on that particular problems.

            So it's a very significant issue.  As far as I know, it has not been studied by the cardiac surgeons, but I would certainly defer to them because it's not my area of expertise, but I believe it's a quite significant area in terms of morbidity, mortality, and impact on clinical use, and you haven't addressed it, and I wonder what you would suggest about that.

            DR. KRAUSE:  Okay. Let's try to work our way through these questions.  The first question was about the difference in the formulations.  What we've done is there's the pre-amendments device, which is what we're classifying, which is basically your Horsley's wax.

            Over the years, we have found other products, namely the absorbable polymers that you're referring to as substantially equivalent to the Horsley's wax in what we consider the most important characteristics of bone wax, which is the control of bleeding, allowing the surgeon to close the patient, and those types of processes and functions of bone wax we received data in the 510(k) where comparisons were made as far as time to hemostasis, things like that, of the polymer bone waxes to the original bone wax, and were able to confirm that there was equivalence, as far as that is concerned, and I think that answers your first two questions.

            As far as the question about the use in cardiovascular surgery, we don't deal with medical techniques and medical practices here.  We try to assure that the labeling fully discloses the potential problems, and if you look at most of the labeling for bone wax, it does say that healing of the bone, regrowth of bone can potentially be inhibited, and that the surgeon, once he has placed the bone wax and once he has achieved hemostasis, should remove as much of the bone wax as is possible while maintaining hemostasis before closing the patient.

            So similar issues come up with some of the absorbable hemostatic agents where they do cause problems when they're left in the patient and can cause problems when not used according to the labeling.

            So we do ask that the labeling is clear about these things, and one of the things we'd like for you to do here is to make recommendations about, you know, what should be included in the labeling and those kinds of things.

            I mean, I certainly think that what you were talking about with the problem with dehiscence of the sternum would certainly be something that should be, you know, put in the labeling so that people can be made aware of that.

            I remember when I was working on a task force for absorbable hemostatic agents that some of the surgeons we talked to didn't know that some of

these absorbable hemostasis agents can swell tremendously, and if you put them in the wrong place, they can cause paralysis and all kinds of problems.

            So I think it's important for, you know, the medical community to, you know, not only recommend to us what we should put in the labeling, but also to read that labeling and make sure that they apply the principles that are in the labeling to the product.

            PANEL CHAIR LoCICERO:  Yes?

            DR. LEITCH:  With respect to the issue of would the synthetic waxes be better for the purpose of wound healing, is there any research that has indicated that they are superior in that regard?

            I would think that even though they're absorbed, the duration of time is long, and so that healing issues would probably be similar between the absorbable and the nonabsorbable, although they might be different with respect to granuloma formation over time.

            So do you know of any data on that?

            DR. KRAUSE:  Most of the data that I've seen show absorption of the absorbable bone waxes to take place by approximately 60 days, whereas the Horsley's wax, if it's applied and, you know, scraped off for the most part, surgeons who have gone back years later can sometimes still find traces of it.  So it appears that it does absorb somewhat slowly, but probably takes years, whereas the new polymers will probably be completely gone.

            You know, the lactate based ones, I think, last a little longer, depending on exactly how much of the lactate is in the formulation.  They might last 90 to 120 days, but the stearate and the alkaline oxide copolymers appear to resorb fairly rapidly.

            DR. LEITCH:  But you don't know anything about the differences in healing between those two?

            DR. KRAUSE:  From the literature and the data that was provided to us, the healing appeared equivalent.

            PANEL CHAIR LoCICERO:  Any other questions for Dr. Krause?  Yes, Dr. Lewis.

            DR. LEWIS:  I have no idea what the experimental evidence is, but in the document passed out under beeswax, it notes inhibits osteogenesis and under polymer bone wax it says permits osteogenesis.  Therefore, they might well affect healing rates since synthesis of the sternal sides is dependent on osteogenesis.

            DR. KRAUSE:  Right.  I agree, and again, the experiments that were done to show that used large amounts of the bone wax and large amounts of the synthetic polymers, and in surgical procedures when we received data from the companies and we asked them to show us that the companies that make bone wax -- we asked them to provide us with data on healing.  They, you know, will cut bone.  They'll make a nice, clean cut.  They'll put the bone wax on.  They'll establish that they achieve hemostasis, and then they'll take most of it off, show that it's not rebleeding and then look at healing.

            So, you know, there's only minimal amounts of bone wax left on the bone, which I think is important when it comes to regeneration.  I think if you leave a big wad of bone wax you're going to definitely have problems with bone regeneration, but if you can get rid of most of it, then regeneration may proceed, probably not as good as with an absorbable wax, but eventually the wax does get absorbed away, and healing can take place.

            PANEL CHAIR LoCICERO:  Any other questions for Dr. Krause?

            (No response.)

            PANEL CHAIR LoCICERO:  Thank you.

            We will now start our panel deliberation portion of the meeting.  This is a general discussion of what we've heard so far and the materials that we received prior to the meeting.

            Dr. Lewis, I think just a correction to your comments earlier.  I think you said coronary arteries.  I think you were referring to the internal mammary arteries of the clinical anastomosis term "internal thoracic arteries."

            DR. LEWIS:  Yes, you're correct.  I was talking about the internal mammaries that you use for coronary revascularization. 

            PANEL CHAIR LoCICERO:  Right.  Dr. Lewis, do you have any additional comments at this point?

            DR. LEWIS:  Well, it's interesting from Dr. Krause's presentation that there are, in essence, none of their reporting complications that come in relative to sternal surgery since that particular problem is not identified as a complication of related bone wax, and so the numbers they're seeing, which are quite low relative to bone wax complications, don't reflect that particular entity since it's due to a lot of other factors as well as the bone wax.

            So I think some appreciation of the magnitude of that problem may not be present, and I suspect most cardiac surgeons are not all that aware of the role of bone wax in the effect on bone healing.

      Panel Chair LoCicero: I might say having observed many cardiac surgeons, there's a wide variation in the method of application of bone wax, and some cardiac surgeons have gone away from the use of bone wax and made their own off-labeled products with antibiotics and other things and have similar rates of dehiscence unfortunately.  So I think it's unclear certainly at this point.

            Dr. Ewing?

            DR. EWING:  I share Dr. Lewis' concerns about the difference between the Horsley beeswax and the absorbable polymer.  In the clinical data that we were given, there seems to be at least a difference in bone regeneration and in osteogenesis, the infection rate, granuloma rates, but it didn't say if that difference was significant or if it was related to whether or not the wax was removed or not, and so I'm not sure how important those differences are, but I think it's something that should be addressed.

            PANEL CHAIR LoCICERO:  Dr. Doyle, do you have any comments?

            DR. DOYLE:  Not at present.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No comments at this time.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  I just had one question.  The presentation you mentioned for paralysis, that a mitigation would be on the labeling, but I didn't see that in the panel packet.  So is that going to be resolved, I assume, after this panel meeting?

            DR. KRAUSE:  Yeah, I think we updated some of the slides during our preparation and since we hadn't -- you know, since paralysis showed up as one of the events, I had inadvertently overlooked it.  So I thought I should add it to the table.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  Thank you.

            I'll make two comments if I might.  First, with respect to the bone healing, as you've mentioned, Dr. LoCicero, surgeons have varied widely in how they apply the bone wax.  I think that when we're worried about bone healing we remove the bone wax, and so I don't know that that's an enormous issue from a regulatory perspective.  I would consider that a surgical practice, that issue.

            For example, not in the cardiac surgery, but in spine surgery that I do, sometimes I'm concerned about effusion, and when I'm concerned about effusion during the decompressive part of the surgery if I need to stop bleeding, I'll put bone wax on the cancellus bone.  When it comes time for the fusion, I'll take a burr and burr away that small area of bone that has bone wax and prepare just like I'll prepare that surface for effusion from a variety of other perspectives.  I'll make certain the bone wax is gone.

            An example of where it doesn't matter is on the anterior surface of a vertebral body.  If we've put a screw in temporarily to hold from external fixation, to hold things still while we're doing the reconstruction, when that's done, that part of the vertebral body is not involved in the fusion.  I'll plug that hole with bone wax and leave it there.

            So I think from a regulatory perspective, I would respectfully submit it's a non-issue.  The surgeon will take care of that with respect to her or his practice.

            That's my only comment.

            PANEL CHAIR LoCICERO:  Any further comment?

            DR. LEITCH:  No.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  I would agree with Dr. Yaszemski.  I think there is a difference between some issues raised with the product and the surgeon's practice.   I think if the product was used properly and with an understanding of its effect on bone healing, then probably its negative consequences of its use would be minimized.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  I understand from some of my colleagues in the community that they commonly see reactions such as foreign body reactions or assist formation from the other formation, but I also understand from them that when you have a lot of bleeding, there's nothing that's quite as effective as the use of wax.  I don't understand though why the comparator -- why the comparison is in our deliberation here.  Is this not something that's already available and we're just trying to classify it, but it's in common use?

            PANEL CHAIR LoCICERO:  Maybe we could just get a clarification from Dr. Krause.

            DR. KRAUSE:  Perhaps Mr. Melkerson should comment on what would happen depending on your recommendation of what class.

            MR. MELKERSON:  In terms of which class for separating reservable or nonreservable?

            DR. KRAUSE:  No, I think Dr. Newburger's question is these are regulated products, you know.  Once this panel makes a recommendation, will these products remain available?  What's going to happen?

            I think, you know, there's a distinction with Class I, Class II, and Class III, depending on their recommendation, what could happen.

            MR. MELKERSON:  Currently if you recommend Class I, Class II, or Class III, if you're recommending Class III, usually there's a time frame associated with providing evidence of safety and effectiveness.  If you're recommending Class I or Class II, it would probably not change the availability of those products.

            DR. KRAUSE:  I think, you know, if you recommend Class III at some point we would probably, you know, have to call for PMAs, and at the PMA submission, if the company did not submit a PMA for the project, it would, I think, legally need to be withdrawn from the market.

            MR. MELKERSON:  That is correct.

            PANEL CHAIR LoCICERO:  Does anyone have any further general discussion?

            (No response.)

            PANEL CHAIR LoCICERO:  At this time we can begin to focus the discussion on the FDA questions.  Dr. Krause would you please put up these questions on the screen for us?

            At this time we will not refer to the reclassification questionnaire.  We will do that after the discussion of the questions is complete.

            Please consider bone wax in all of its forms while responding to this question.

            Question number one:  please discuss the proposed classification for bone wax.  Please also discuss what descriptive information and intended use indications should be included in a classification identification.

            Let's begin with Dr. Ewing.

            DR. EWING:  I think it's important.  It seems one of the important factors for using bone wax, either the Horsley or the absorbable polymers to make a notation for the user of that device to make sure that they try to remove as much of it as possible, and so I think that that should absolutely be included in the descriptive use of this device.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  Well, it appeared that there was agreement on Class II by the FDA and the parties.  That seems appropriate, given what's been presented.  I do think descriptive information should include adequate information distinguishing between the two types of bone wax and what is known about them in terms of the metabolism, and I think as already mentioned, the use in external surgery is a bit different than the use in orthopedic indications.  It might be highlighted as an issue that should mandate removal when possible with the prior closure.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  I agree with these comments and would like the underline the areas where non-union in theformer generation is critical, that significant measures be taken to remove  all nonabsorbable bone wax.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  I think a Class II is a sensible classification, and the guidance document which clearly describes how they perform some of the issues related to their use would be adequate.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  I think Class II is a reasonable classification for this product.  I think as others have said, the discussion of its impact on healing, you know, if you say don't use a lot of extra rats, say what the reason is, that it is an issue of healing. 

            I think Dr. Newburger was suggesting that you might make the point of the difference between the absorbable and nonabsorbable with respect to healing, but I'm not sure we have data to say that that's correct.

            Again, I think a 60-day absorption, the healing stuff that has to go on is happening before that, and so I'm not certain one could -- there is data that you would put in -- unless you could find it, that you could put in the document to say that an absorbable would be preferable in the circumstance of the healing, you know, requiring fusion because I think some of those initial steps in healing that go on would be impacted by either product at the early onset.

            PANEL CHAIR LoCICERO:  The ultimate wound healing may be the same.  Is there a difference, do you think in the one product imbibing water, absorbing, becoming more voluminous?  Would that be an issue?

            DR. LEITCH:  I mean, I think this issue of, you know, the swelling and nerve compression could be.  I don't know.  I mean, I suppose it could be at a micro level an issue on healing as well if there were, you know, substantial swelling.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  I have nothing new to add, and I agree with Class II

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  I agree with Class II, and I think in terms of some of the comments that have been made by some of the other panel members, I think maybe perhaps that might be more appropriate in the guidance document in terms of what the companies need to put in their labeling as opposed to the identification of, you know, what this classification is.

            There is a proposed identification in the slide that Dr. Krause presented, and just in my experience I find that that's a more generic description of what the classification is as opposed to specific like warnings or indications for the device.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I have nothing to add.  It seems to me Class II is appropriate.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I believe Class II seems sensible.

            PANEL CHAIR LoCICERO:  To summarize, there is consensus that Class II would be the appropriate classification and a further identification that there are two groups, nonabsorbable and absorbable, and that these may have some implied differences.

            Some of the other discussion leads toward the labeling.  Is this sufficient to answer FDA's first question?

            MR. MELKERSON:  Yes, it is.

            PANEL CHAIR LoCICERO:  The second question:  please discuss the possible risk to health that may be associated with bone wax.

            Let's begin with Dr. Doyle.

            DR. DOYLE:  I'd like to hear Dr. Newburger speak a little more about the database that she found that had more risks to health.

            PANEL CHAIR LoCICERO:  Maybe this would be an appropriate time to just briefly talk about that.

            DR. NEWBURGER:  If you go on to the CDRH MAUDE database you get a two-year grouping, reported adverse events, and if you just type in bone wax, you know, for the most recent year there's about a dozen adverse events, including nonunion or cyst formation.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Blumenstein?

            DR. BLUMENSTEIN:  I have no comments.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  No comments.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski?

            DR. YASZEMSKI:  I'm looking at the identified risks from the reading materials that we were given, and I'm going to make this comment again just as an emphasis of the comment I made before that we try as best as possible to separate surgical practice from risks that are inherent to the device itself.

            And I think here uncontrolled bleeding due to device failure.  I would argue that that's a surgical thing because at the point that the surgeon says the bleeding is controlled, he or she has to be certain of it, and I don't know that it depends on the device.  I don't know that.  I could envision a situation where I looked at a cancellous bone that was bleeding, thought that the hemostasis was appropriate based upon the application of bone wax, and then after making that decision, a failure was because of the bone wax.  I would submit that the failure would have been because I didn't make the correct decision that it was an appropriate hemostatic treatment.

            Infection, I think that's probably something to deal with, the second one on the list, and due to improper sterilization, I think that we ought to insist that they're sterilized properly.

            Inflammation and edema, I would agree that their risks, body reactions to the material and should be addressed.

            The same to be with granuloma formation.

            Failure to be absorbed, we've just heard a lot of discussion about the two types, and one type is supposed to be absorbed.  So it would be certain that that isn't something that's applied to both because the general person reading this, even a physician, may not understand the difference between the absorbable polymer type and the bees wax type.

            Reduced strength of methyl methacrylate.  Again, I hope that folks who are using methyl methacrylate understand that you can't put bone wax between methyl methacrylate and the bone it's supposed to move into to provide a mechanical interlock.  I don't think that has anything to do with the bone wax itself.

            Antiplatelet drug therapy and heparinization, again, that I think is a medical thing.  If the person is more at risk to bleed than that person, the surgeon doing the procedure needs to understand that and use perhaps a different method of hemostasis.

            And interference with bone regeneration, I would say to Dr. Lewis I was listening when you talked about the differences before between cardiothoracic surgery and orthopedic surgery.  I guess I would think that the bone biology is the same, and again, it's a surgical technique, and maybe just like all orthopedic surgeons don't understand the inhibition to bone healing when the bone wax is on the surface of the bone, perhaps not all cardiothoracic surgeons understand, and I would suggest that we all need to educate each other, and that's not an inherent property of the bone wax.

            So a couple of these apply, but a couple of them I think don't apply.

            Thank you.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  I agree with many of those comments as well.  I think it's sort of one of my pet peeves about listing risks that really aren't attributed to the device function itself but something else that's going on, and that would be uncontrolled bleeding due to device failure.  I mean, you have to apply it, but if you sit there and it's bleeding then, you know, there's something else that has to be done.

            And the same thing of anti-platelet therapy and heparinization.  I mean, you're looking at a mechanical compression device versus other types of hemostatic agents.  So I think it's not that that therapy, quote, makes the bone wax work less better because it interacts with it in some way.  It's that bleeding is more likely to be more extensive if you have those therapies going on.

            So, you know, sort of explaining and in a risk discussion to explain how that really is related, and then you know, this interference with bone regeneration, I think, again, as a discussion of application techniques so that it's handled properly.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  I don't have anything to add.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Nothing further.

            PANEL CHAIR LoCICERO:  Dr.  Lewis.

            DR. LEWIS:  In looking at the table, I would agree with many of the comments of Dr. Yaszemski.  I think the listing of uncontrolled bleeding due to device failure is really not a failure with risk of bone life.  I think that's a function of the underlying situation, and that doesn't seem appropriate.

            Infection due to improper sterilization seems to me not to be a property  of bone life itself and would come off, and antiplatelet drug therapy and heparinization increasing the risk is kind of a general problem.  It's not unique to bone wax.

            Those three things seem to me to be inappropriate.  I would take them off.  The other five seem appropriate, and I would add something in regard to the difference in behaviors in the two types of bone wax since that's not highlighted in anything here.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Ewing.

            DR. EWING:  I have to agree with those comments.

            PANEL CHAIR LoCICERO:  Mr. Melkerson, there seems to be general agreement that the risks are inflammation and edema, granuloma formation, and failure of absorption for the absorbable product.  I think the panel feels that there needs to be some language that distinguishes between the two types, although they both perform the same function.

            There was less agreement about infection and bone inhibition, however. 

            Does this answer the FDA's concerns?

            MR. MELKERSON:  Actually I have a question back to the panel.  Some of the comments that I understood were with regards to it's education of the surgeon.  One of FDA's mechanisms for doing that is labeling whether it's precautions or warnings, just to point out the fact of removing excess bone and some of these other issues.

            Would that be an appropriate thought for some of these that you were describing as maybe not being inherent to the bone wax, but are inherent to the education of the surgeon using the product?

            PANEL CHAIR LoCICERO:  So this would be an issue of labeling concerning removal of excess bone wax.  Does anyone disagree with that?

            (No response.)

            PANEL CHAIR LoCICERO:  Does that answer your question?

            MR. MELKERSON:  I believe so.

            PANEL CHAIR LoCICERO:  Okay.  Question number three:  please discuss whether the special controls listed in the FDA guidance document are adequate.  Let's begin with Dr. Leitch.

            DR. LEITCH:  Are those the mitigation measures?

            DR. KRAUSE:  I think what we're getting at there is next to each risk there is a method to alleviate the risk.

            DR. LEITCH:  Right.

            DR. KRAUSE:  And it refers to a part of the special controls guidance document.

            DR. LEITCH:  Okay.  Again, like uncontrolled bleeding due to device failure, let's see, animal testing, clinical data, and labeling, I guess the first issue is, you know, does bone wax work for achieving hemostasis, and I guess that's what you mean by animal testing.  Okay.

            DR. KRAUSE:  Yeah, there's a test like where the company would assess how well the bone wax adheres to bone.

            DR. LEITCH:  Okay.

            DR. KRAUSE:  And they would provide us with that data, and they would compare their product to the bone waxes that have previously been marketed.

            DR. LEITCH:  Okay.

            MR. MELKERSON:  Dr. LoCicero, just to focus everybody, the proposal of what a special control would look like is actually part of Dr. Krause's presentation.  So if you're looking for that information, I've seen people shuffling papers.

            PANEL CHAIR LoCICERO:  Okay, and just to clarify further, this would be if a new product were to wish a classification in this area as receiving the same indication, this is the sort of information that FDA would want to see.

            MR. MELKERSON:  Right.  This is guidance to industry as well as the review staff on what are the appropriate questions to be addressed in the 510(k) submission.

            DR. LEITCH:  Then, you know, the interference with bone regeneration, I think what everybody has said before is that the labeling talking about application issues would be important, not just the description of the animal studies, but more the issue of, you know, adding to that how you can avoid those problems or mediate those to some extent.

            I think those are my main comments.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  I'll start by saying that I'm page 8 of Dr. Krause's handout that goes over potential risks and controls.  There are nine of them.  So assuming that we keep all nine of them because our prior discussion was that perhaps some of them aren't necessary on this list, but assuming we keep all nine of them, I would think that under uncontrolled bleeding labeling would be enough, and I'll also preface the comments by saying I agree enthusiastically with the discussions that have said it should be noted whether any new formulation is beeswax or a polymer that has either been used before or is a novel polymer.  I think that the users ought to know that, especially if a bone wax comes out that's a polymer that hasn't been used before.  Then I think bees controls become very important in that situation.

            And so infection, I guess animal studies if it's a new polymer would be fine.  I'll agree with what's listed there.

            Similarly for inflammation and edema.

            I agree with paralysis as labeling, and although there's been a case report of paralysis and it's such a significant complication that it should be  probably mentioned separately as it is.  I think that a general labeling comment that we try not to leave excess bone wax around.  It behaves like any other solid foreign body.  It can go places that it's not supposed to go would be enough.

            Granuloma formation, okay there.

            Failure to be absorbed, again, there has to be a clear distinction as to whether it's one that's supposed to be absorbed, and that can be done with labeling, and if it's one that's supposed to be absorbed, animal studies are fine.

            The interference with MMA labeling is fine. 

            Product failure due to anticoagulation therapy, I would say that animal studies probably aren't necessary.  If someone is on anticoagulation, the physician simply needs to know that, and labeling would be fine.

            And similarly, for interference with bone regeneration, I think labeling would be fine.  We know if it gets in the way it's going to interfere with bone regeneration.

            That's all I have.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  On that same list for infection and fever I assume bench testing includes things like sterilization validation.  Is that --

            DR. KRAUSE:  Yes, quality system review.

            DR. BARTOO:  Okay, and also just to clarify, there's the outline in your presentation, but there was also some text.  That proposed text was what would go in those sections, right?

            DR. KRAUSE:  Yes.

            DR. BARTOO:  So that's also what we're supposed to be commenting on?

            DR. KRAUSE:  Right.  The text is in the memorandum that we sent you, not in my slide presentation.

            DR. BARTOO:  Right, okay.  I don't actually have any comments on that.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No comment.

            DR. DOYLE:  Nothing to add.

            PANEL CHAIR LoCICERO:  Okay, Dr. Doyle.  Thank you.

            Dr. Ewing.

            DR. EWING:  Again, I just want to also agree that the uncontrollable bleeding and what's to be employed is not inherent in so much as a device failure, but a use by the providers.  But I think device labeling is very important for those, too.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEITCH:  I agree with those comments.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Also concur.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  Can I just ask one question?

            PANEL CHAIR LoCICERO:  Yes.

            DR. MILLER:  This is supposed to not just address the current, but if somebody comes up with a new product, what they have to demonstrate.

            PANEL CHAIR LoCICERO:  Yes.

            DR. MILLER:  Is that correct?

            PANEL CHAIR LoCICERO:  Yes, sir.  Yes.

            DR. MILLER:  And so I think that, you know, uncontrolled bleeding is not necessarily a device failure with current products, but if someone sells a new product, it could not work because of the failure of not adhering to bone or whatever so that it has to be proven to work.

            I understand the function of the guidance document is to do that.  So I think it's appropriate to include the resolving this in animal studies and clinical data.

            Is the labeling sufficient to cover the issue of certain education?  Is that considered sufficient?

            PANEL CHAIR LoCICERO:  Okay, and did this bring up any additional comments for anybody?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  To summarize in general, these suggested controls are adequate.  I think there is some discussion or fair agreement that failure due to anticoagulation therapy is not something that needs testing, but labeling would be sufficient and there is an important issue concerning new products and uncontrolled bleeding that fell off after 15 minutes and didn't work, that maybe that would be an issue.

            So do these summaries of this information, is this adequate for the FDA?

            MR. MELKERSON:  Yes, and I would make one comment and try to respond to your question.  It's a product that we submitted to the FDA and did not control bleeding.  FDA, based on the guidance document and the review of that 510(k) submission, could find it not substantially equivalent, not allowing it to be marketed.

            So for new products as you describe, those are important issues that need to be addressed.

            PANEL CHAIR LoCICERO:  We're running a little bit ahead of schedule, which is nice.  We do have time, I think, to begin the open public hearing session regarding bone wax.

            All persons addressing the panel are asked to speak clearly into the microphone as the transcriptionist is dependent on this as a means of providing accurate record of this meeting.

            Before the first speaker, I would like to read the following statement into the record.  Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.  To insure such transparency at the open hearing session of the Advisory Committee, the FDA believes that it is important to understand the context of an individual's presentation.

            For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you have with any product manufacturer of interest group.

            For example, this financial information may include a manufacturer of interest group's payment for 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 relationships.

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

            Dr. Tad Wellisz has asked to address the panel.  We would like to invite him to the podium.

            DR. WELLISZ:  Thank you very much, Dr. LoCicero, and Dr. Krause.

            I'm going to try to just cover some of the unanswered questions that I heard the panel discussing.  I have appointments in plastic and reconstructive surgery, as well as neurosurgery at the University of Southern California.  I have an appointment in both plastic surgery and neurosurgery at the University of Southern California, and my interest over the last 15 years has been mostly tissue substitutes.

            I do have an interest in Ceremed, which is a company that was formed in order to market a polymer bone wax.  We actually got into this by accident.  I was looking at other tissue substitutes, and we were rather frustrated with what is available in the industry.

            I'm going to try to limit my comments and everything in the handout here is what's in peer reviewed clinical literature.  So I didn't want to bias anybody.  So hopefully everything that I tell the panel is actually peer reviewed.

            PARTICIPANT:  Do you have a handout?

            DR. WELLISZ:  And that's the handout that I think many of you have. 

            I do need help with this.  Shift, enter page down.

            I think we heard about bone wax.  I do want to differentiate.  Bone wax certainly is something that is used to tamponade bone.  The other materials that we've discussed briefly in terms of the ones that swell are usually used for soft tissue.  They're either animal based, collagen based products or they're cellulose based products, and those are actually designed to tamponade the bone, and they need to be removed, such as a collagen sponge.

            There really is nothing else other than a bone wax.  I certainly agree that it's a Class II product, and I certainly want to address some of the labeling issues that I think have come up.

            Bone wax is very important in many surgical specialties.  We mentioned orthopedic, cardiac, neurosurgery, spin,.  but I certainly think that I agree with the panel that there are two categories of bone wax which we've all agreed upon, but I think this is something that very few people understand outside this room.

            These are some of the products that we've seen already.  A comment on these.  The auto suture bone wax from US Surgical is an absorbable co-polymer.  None of these polymers are actually the lactate (phonetic) polymers.  So they are designed to be absorbed rather quickly.

            There seems to be a differentiation.  Certainly when I was going through the European CE marking process, there's a big difference between the definition of absorbable, which tends to imply some sort of metabolism by the body, whether it's hydrolysis or some sort of metabolism. 

            The alkaline oxide co-polymer is actually the reason we use those, is that they're water soluble.  It's a very common nonreactive, inert agent that's used as an excipient in pharmaceuticals.  It's actually used to prime heart-lung bypass machines.  It has been around for 40 years, and it is just formulated as a wax.  So those polymers actually dissolve into the blood stream and are excreted unchanged.

            I think one of the things that I noticed, there was a very big difference between what we see in the clinical literature and what is submitted to the Food and Drug Administration.  I think that from a manufacturing standpoint the manufacturers try to submit the information that's asked for.  So i did notice a big difference between what I've been reading when I did the literature review for this and probably what's -- certainly what we submitted to the FDA is quite different. than what we look at in the literature.

            I want to show  a picture of Victor Horsley.  He seems to always be with his dog.  Interestingly, this first application of his beeswax, the beeswax did need to be removed because there was an infection around it.

            The three major problems, and I agree with the panel, inhibition to bone healing, that's probably -- well, the three major adverse effects of beeswax are inhibition of bone healing inflammatory reactions, and increased infection rates.

            How long beeswax remains is a little bit of an open issue, but I think most of us would agree that it remains in the site indefinitely.  There is some breakdown of beeswax because you do find it within macrophages in those sites where you have inflammation.

            What's been known for a long time is that bees wax completely inhibits the formation of new bone.  In looking at the product, IFUs from the manufacturers, they tend to say that this is due to an obstructive effect, and I think we heard some of that in the panel.

            But if you look at the animal studies, the first one, Alberius, when he put the beeswax on the edges of the bone, there was only a thin layer put on, and there was the complete absence of bone healing even when there was very little beeswax.

            The one that I find most interesting was an experimental defect where they put beeswax onto a bone, left it on for ten minutes, and then actually scraped it off with a raunjour (phonetic), and even when they scraped it off, there was a complete inhibition of all bone regeneration.

            So I believe that beeswax -- I don't know what part of beeswax -- has some sort of effect on the bone forming cells themselves, and it's not a mass effect.  I think if you talked to somebody who takes an instrument and actually removes an entire layer of bone, you probably will not have that problem, but certainly it looks as though beeswax does interfere with bone healing more than just a mass effect.

            This is an article is in the neurosurgery literature.  There are a lot of interesting articles in the neurosurgery literature.  Rather recent, a file was used to make a defect in the rat femur, and if you look at Box A, that's a histology section of that femur after six weeks with beeswax being put into the defect.  These defects were filled rather than just coated.

            But if you look at slide B, that's that same defect filled with a water soluble polymer.  In ten days you have basically new bone.  It has completely filled that defect, and in six weeks you have mature bone.

            I agree that bone healing occurs quite quickly, which is why the optimal formulation should be one that creates a tamponade long enough to prevent bleeding but is actually gone soon enough so you can have bone healing. 

            Actually there are two places where -- well, actually the most important place that I believe that bone healing is a problem is in the cardiac surgery and nonunion of the sternum is a devastating consequence of cardiac surgery because it often leads to infection.  It's a well documented problem.  To my knowledge, most cardiac surgeons do not use any form of beeswax or bone wax for that matter, and they try to find other ways to stem the bleeding.

            And one of the reasons it is also important is obviously during cardiac surgery you have an anticoagulated patient.  So external bleeding is a problem.

            What I failed to mention earlier, which I think is very important and I'll try to stress again, if you looked at the original slide that Dr. Krause showed, originally bone wax, the definition from the FDA, included the statement that it contained beeswax, and I think that that the vast majority of practitioners equate bone wax with beeswax, and I think that because beeswax is such a commodity, I believe that the reason we haven't had better bone waxes made earlier was there really wasn't a financial incentive for the large companies to do this.

            Inflammatory reactions, those are well known.  Beeswax remains as a foreign body.  There are various stages of inflammation.  Most of the complications or adverse effects that I've seen in the clinical literature had to do with pain and swelling.  Whenever large amounts of beeswax were left in on top of a bone, especially near the skin, that seems to be a problem, sites such as bone graft sites, specially.

            Beeswax does more than just create a foreign body, as is indicated.  There's actually a decreased ability of bone to clear bacteria in the presence of beeswax, and usually if these studies are done correctly, different types of foreign bodies will be put in and beeswax actually potentiates bacteria.

            The amount of bacteria needed to produce a bone infection is several orders of magnitude lower in the presence of beeswax than it is in the presence of other materials, and in a new study that I just came across, it looked at spine surgery, and they noticed a very dramatic difference between infection rates when beeswax, base bone wax was used versus when it wasn't used.

            All of these references should be in your handout.

            These are the complications that I find in the clinical literature.  Again, this is more than, you know, the last ten years, and this is international as well.  If you look at those complication, most of them have to do with granulomas.

            The other place outside of cardiac surgery where I've seen a lot of issues with beeswax is apparently no surgeons use beeswax to block the mastoid cells.  They're trying to keep the cerebral spinal fluid from leaking.  It's probably an off-label use, but there seem to be problems with cerebral spinal leaks.  There seem to be problems with beeswax actually being pushed into the sigmoid sinus.

            I don't know whether an absorbable material will help this problem or not, but that's just something that the panel may want to consider as a frequent question that I get from neurosurgeons when I ask them about these live complications.

            I also believe that it's been 35 years.  The scientific journals basically know that beeswax is a problem, and they don't seem to be that interested in publishing new reports, but I think there's a big discrepancy between what the editors of scientific journals understand and what the public is aware of.

            And one thing that's clear is that the public is not aware of the fact that there are alternatives.  I'm not sure that this is much different than the whole catgut controversy was where basically in a lot of markets catgut is gone, and it has been replaced by polymers.

            There is a whole host of polymers that you can use that go away.  Some of them can be water soluble.  Some of them can be hydrolyzed, and there are at least two that are legally cleared to be marketed in the United States that I've seen and maybe now three.

            Again, I do believe that there's a distinction between bone wax and polymers.

            In conclusion, bone wax has a very long history of use.  It's a very important device.  There's nothing else that creates tamponade of bleeding bone.  The other hemostasis materials that are used when beeswax can't be used are far less effective.  It's much less effective to use gelatin foam or collagen or something on the bone than it is to use a wax that tamponades the bleeding.

            As we said, there are two categories available.  Surgeons are very much unaware that there's a distinction, and beeswax is usually synonymous with bone wax, and hopefully with education that may change.

            And I think despite the current labeling it's always frustrating.  Surgeons don't seem to read instructions for use.  Luckily certainly in my hospital the nurses tend to read these instructions, and they'll tell me off if I'm doing something I'm not supposed to.

            Recommendations.  I agree with everything the panel says.  I would certainly think that it would be a good idea to put under the indications that there's actually a choice of the hemostatic materials.  I think proper indications and instructions for use should remind a doctor that there's a choice between using one compound and another and that there were different adverse reactions depending on what compound is chosen.  Reading the instructions for use from beeswax containing materials, I do find them somewhat ambiguous.  They do mention there are three categories of complications that I discussed, but most of them talk about delaying bone healing.  I think it's clear that it's more than a delay of healing.

            So I would love to as a practitioner get instructions for use that have a little bit more information in them than the ones we have now.

            And I'd love to entertain any questions if anybody has any questions for me.

            PANEL CHAIR LoCICERO:  Thank you, Dr. Wellisz.

            Does anyone from the panel wish to ask any questions?

            DR. MILLER:  I'd like to ask a question.

            PANEL CHAIR LoCICERO:  Yes.

            DR. MILLER:  What's the difference in cost between a beeswax product and a polymer product, in general?

            DR. WELLISZ:  If the polymer products were available at the same volume that the beeswax products would be available at, there would probably be almost no difference whatsoever.  The polymers themselves are very inexpensive.  What's expensive is having low volume production and a new product, but certainly the polymers may even be cheaper than synthetic beeswax for all I know.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  One of your slides you said there's no evidence of the infection potentiation.

            DR. WELLISZ:  Right.

            DR. LEITCH:  What is the --

            DR. WELLISZ:  Well, actually these polymers, these are the same polymers that are used to coat shunts and things where you try to decrease bacterial adherence.  Again, a lot of these studies aren't directed towards the hemostatic application, but a polymer that tends to -- that's non-resorbable and tends to coat a bacteria will actually make it more virulent because it keeps the immune systems from being able to recognize it, but on the other hand, a polymer that will decrease the ability of a bacteria to adhere to a site may actually decrease the amount of infection.

            So I know there have been a number of studies in the neurosurgery literature where they'll take shunts and coat them with these types of polymers and actually decrease the infections.

            Certainly there's no evidence that they increase infections, and there's a lot of evidence that these kinds of polymers will actually decrease the infections.

            DR. LEITCH:  But that data is on what kind of a --

            DR. WELLISZ:  Well, right now the way the 150(k) process works is that you want to show substantial equivalence to the predicate device, and since the predicate device is the Horsley wax, we're not -- how do we put this? --

            DR. LEITCH:  It seems to me like --

            DR. WELLISZ:  -- we don't tell the FDA ‑-

            DR. LEITCH:  -- theoretically, theoretically that would be the case.

            DR. WELLISZ:  Theoretically that would be the case.  Certainly --

            DR. LEITCH:  But it hasn't been --

            DR. WELLISZ:  It's not shown in human studies, no.

            DR. LEITCH:  No.

            DR. WELLISZ:  It's shown in animal studies, but not in human studies, and it's not something that would be added to the labeling.

            DR. LEITCH:  And I guess the other thing ‑-

            DR. WELLISZ:  Because the process would require a very different type of -- if a medical device company wanted to make that claim on its labeling, it would be required to basically go through a different regulatory process than if it said, "Do you know what?  This is equivalent to, let's say, beeswax.  Doctor, you decide what you want to use on your patient."

            Is that fair, Dr. Krause?

            DR. LEITCH:  -- for us to make a statement in these documents that --

            DR. WELLISZ:  The statement that I would ‑-

            DR. LEITCH:  -- that the polymer would make bone healing better, I think, you know --

            DR. WELLISZ:  The statement means there -- the way that I would make the statement is in the negative.  There is no evidence that -- there is evidence that -- in terms of healing of bone there is extensive evidence that beeswax interferes with bone healing, and there's no evidence that the polymers interfere with bone healing based on literature that is peer reviewed.  That information has been submitted to the FDA, but it is buried inside the documents because what we're required to show is that we are at least as good as.

            So, for instance, the document that we submitted to the FDA where we showed bone healing, we showed in that particular document that was submitted the defects that were filled with beeswax did not heal, and they had inflammation around them.  The defects that were filled with a polymer wax healed with no inflammation.

            So the statement that was made was that the polymers functioned at least as well as the beeswax.  We didn't take that very same information and say, "Based on what we presented to you we want to make the claim that causes less inflammation and it doesn't interfere with bone healing." 

            And that's something that probably the industry -- it would be up to us to --

            DR. LEITCH:  I guess I would say that, you know, the idea of the -- I mean, the things that people mentioned, the concerns of things like external dehiscence and that sort of thing; I mean, do you have any data to say that the polymer product is better in that regard?

            DR. WELLISZ:  No.  And that kind of data, the strategy that we had is you released the product, and you let completely independent doctors do their clinical studies and publish the data in peer reviewed journals, and that will take years for that to come out.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  In terms of substantial equivalence, do you actually have head-to-head comparator data with the performance in terms of hemostasis of this polymer --

            DR. WELLISZ:  Oh, yes.

            DR. NEWBURGER:  -- to these regs?

            DR. WELLISZ:  yes.

            DR. NEWBURGER:  In animals or in the clinic?

            DR. WELLISZ:  All of the data is done in animals, and then we have post marketing data that we've been collecting from doctors.  I think anything that sticks to the bone is going to stop the bleeding.  So I haven't had any reports that one works better than the other.

            They handle slightly differently.  One will be a little gummier or something.  We have half of the doctors say it works better and we have half of the doctors say it doesn't work as well.  So it means it probably works about the same.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  Thank you. 

            I'm going to make a general request of us.  This will not be a specific question to you, but will be based upon one of your slides.

            To be specific when we use the word "polymer" or "the polymers" I've heard because there's a world of polymers out there that behave in very different ways from one another.  Beeswax itself is a polymer.  It's a natural polymer. 

            On your slide you show two, a co-polymer.  Well, I'd have to know what that co-polymer is to say how it behaves.  It can be a co-polymer of anything.

            DR. WELLISZ:  Correct.

            DR. YASZEMSKI:  Also the other thing -- and thank you, by the way, for the literature search.  I recognize that's not yours, but you're presenting something that was in the literature, but the word "alkaline oxide," there are many, many alkaline oxides.

            DR. WELLISZ:  There were definitely.

            DR. YASZEMSKI:  Propylene oxide is different than butylene oxide.  So I would say that when we're done with our determinations, one of the things that should come from this is that we insist on persons who say they have a polymer or a synthetic polymer as opposed to a natural polymer like beeswax product, that they tell us what that polymer is, and as an example, I'll look in the suture literature here.

            There's polydioxanone, polylactic coglycolide, polyethylene teraphthalate or Dacro, polytetrafluoroethylene, Teflon.  These all behave differently.  I mean, the vascular surgeons, I think, would suggest that  Teflon venous prosthesis behaves a lot different than a Dacron arterial prosthesis, and to lump them together and call them polymers just doesn't fit.

            DR. WELLISZ:  It gets worse because what Teflon is is very complicated.

            DR. YASZEMSKI:  In other words, my plea is that we identify polymer in any deliberations, in any outcome that we have at this meeting.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  I think, too, I like the approach that is taken where a product has to show equivalence, and I think we need to avoid or be very careful about creating labels which become sort of a marketing assist by how the labeling is structure because I have seen nothing which sort of validates the idea that there's a sort of superiority of these polymer absorbable products over the sort of time line of beeswax products.

            Even theoretically, I mean, if you put a polymer in that absorbs even in ten days, it has just as much potential for infection because it's a foreign body for those ten days as the beeswax does in the first ten days.

            So there's lots of questions that are raised, and the labeling needs to be very, very conservative and very unambiguous and all of these other issues need to be resolved by very well performed studies, and then just taken to the marketplace of physicians with good data.  You know, I think that's the approach.

            PANEL CHAIR LoCICERO:  Any further questions for Dr. Wellisz?  Yes.

            DR. BARTOO:  Just a comment on Dr. Yaszemski's comments regarding material specification.  In the document that was sent in our packets there is a section for material specifications, but there wasn't anything written up in terms of what should go in the labeling.  So maybe that would be a consideration to make sure it's also in the labeling.

            PANEL CHAIR LoCICERO:  If there are no further questions, thank you, Dr. Wellisz.

            DR. WELLISZ:  Thank you very much.

            PANEL CHAIR LoCICERO:  We have reached our time for a break.  We will reconvene in 15 minutes at 10:30.

            (Whereupon, the foregoing matter went off the record at 10:19 a.m. and went back on the record at 10:37 a.m.)

            PANEL CHAIR LoCICERO:  While that is going on, also we need to ask is there anyone else who wishes to make a comment to the panel this morning concerning bone wax.

            We have one additional person.

            DR. STAGG:  Good morning.  My name is Dr. Del Stagg.  I work with Artes Medical, and we have no direct interest in this product per se.

            My question is a procedural one for the panel and I guess the FDA, and it was related to a potential for a class label.  I found it of interest that you noted that there was a single case of paralysis, I believe, associated with this product, and yet it appears that you're willing to put into a class label that this could occur with this product and its use.

            I'm not sure that that is a property of bone wax, as itself, as an entity.  Maybe more of a practice of surgical intervention.

            So one case out of several million applications, is that really something that warrants going in as a class label?  And so it's a procedural question I'm presenting before the panel.

            Thank you.

            PANEL CHAIR LoCICERO:  Thank you.

            Since there is no additional request to speak in the open public hearing, we will now proceed to the classification questionnaire and vote.

            We will now fill in the classification questionnaire and supplemental data sheet.  Ms. Marjorie Shulman from the Office of Device Evaluation will assist us as we go along.

            After a panel discussion of each question I will note our answer for each blank on the data sheet, and Ms. Shulman will record it on the overhead for all to see.  We will vote on the completed questionnaire and supplemental data sheet.  It will become the panel's recommendation to the FDA.

            Are there any questions before we proceed?

            (No response.)

            PANEL CHAIR LoCICERO:  Ms. Shulman, will you please help us with this questionnaire?

            MS. SHULMAN:  Okay.  Thank you.

            Just one clarification.  We're not going to record it up there.  We'll use the overhead up there for the audience to see what we're going through.

            Everyone has their own form, and everyone should fill out their own form, and then you can write additional comments, and the panel chair will keep the main form for the vote itself.

            So the first section is panel member and the date and then the generic type of device.  So we'll get to the first question.

            Is the device life sustaining or life supporting?  So I don't know where on the panel you'd like to start going around for the vote for the answer.

            PANEL CHAIR LoCICERO:  This one we may be able to do by a hand vote.

            Is there anyone who feels that this is life sustaining or life supporting?

            (No response.)

            PANEL CHAIR LoCICERO:  The answer then is no.

            MS. SHULMAN:  Okay.  The first one is no.

            Number two, is the device for a use which is of substantial importance in preventing impairment of human health?

            PANEL CHAIR LoCICERO:  Let's briefly go around.  Dr. Yaszemski.

            DR. YASZEMSKI:  I think since it will only be used during a surgical procedure, it's important for human health.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  Yes, I agree.

            PANEL CHAIR LoCICERO:  Then it's unanimous, yes.

            MS. SHULMAN:  Okay.  For number three, does the device present a potential unreasonable risk of illness or injury?

            PANEL CHAIR LoCICERO:  Dr. Leitch?

            DR. LEITCH:  No.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  No.

            PANEL CHAIR LoCICERO:  Dr. Newburger?

            DR. NEWBURGER:  No.

            PANEL CHAIR LoCICERO:  Dr. Lewis?

            DR. LEWIS:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing?

            DR. EWING:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  No.

            PANEL CHAIR LoCICERO:  The unanimous vote is no.

            MS. SHULMAN:  Okay.  So number four, did you answer yes to any of the above three questions?  And we did answer yes to number two, correct?

            PANEL CHAIR LoCICERO:  We answered yes to number two.

            MS. SHULMAN:  So then we will go to Item No. 6.  Is there sufficient information to establish special controls in addition to general controls to provide reasonable assurance of safety and effectiveness?

            And this is a yes/no answer also.

            PANEL CHAIR LoCICERO:  Okay.  This we may be able to do by vote again.  Does everyone feel that the answer to this question should be yes?

            (Show of hands.)

            PANEL CHAIR LoCICERO:  The answer is unanimous.  The answer to six is yes.

            MS. SHULMAN:  Okay.  Since six is yes, we go to number seven.  Is there sufficient information to establish special controls to provide the reasonable assurance of safety and effectiveness?  Identify below the special controls needed to provide such reasonable assurance for Class II.

            And the choices, because you can't read, is guidance documents performance standards, device tracking, testing guidelines, and other, for the catchall phrase, for recommendations such as sterility, biocompatibility, et cetera, patient registries, anything like that.

            PANEL CHAIR LoCICERO:  Okay, and just for clarification before voting, the FDA has recommended testing guidelines.

            MS. SHULMAN:  Guidance document in --

            PANEL CHAIR LoCICERO:  Guidance document.

            Dr. Ewing?

            DR. EWING:  Will this also include the addition of the device labeling that we discussed earlier?

            PANEL CHAIR LoCICERO:  Labeling comes later, I believe.

            MS. SHULMAN:  I believe the labeling is in the guidance document.

            PARTICIPANT:  That is correct.

            PANEL CHAIR LoCICERO:  So this includes the labeling.

            DR. EWING:  Okay.  Yes.

            PANEL CHAIR LoCICERO:  So yes?

            DR. EWING:  Yes.

            PANEL CHAIR LoCICERO:  You're voting for a guidance document?

            DR. EWING:  Yes.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Lewis.

            DR. LEWIS:  Guidance document.

            PANEL CHAIR LoCICERO:  Guidance document.  Dr. Newburger?  Guidance document.

            Dr. Miller, guidance document.

            Dr. Leitch --

            DR. LEITCH:  Yes, guidance document.

            PANEL CHAIR LoCICERO:  -- guidance document.

            Doctor -- okay.  Everybody is yes for a guidance document.

            Does anyone wish to have other controls apply?

            DR. BARTOO:  I just had a question.  Is the guidance document going to specify any of the biocompatibility or sterility standards?

            PANEL CHAIR LoCICERO:  Those are standard elements of the guidance document for medical devices.

            DR. KRAUSE:  No, the guidance document refers to 10-993, which all manufacturers know what that is.

            PANEL CHAIR LoCICERO:  So the panel has voted on number seven to specify guidance document as the controls.

            MS. SHULMAN:  Okay.  Thank you.

            For number eight and nine, we can skip because those two questions all you have to do for a performance standard.

            Question ten we can skip because that's only for Class III devices.

            Question 11 is identify the need of restrictions, and the first one is the prescription statement.  The second is for use only by persons with specific training or experience in its use.  The third one is for use in only certain facilities, such as MRI machines, and then the last is in "other," if you want to add any "other."

            PANEL CHAIR LoCICERO:  Okay.  Let's start with Dr. Doyle.

            DR. DOYLE:  No comment.

            PANEL CHAIR LoCICERO:  No comment.

            Dr. Blumenstein.

            DR. BLUMENSTEIN:  No comment.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  I recommend prescription labeling. 

            PANEL CHAIR LoCICERO:  So you would say that this test should be done by prescription?

            DR. BARTOO:  Yes, the first option.

            PANEL CHAIR LoCICERO:  The first option.

            Dr. Yaszemski.

            DR. YASZEMSKI:  No, nothing to add.

            PANEL CHAIR LoCICERO:  Dr. Leitch?

            DR. LEITCH:  I guess this is kind of a technicality thing.

            PANEL CHAIR LoCICERO:  Yeah.

            DR. LEITCH:  Oral authorization could just mean requesting it in the operating room, right?

            PANEL CHAIR LoCICERO:  Yeah, on the floor, in the operating room.

            DR. LEITCH:  Not writing a prescription, right?  Yeah.  So I would say that, yes, the first one.

            PANEL CHAIR LoCICERO:  Number one.

            Dr. Miller.

            DR. MILLER:  I would say all of these because I think a person needs to understand how to use it properly and be trained.  It needs to be a surgeon or somebody who operates on bone, and then it should be used in an operating room under sterile conditions.  You shouldn't be putting it in contaminated wounds or in the emergency room or something.  I think all three of these would apply to using a device like this.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  I agree with Dr. Miller.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Lewis.

            DR. LEWIS:  I would say the first two.  I don't think the facility -- and obviously it's going to be used in the operating room, but I don't know that that needs to be a restriction put on the device, but I think someone should have some knowledge of its use, and it should be by prescription.

            PANEL CHAIR LoCICERO:  Okay.

            MR. MELKERSON:  May I?

            PANEL CHAIR LoCICERO:  Yes.

            MR. MELKERSON:  For the persons with special training, do they need special training beyond their current medical training or is that something that can be done with the labeling?

            Generally that box is for additional mandated training beyond what you're --

            PANEL CHAIR LoCICERO:  This is like a training in addition to what you would get to be trained as a surgeon who would be operating on bones?

            MR. MELKERSON:  That is correct.

            PANEL CHAIR LoCICERO:  I don't think you need special training.  I think you just need to be trained as somebody who does bone surgery.

            DR. MILLER:  So is that kind of covered by the practitioner licensed by law?

            MR. MELKERSON: That is correct.

            DR. MILLER:  I mean, is that where you kind of cover that issue?

            MR. MELKERSON:  Yes.

            PANEL CHAIR LoCICERO:  Okay.  So these other two are covered by -- I don't mean to make it more complicated.

            MR. MELKERSON:  I just wanted to make sure that you  understood that.  Generally it's training beyond what you would normally get for your specialty.

            DR. MILLER:  Okay.

            MR. MELKERSON:  So you would like to revise your recommendation to number one?

            DR. MILLER:  Yeah, number one, I think is adequate.

            MR. MELKERSON:  Okay. 

            PANEL CHAIR LoCICERO:  Dr. Lewis agrees.  Dr. Ewing?

            DR. EWING:  I just wanted some clarification on certain facilities.  Does that specify that it has to be a medical facility or --

            PANEL CHAIR LoCICERO:  Certain facilities, in other words, some products are intended for use at home, elsewhere, but certain facilities generally are identified as a doctor's office or surgical suite.

            DR. EWING:  Okay.  I agree.

            PANEL CHAIR LoCICERO:  With recommending number one or one and three?

            DR. EWING:  One and three.

            PANEL CHAIR LoCICERO:  One and three.

            We have a couple of votes for the third option, and I just want to be sure we get that clarified.  Can we see by a show of hands who wants number three?

            DR. MILLER:  Can I ask?  I don't mean to make this overly done, but I'm a little confused.  If you say no special facility, then somebody could like take bone wax and use it anywhere they want technically.  Is that what you're saying?

            I mean, it should be used in an operating room.  Does that mean we have to say it needs to be in a special facility or --

            MR. MELKERSON:  Or is that something that could be used as far as the labeling?  In other words, special facility is a special control that you would actually put in, may only be used in a particular facility or setting.  So that would be something that could be included under labeling. 

            PANEL CHAIR LoCICERO:  Dr. Yaszemski.

            DR. YASZEMSKI:  I think it would be adequate control without listing it because by the time somebody needs to use it, they're doing an operation, and whether they've chosen to do that in a formal operating room in an out-patient theater, maybe some small procedure in the office, if they've made a decision to operate and the location is appropriate for an operation, then it's also appropriate, I would think to use bone wax without anything special on the bone wax label.

            PANEL CHAIR LoCICERO:  Okay.  So let' just go through number three again.  How many want number three to be a stipulation?

            (No response.)

            PANEL CHAIR LoCICERO:  And there are no hands.  So we're going to go with number one, prescription.

            MS. SHULMAN:  Thank you.

            That's the end of the first sheet.  If we can put up the supplemental data sheet, and the first question, again, generic type of device, and in the second question, Advisory Panel.  The third question is the device in implant.

            PANEL CHAIR LoCICERO:  Are we going to consider this an implant?  Dr. Leitch.

            DR. LEITCH:  I guess -- do you want to advise us on what you mean by that?

            MR. MELKERSON:  Actually the regulations identify an implant as anything that's in the body greater than 30 days.

            DR. LEITCH:  So it is then.  So yes.

            PANEL CHAIR LoCICERO:  Okay.  Since that has been defined, since it has been defined that way, does anybody object to listing this as an implant?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  So, yes, it's an implant.

            MS. SHULMAN:  Number four, the indications for use in the device labeling, you may say "as presented" or you may make comments to the indications for use that was presented earlier in the discussion.

            PANEL CHAIR LoCICERO:  So the indication for use is to stop bleeding in bone by tamponade.  Are there additional statements that need to be made to that?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  So we'll go with the wording of --

            MS. SHULMAN:  As presented?

            PANEL CHAIR LoCICERO:  As presented.

            MS. SHULMAN:  Number five, the identification of any risk to health as presented by the device, and you can, again, either say as presented earlier in the discussions, or you can add and you may want to now.

            PANEL CHAIR LoCICERO:  The panel made some recommendations when we addressed the questions.  So let's go through everybody and see if there are any additional comments anybody wants to add.

            Dr. Ewing.

            DR. EWING:  No additional comments.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  Nothing additional.

            PANEL CHAIR LoCICERO:  Dr. Newburger?  No.

            Dr. Miller?

            DR. MILLER:  No.

            PANEL CHAIR LoCICERO:  Nothing.  Dr. Leitch.

            DR. LEITCH:  Well, I mean, I guess I would just delete antiplatelet drug therapy and heparinization as a risk for the device failure.

            PANEL CHAIR LoCICERO:  And that was our recommendation.

            DR. LEITCH:  Yeah.  So if that's understood, then --

            PANEL CHAIR LoCICERO:  Dr. Yaszemski?

            DR. YASZEMSKI:  No additional.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  None.

            PANEL CHAIR LoCICERO:  Dr. Doyle?

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Okay.  So it will be listed as discussed earlier.

            MS. SHULMAN:  Correct.  Number six, the recommended advisory panel classification and priority of the classification was into II, and the priority you had suggested, if it's a high, medium, or low.  For when we go back out quickly, do you want us to develop the proposed regulation, get it out for comment and all?

            Of course there is no time frames associated with high, medium or low.  So it's just your current thought.

            (Laughter.)

            PANEL CHAIR LoCICERO:  I love it.  Dr. Doyle.

            DR. DOYLE:  They say the right answer is always the middle one.  So I'll go with that one.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  It seems like a point of total ignorance.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  Nothing to add.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski?

            DR. YASZEMSKI:  Nothing to add.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Leitch?

            DR. LEITCH:  Medium.

            PANEL CHAIR LoCICERO:  Medium.  Dr. Miller?

            DR. MILLER:  Low.

            PANEL CHAIR LoCICERO:  Low.  Dr. Newburger.

            DR. NEWBURGER:  Medium.

            PANEL CHAIR LoCICERO:  Medium.  Dr. Lewis.

            DR. LEWIS:  Low.

            PANEL CHAIR LoCICERO:  Low.  Dr. Ewing?

            DR. EWING:  Low.

            PANEL CHAIR LoCICERO:  We've had three lows and three mediums.  The Chair takes the prerogative to break the tie and will go low.

            MS. SHULMAN:  Thank you.

            Okay.  Number seven, if device is an implant or life sustaining or life supporting and has been classified in a category other than III, explain fully the reasons for the lower classification with supporting documentation and data.

            You may also answer this one that the general and special controls can handle the risks, and it's not an unreasonable risk, and anything else that was presented this morning.

            PANEL CHAIR LoCICERO:  Okay.  So we would say not an unreason -- say that again.

            MS. SHULMAN:  That it's not an unreasonable risk, why it's not in Class III, why it's in II.

            PANEL CHAIR LoCICERO:  So not an unreasonable risk.  Do we have any objection to using not an unreasonable risk as an answer for number seven?

            (No response.)

            PANEL CHAIR LoCICERO:  Seeing no objections, we will say not an unreasonable risk.

            MS. SHULMAN:  Number eight, the summary of the information including clinical experience or judgment upon which the classification recommendation is based, and you may also answer if you wish "as presented in the panel meeting."

            PANEL CHAIR LoCICERO:  Okay.  Does anyone want to add additional statements to "as presented in the panel meeting"?

            (No response.)

            PANEL CHAIR LoCICERO:  No one is volunteering additional.  So it will be as listed in the panel meeting.

            MS. SHULMAN:  Okay.  Number nine is the identification of any metered restrictions on the use of the device, such as special labeling, training, prescription use.  We did handle the prescription use question and Question 11 of the general questionnaire.  So we can put down prescription use there and then if there's anything else anyone wanted added at this time, they can recommend it.

            PANEL CHAIR LoCICERO:  Does anyone wish to add an additional stipulation under Question 9?

            Yes, Dr. Newburger.

            DR. NEWBURGER:  Does this include the labeling that we've discussed which would include the removal of the material as soon as hemostasis is achieved and the labeling to indicate other potential problems, risks?

            Is this the label in the identified risks and special instructions for use?

            PANEL CHAIR LoCICERO:  As I understand it, this is for restrictions on use.

            MS. SHULMAN:  Restrictions on use.  So the labeling would be addressed in the guidance document still.

            PANEL CHAIR LoCICERO:  Okay, okay.  Anyone else?

            So it is going to say prescription use here.

            MS. SHULMAN:  Right.  Okay.  On the second page of the sheet, number ten we can skip because that only has to do with Class I devices.

            Number 11, if the device is recommended for Class II, recommend whether FDA should exempt it from pre-market notification.  So that means we would not receive 510(k)s.  So there would still be a Class II device subject to the special controls, but we would not receive 510(k)s.  So that's a yes or a no for a vote.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski?

            DR. YASZEMSKI:  I'd like to say it should receive a 510(k) because as we've talked a lot, the beeswax seems to be pretty standard, but there's new polymeric materials coming in regularly, and it would be nice to hear about them and have an opportunity to decide what extent of scrutiny they should get when they come in.

            So I would vote yes for 510(k).

            PANEL CHAIR LoCICERO:  So a nonexempt status.  Okay.

            DR. BARTOO:  I agree.

            DR. YASZEMSKI:  Yes, sir.

            PANEL CHAIR LoCICERO:  And Dr. Bartoo agrees.

            Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  Agreed.

            Dr. Newburger.

            DR. NEWBURGER:  Agreed.

            PANEL CHAIR LoCICERO:  Agree.  Dr. Miller.

            DR. MILLER:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  Agree.

            PANEL CHAIR LoCICERO:  Okay.  So this is not exempt.

            MS. SHULMAN:  Correct, and number 12, if anyone knows of any existing standards applicable to the device, device subassembly, components or device materials.

            PANEL CHAIR LoCICERO:  Is anyone aware of standards for this device?

            (No response.)

            MS. SHULMAN:  Okay.

            PANEL CHAIR LoCICERO:  No one is aware of any standards.

            MS. SHULMAN:  Okay.  Now, please, you'll take one final vote on the classification questionnaire and the supplemental data sheet as a whole as being a Class II device subject to 510(k) with the special control being the guidance document.

            PANEL CHAIR LoCICERO:  Okay.  So we're going to vote on the recommendation as outlined in these two documents.  Can we have a show of hands for the documents as we have outlined?  Who's voting for the documents?

            (Show of hands.)

            PANEL CHAIR LoCICERO:  And we have a unanimous vote for the document as written.

            MS. SHULMAN:  Thank you very much.  Done.

            PANEL CHAIR LoCICERO:  Okay.  Thank you.

            Okay, all right.  We're going to begin the next section since we are somewhat ahead of schedule, and it is a pleasure to introduce at this time and we will begin a discussion of classification of medical maggots.

            As we have no industry representative to comment, we will start with the FDA presentation.  Following the FDA presentation, we will have a general panel discussion on this topic, followed by a more focused panel discussion aimed at answering FDA's questions.

            Following the panel discussion, we will complete the reclassification work sheet and supplemental work sheet.  The vote on these work sheets will constitute the panel's recommendation to the FDA.

            There will also be time for public comment before the vote.

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

            May we now have the FDA presentation?

            DR. KRAUSE:  Before Dr. Durfor starts, could everybody pass their filled out work sheets toward the center so I can collect them?

            Thank you.

            DR. LEITCH:  Can I just ask a question on this supplemental data sheet?  Is our name supposed to be on that one anywhere?

            DR. KRAUSE:  Just write it on the top.

            PANEL CHAIR LoCICERO:  Dr. Durfor, I think we're ready.

            DR. DURFOR:  Thank you very much. 

            Good morning, panel.  We're moving on to two medical devices that wiggle.

            (Laughter.)

            DR. DURFOR:  I want to apologize to the panel to start with that in the time between when my slides were photocopied and the final slides there were some small changes.  So I think there's one slide that's out of order and some other small changes, and I apologize for that.  But I do appreciate your time in helping us get a recommendation from you on the use of maggots as medical devices.

            As you've already heard today, medical devices are regulated and classified with regard to their risk, and with that in mind, we're looking forward to your comments on a recommendation on this particular product class.

            To give you a history, the modern age, if you will, of maggots for debridement therapy began in the 1930s and actually was sold by Lederle Labs at that time.  As antibiotics became more prevalent in the late '30s, early '40s, their use waned, and then once again, there has been somewhat of a resurgence in the late '90s.

            To that point, FDA cleared the first 510(k) for this type of product last year, 2004, and we cleared it as an unclassified medical device.

            Just to give you a sense of what the review of that particular application involved, I thought I would walk you through it.  In terms of the insects themselves, there was concern about making sure that the larvae were of one particular strain and species because that particular strain and species are well characterized and tend to feed on necrotic tissue rather than living tissue, and not only were they a single strain and species, but there was considerable effort done in the facility to make sure that no parasites or predators or other insects would enter the facility where they were made.

            There was information as well in the application with regards to how the insects were fed, and a little bit more problematic was the use of a mammalian tissue for egg laying, and so there had to be some level of control in terms of how that material was vetted.

            As you'll see in a minute, disinfection of the eggs themselves is important to reduce any concern of infectious disease.  When you do disinfection, you not only need to look for anaerobic and aerobic cultures to make sure that you have had an effective disinfection, but you also want to make sure that the eggs will hatch with a certain amount, certain percentage.

            As you're well are, the use of this type of therapy requires maintaining the insects, the larvae at the wound site, and so this particular application contain not only the methods for developing the larvae, but also for two different types of dressings that would help retain the larvae at the site.

            And then, of course, packaging and shipping for any living organism is important because you want them to arrive and be viable.

            It's probably no surprise that the first 510(k) for this product was cleared last year, and so we have not at this time received  any medical MDRs, but there's obviously considerable published literature in the area, and I just want to walk you through a couple of them.

            In the '30s, when this type of maggot debridement therapy was in use, people were using -- and the term "sterile" and "not sterile" is probably inappropriate.  It's more disinfected -- but they were essentially using the insect larvae without any sort of disinfection treatment, and that resulted in numerous cases, under ten, but a couple of cases at least of tetanus and other septicemia so that there was a general amount of research done in the mid-'30s trying to figure out how to reduce infectious disease transmission.

            Once again, there's an importance for maggot containment because of both the aesthetic and sort of the psychological well-being of the patient.

            The maggots themselves do, indeed, have digestive enzymes that can at times cause erythema or cellulitis on a patient.  So that is, of course, a concern, and then you would want to, of course, use a biocompatible sound dressing as well.

            Pain and itching are some of the major concerns, and they're also handled by analgesic use, and one also needs to be careful about making sure that the insects remain on the necrotic tissue and not the viable tissue, that they do not go beyond where you want them.

            So with that in mind, we have begun to think about what are the risks to health, and I would like to sort of walk you through some of them.  This is the basis, if you will.  You saw in Dr. Krause's presentation how the risks were health, were then used to generate a special controls guidance document, and we are moving in the same direction here with a proposed Class II recommendation for which we seek your recommendation.

            With regard to infection control, and there is a concern about infection control, I have already spoke to you about disinfection of the eggs, but obviously sterilization of any wound dressing or any packaging material is also important.

            And manufacturing controls are important to make sure, once again, the facility has a pure species and genus.  I like to refer to the one application we saw since we do a lot of work with TSE that is actually a closed herd of flies, but in this particular instance, that was how they control it, and there needs to be some level of manufacturing control.

            The insects themselves are often fed on a pretty simple sugar and protein diet that doesn't seem to pose much concern, but once again, the egg laying is done in mammalian tissue, and so there can be concern about infectious disease transmission there.

            Clinical data is not in our minds required, but is always helpful to find out how a product performs and how well the manufacturer's instruction for use adequately describes how the product is used, as well as any other concerns that can be related, and of course, labeling is important as well to help people understand how to control the product and use it in an appropriate manner.

            The other major risk to health that we have believed is appropriate for this product class is adverse tissue reactions.  Biocompatibility is, of course, important for both any wound dressing material that might be used, as well as any leechable material that might be in the packagings or in the egg laying area.

            Once again, manufacturing controls are important so that you know exactly what's going in the product, that you don't have unwanted, nonbiocompatible materials in the process so that you would have the adverse tissue reactions.

            Similarly, with clinical data and labeling, information such as that is always important to help us understand and help all users understand how the product can be used appropriately.

            So with that in mind, the FDA proposes an identification of medicinal maggots.  We propose that they would be identified in the Code of Federal Regulations as a medical maggots or larvae intended for debridement of nonhealing necrotic skin and soft tissue wounds.

            The classification that we are proposing and seek your recommendation on would be Class II with a special controls guidance document and a special controls guidance document would be something tied along the lines of special controls guidance document for FDA and industry on medicinal maggots.

            With that in mind, I would be happy to entertain any questions, and we also, all of us, seek to hear your comment on the following classification questions.

            Thank you very much.

            PANEL CHAIR LoCICERO:  Thank you.

            I must say that I learned something this morning.  I now know that a collection of flies is called a herd.

            DR. DURFOR:  No, actually it's not called a herd, but I kind of applied it to that because of the way they did, indeed, use generation after generation.

            PANEL CHAIR LoCICERO:  I see.

            DR. DURFOR:  So, no, sorry.  It's not a herd.

            PANEL CHAIR LoCICERO:  What is the term for a collection of flies?

            DR. DURFOR:  That's a good question.

            PARTICIPANT:  Swarm.

            DR. DURFOR:  A swarm.  Thank you.  A muddle.  I'm not sure.

            PANEL CHAIR LoCICERO:  Fascinating.  I'm sure that this will generate some questions.  There are a few of us at the panel who have used maggots, and I heard this morning that Dr. Ewing did at one time use some maggots.  So let's start with her.

            DR. EWING:  Well, when I was a resident and I was an intern, and I was appalled.

            (Laughter.)

            DR. EWING:  That was when my chair insisted that we use medical maggots on a wound that was nonhealing, and it was to my amazement that it worked extraordinarily well.  So that was my small experience with maggots on one occasion.

            PANEL CHAIR LoCICERO:  Any questions for Dr. Durfor?

            DR. EWING:  I do have one question.  In your review it talked about a skin preparation that you needed in the normal skin that surrounds the nonhuman area, and there wasn't much to describe how you protect that skin from excoriation from the maggots.

            DR. DURFOR:  In the particular application I've seen, in other applications, it's more a matter -- and if you have clinical experience I think I could draw much more from your experience than what I've read -- but there are bandages and bags that will restrain them to the necrotic area, and then monitoring the particular dressing to make sure that once they have completed the debridement process they're removed, but if you have other guidance, I would certainly appreciate it.

            PANEL CHAIR LoCICERO:  Dr. Lewis, questions?  No questions.

            Dr. Newburger?  Dr. Miller?

            DR. MILLER:  No question.

            PANEL CHAIR LoCICERO:  Dr. Leitch?

            DR. LEITCH:  Well, I guess part of it is this idea of the corralling of the wound and the maggots, you know, that you prevent injury to surrounding tissues and also prevent the maggots from being somewhere they're not supposed to be, particularly if you're using them in a hospital.

            So I don't know how much we have to put in terms of specifications, but I think, you know, that part of it needs to be clearly addressed with the manufacturers.  That's the concern I think you have using it in a hospital environment.

            PANEL CHAIR LoCICERO:  Dr. Yaszemski?

            DR. YASZEMSKI:  No comments.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  Just a question.  You mentioned that there's only one 510(k) on medical maggots, and that was only last year.  So are there pre-amendment devices that are actually in use?

            DR. DURFOR:  Well, there was a pre-amendment device that I identified for you that was with Lederle Labs, and they are no longer commercially distributing that.  At this point I am unaware of other manufacturers who are distributing it.  They may also be unaware that it's a regulated product.

            And so when they do become aware if they are pre-amendments, we will certainly ask them to register the establishment.

            DR. BARTOO:  Okay.  So right now we don't have recorded use with just that one product that was cleared last year?

            DR. DURFOR:  Well, we have the pre-amendments product, and there's considerable literature with that, and then we also have the one 510(k), yes.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein, any questions for Dr. Durfor?

            DR. BLUMENSTEIN:  Certainly no comments.

            PANEL CHAIR LoCICERO:  Dr. Doyle?

            DR. DOYLE:  No comment.

            PANEL CHAIR LoCICERO:  Concerning disposal, does the FDA have concerns about disposal of the product, the device, once it has accomplished its job?

            DR. DURFOR:  Yeah, that's a good point.  It's an excellent point, that they should be viewed as a biohazard, and so disposal is an important aspect of insuring the safety of other patients and the practitioners as well, yes.

            PANEL CHAIR LoCICERO:  Does the FDA have any literature or recommendations concerning escape from some of these that transform?  They go from maggots to flies.

            DR. DURFOR:  Right.  I'm unaware of any data at this point in terms of them turning into flies while they're underneath the dressing.

            Escape I believe is a concern, and that's part of the reason that the labeling and looking at how the product works and works well in terms of the dressings, maintaining the insects at the site of the wound, and also I think the labeling is very critical in terms of your concern about removal and adequate disposal as a biohazard, yes.

            PANEL CHAIR LoCICERO:  Okay.  Thank you.

            I will now start panel deliberation.  We sort of went around the room and everybody had an opportunity to speak concerning this issue of disposal.  One of my colleagues talked about when he was a resident, one of the residents was working in the lab with maggots, and he left his experiment over the weekend and came back to find flies all over the lab.  So we certainly need to think about that.

            I'm sure there's got to be some additional comments.  Dr. Leitch.

            (Laughter.)

            DR. LEITCH:  Well, that's kind of my big comment, is the management of the aftermath, and you know, the environment where these are likely going to at least start to be used would be in the hospital.  You know, that's where it's going to be, and so you know, you have the issues of maintaining safety for the hospital as well as for the patient.

            The other thing I noticed, you know, in the handout that we got, they had searched for side effects, device related adverse events, and none were found, and I just was wondering, you know, what's the magnitude of use currently in the country.  Do we have any idea of that?

            PANEL CHAIR LoCICERO:  Do we have any estimates from anyone?

            DR. LEITCH:  Because, I mean, you know, you don't get much reporting if there's not much use, and so --

            PANEL CHAIR LoCICERO:  I'm sure availability has been an issue.

            DR. KRAUSE:  Now, it's unlikely that anything would be reported up until now because the previous company that we know of that manufactured these, the pre-amendments device was Lederle Labs, and they did so in the 1930s.  I'm not sure how long that went on, but the device, you know, reporting system was put into effect in about 1996, and at that time there was no registered manufacturer, and we've only just cleared one 510(k) fairly recently last year, I guess.

            So nothing has made it into the NVR system, but, you know, I think maybe Charles could give us an idea of what he knows about how much it's being used now.

            DR. DURFOR:  Right.  The 510(k) data that was supplied, the clinical data that was supplied, was based on more than 2,000 treatments between 1990 and 1995, and the manufacturer suggested as well that they had shipped approximately 3,000 bottles between '95 and 2003.  That was one supplier who I believe is a major source.

            So millions?  No.  Thousands?  Yes.

            PANEL CHAIR LoCICERO:  Great, and that may be somewhat under reported since many patients come in with their own supply.

            (Laughter.)

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  This may become more popular.  I mean, I haven't used medical maggots and I've only seen them as Dr. Ewing, as a resident.  However, because of this full review with this panel, there is a growing interest  in using maggots actually to debride difficult wounds, and there have been some controlled studies which show that maggots actually are superior in many ways to what's conventionally done for things like diabetic foot ulcers.

            You can buy all of these enzymes to put in wounds and everything that are very expensive and have marginal effect.  The maggots use an enzymatic process to degrade the necrotic material, and they actually are antibacterial, and they control methicillin resistant Staph. very effectively.  In some of the papers I looked at, they actually recommended using maggots if you have wounds with MRSA in them.

            And so I think maybe we're coming full circle here.  I've become actually quite a maggot enthusiast after --

            (Laughter.)

            PANEL CHAIR LoCICERO:  When you come back to visit, you'll be a maggot mavin.

            (Laughter.)

            PANEL CHAIR LoCICERO:  Dr. Durfor.

            DR. DURFOR:  You've raised an important point, and I wanted to make a comment that there are publications that suggest antibacterial activity, and at this point that's not the focus of what we're classifying, and that sort of claim structure would require its own data set.

            So I appreciate you bringing that up.  Thank you.

            PANEL CHAIR LoCICERO:  Excellent.  Dr. Newburger.

            DR. NEWBURGER:  I have a philosophical question, which is, you know, we're dealing with little animals here.  They're not single cell organisms, and we have an unusual political climate, and I'm wondering what the impact of dealing with animals and then disposing of them after they fulfilled their use is going to be.

            PANEL CHAIR LoCICERO:  Interesting point.

            DR. DOYLE:  Do you think PETA is going to be upset?

            PANEL CHAIR LoCICERO:  We certainly need to keep that in mind as we regulate this product.

            Dr. Lewis.

            DR. LEWIS:  No comment.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I guess as the consumer rep. what I want to know is are you going to give me a little psychiatric or psychological support when you apply these to my wound.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No comment.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  No comment.

            PANEL CHAIR LoCICERO:  Yes, Dr. Leitch.

            DR. LEITCH:  Well, in response to Dr. Doyle's comment, I think I think, you know, you do have to address that, you know, because it to the patient would be sort of a disconcerting experience, and so you know, I think one of the articles we had talked about being able to show patients pictures of wounds kind of before and after, and so you know, for the manufacturers, you know, if they were so inclined that they could provide photos that physicians would use to demonstrate to patients the potential benefit for it and, you know, the physician would be prepared to give sedative medications if the person was experiencing a lot of anxiety.

            I mean, I think, you know, you do have to look at sort of the quality of life of the patient during this type of treatment and be prepared to address that. 

            PANEL CHAIR LoCICERO:  Any other additional comments?

            (No response.)

            PANEL CHAIR LoCICERO:  At this time we can begin to focus our discussion on the FDA questions.  Dr. Durfor, would you please put these questions  on the screen for us?

            And he is lightning fast.

            At this time we will not refer to reclassification questionnaire.  We will do that after our discussion of the questions.  Please consider medical maggots while responding to this question.

            Please discuss the proposed classification of medical maggots for debriding nonhealing necrotic skin and soft tissue wounds, and the recommendation is a Class II with controls.

            Dr. Lewis.

            DR. LEWIS:  I think the justification of Class 2 is the need for a guidance document in the management of these, and obviously the specifics of the indications and how they would be used.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  I would agree with Class II on those reasons.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  I think Class II.  I would just add that it might be nice to specify that the soft tissue wound should be open, soft tissue wounds, because there are some soft tissue wounds that are buried in the pelvis or something.  I mean, I think, you k now, if you're going to use maggots the wound needs to be accessible and open.  An open soft tissue wound should be specified.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Newburger.

            DR. NEWBURGER:  Agreed.

            PANEL CHAIR LoCICERO:  Agreed.  Okay.  So on Question 1 we would say that this should be classified as a Class II, and that we would add the statement "open, nonhealing, necrotic skin and soft tissue wounds."  Maybe we should put it in a different place.

            Debriding nonhealing necrotic skin and open soft tissue wounds.  Does this satisfy the FDA's Question No. 1?

            MR. MELKERSON:  Yes.

            PANEL CHAIR LoCICERO:  We're going to Question No. 2.  Please discuss what descriptive information an intended use should be included in the proposed classification in identification.

            Dr. Miller.

            DR. MILLER:  I know it's tough to enumerate all of the issues.  Some of the things we've talked about already, I think there should be some kind of language reminding the user that these are living organisms, and that steps need to be taken to keep them at the site of injury, proper dressing used.  All of those details which are well recognized in all of this literature should be enumerated in the description of use.

            PANEL CHAIR LoCICERO:  Yes.

            MR. MELKERSON:  Just a point of clarification.  The question that is being posed is actually referred to as the proposed identification in the second to the last slide in Dr. Durfor's presentation.  The statements that you were describing would be potentially issues covered by scope or any special controls guidance.

            DR. MILLER:  Okay.  So this question, we're basically asking for the indication for use?

            MR. MELKERSON:  The intended use or the indications for use for the proposed identification.

            DR. MILLER:  Is that what you want?

            MR. MELKERSON:  Yes.

            DR. MILLER:  Okay.  I think that --

            DR. DOYLE:  So you just need to have an open --

            DR. MILLER:  Yeah, I would leave that open soft tissue wounds.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Newburger.

            DR. NEWBURGER:  I think they won't survive if it's not an open wound since they need to have oxygen.  So it won't be effective, but I don't know if -- is that under instructions?

            MR. MELKERSON:  The adequate instructions for use.

            DR. NEWBURGER:  Separate from the identification.

            MR. MELKERSON:  Right.

            DR. NEWBURGER:  So I like it as is.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Lewis.

            DR. LEWIS:  It seems the intent here is, I think, not to start treating all wounds with these.  Most wounds are more than adequately treated with conventional techniques, and so some definition of the types of wounds which are difficult to debride using conventional techniques is probably needed.

            Ischemic wounds, wounds that cannot either be sharply debrided or debrided in other ways, I don't have a written description for that, but I think you need some guidance here for people who are not familiar with it, where these would be intended to be used so that you have some distinction.

            Ninety-nine percent of all open wounds that are being treated can be treated perfectly well with conventional dressings and dressing changes and so forth.  So the need for these should be focused on the difficult to manage wound which cannot be adequately treated with conventional techniques.

            PANEL CHAIR LoCICERO:  Would you say it should be limited to those?

            DR. LEWIS:  Yes.

            PANEL CHAIR LoCICERO:  Limited.  Okay.

            Dr. Ewing.

            DR. EWING:  I agree.  I think that it should be managed with wounds that are recalcitrant to standard of care, but there are some situations where you want to minimize sharp debridement, for instance, on the face or areas that you don't want to compromise a lot of viable tissue, that that may also be included.

            Again, I'm not sure how to word that because that's a clinical judgment.

            PANEL CHAIR LoCICERO:  Dr. Miller is a fan of vague language.

            DR. MILLER:  Well, in my newfound enthusiasm for these animal, you know, what comes to mind is a couple of papers that I did see where they controlled comparison between diabetic foot ulcers debrided with maggots and diabetic foot ulcers treated in a conventional way with dressings, and they found a significant superiority over the use of the maggots in terms of the thoroughness of the debridement and the speed of the debridement and the speed of the debridement and the localized nature of the debridement where only the nonviable tissue is debrided.  With a nicely designed study, that was significantly different.

            So I think some rule may be justifiable for maybe referring to chronic wounds, but not be too limited in what the regulation says for the use of them.

            PANEL CHAIR LoCICERO:  Okay.  What Dr. Lewis proposed was that it be limited to the difficult to manage wound and one of those that was mentioned was the ischemic wound, which would be the diabetic foot ulcer situation.

            So it might be covered by this vague additional statement.

            DR. MILLER:  Sure, okay.  I can live with that.

            PANEL CHAIR LoCICERO:  Limited to the difficult to manage wound.

            DR. MILLER:  Yes.  Maybe you could say chronic, chronic wound, something.  Difficult to manage is very vague.  I mean, there are wounds that are acute that are difficult to manage because of location or something.  I don't want to be wordsmithing here, I guess, but I want to make sure we have access to the maggots.

            (Laughter.)

            PANEL CHAIR LoCICERO:  Okay.  Dr. Doyle.

            DR. DOYLE:  Is part of this the distinction between what goes in the labeling and what goes in the identification here, which would seem to me nonhealing would be a very generic term that would take in everything that was discussed here and then the more specific areas might be in the labeling, I would think, rather than in this sort of higher level.

            PANEL CHAIR LoCICERO:  Dr. Lewis, what do you think in that term?

            DR. LEWIS:  I'm not sure about exactly where it should go in terms of the various documentation.  I do think that having in my life taken care of thousands and thousands of the kinds of wounds we're talking about here that the differences by and large in the difficult wound that you're talking about that these would be used for would be those that have suffered some form of damage that limit the blood flow, either prior frost bite, diabetes, ischemia from other causes.

            A normally vascularized wound with conventional treatment will granulate quite readily with conventional treatment, and these would not be necessary for that.  So I do think the focus on the wound, probably ischemic as a generic term is the most applicable term to the wounds that are difficult to heal.  There are multiple causes for why that ischemia can occur, but if you want to include some additional definitional term, that might be appropriate.

            And so it would be chronic, nonhealing, ischemic, or difficult to manage wounds.

            PANEL CHAIR LoCICERO:  This reminds me of the questions in the medical student:  name the five reasons for nonhealing wound.  Infection, foreign body, radiation, cancer, you know.

            Dr. Blumenstein.

            DR. BLUMENSTEIN:  No comment.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  I guess my only comment would be to be sure we don't restrict the intended use so much that if maggots can be found to maybe treat a different kind of wound, that we have to do a whole new classification for that.

            PANEL CHAIR LoCICERO:  Okay.  The question is do we put it at this point in the indications or is this something that we can address in the labeling, instructions for use.

            Comments?  Dr. Leitch.

            DR. LEITCH:  Well, you know, by describing it as necrotic tissue, I mean, I think people -- I would think most surgeons' impression of a wound, you know, there's one thing to have a little bit of stuff that you can ship off and another thing that you've got a bed that's totally necrotic and, you know, I can think of, you know, paraplegics that have large, soupy ulcers and you do the dressings every day and they're still soupy the next day, you know, and you debride and it's still, you know.

            I mean, I think people have a sense of the type of wound.  Whether they'd be willing to make the commitment because there are little dressing maintenance issues here, you know.  So I don't think the users are going to sort of casually use it for a little something, but would use it for something that is difficult to manage.

            And actually some of these pictures, you know, the wounds weren't -- in some of the pictures the wounds aren't huge, but they're necrotic.  So I think that it is -- you don't want it to say that it has to be the worst wound that you've ever seen your entire life to use it.  You don't want to make it sound like that, I think.

            PANEL CHAIR LoCICERO:  Dr. Newburger, any additional comments?

            DR. NEWBURGER:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing?

            DR. EWING:  No.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  No, no further comment.

            PANEL CHAIR LoCICERO:  I think I'm getting a consensus that we would leave the labeling the same -- I'm sorry -- the indication the same, but address these issues of use in the labeling portion of the document.

            Does this answer your question?

            MR. MELKERSON:  This is adequate.  Thank you.

            PANEL CHAIR LoCICERO:  The third question, please discuss the risk to health during the use of these devices.  Dr. Bartoo.

            DR. BARTOO:  The two risks to health that were identified were adverse tissue reactions and infection.  I think we also need to, as discussed earlier, think about risk to other people's health in terms of potential escape of the device.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  I was somewhat born and raised in the South.  There's nothing more satisfying than the sound of a bug zapper.

            (Laughter.)

            DR. BLUMENSTEIN:  This is a joke.  Maybe it should require the manufacturer to supply a bug zapper to be put in the room with the patient to protect the hospital.

            That's a joke.  I have nothing more to say.

            (Laughter.)

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I guess I repeat the mental health aspect, not to forget it.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Ewing.

            DR. EWING:  No additional comments.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  No additional comment.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Nothing to add.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  Nothing to add.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  I think these are fine as stated.

            PANEL CHAIR LoCICERO:  Okay, and we would go with the stated risks to health as outlined previously.  Does this answer the FDA's question?

            MR. MELKERSON:  Yes.  Thank you very much.

            PANEL CHAIR LoCICERO:  Okay.  Okay.  We've had quite a morning already.  So I think we're going to break for lunch and come back and do our documentation after lunch.

            We wanted to have everybody back here by 12:30.

            (Whereupon, at 11:39 a.m., the meeting was recessed for lunch, to reconvene at 12:40 a.m.)

 


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

                                      (12:40 p.m.)

            DR. KRAUSE:  Dr. Durfor asked me to make sure that I took blame for scheduling maggots and leeches around lunch.

            (Laughter.)

            DR. KRAUSE:  So I don't want you to blame him.  So I will certainly take full credit.

            So anyway, let's continue with the meeting and go back to Dr. LoCicero.

            PANEL CHAIR LoCICERO:  We were able to get most of our discussion done this morning.  We will now proceed to the open public hearing session regarding medical maggots. 

            All persons addressing the panel are asked to speak clearly into the microphone as the transcriptionist is dependent on this means of providing an accurate record of this meeting.

            Is there anyone who wishes to address the panel concerning medical maggots?

            (No response.)

            PANEL CHAIR LoCICERO:  Since there are no individuals requesting to speak before the panel concerning medical maggots, we will now proceed to the classification questionnaire and vote.

            Ms. Shulman of the Office of Device Evaluation will assist us as we go along.  After panel discussion of each question, I will note our answer in the blank on the data sheet, and Ms. Shulman will record it on the overhead for all to see.

            Actually that is not quite the way it is going to work.  We'll just show the questionnaire, and I will record the information.  We will vote on the completed questionnaire and the supplemental data sheet.  It will become the panel's recommendation to the FDA.

            Are there any questions on how we are to proceed?

            (No response.)

            PANEL CHAIR LoCICERO:  The panel will take a moment to fill out the upper portion of the questionnaire.

            (Pause in proceedings.)

            PANEL CHAIR LoCICERO:  Okay, Ms. Shulman, let's get started.

            MS. SHULMAN:  Okay.  Again, the panel name, panel member, date, and generic type of device, medical maggots.

            Okay.  First question, is the device life sustaining or life supporting?

            PANEL CHAIR LoCICERO:  Dr. Leitch, do you want to lead us off?

            DR. LEITCH:  No.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  No.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  No.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  So the answer to question number one is no.

            MS. SHULMAN:  Okay.  Number two, is the device for use which is of substantial importance in preventing impairment of human health?

            PANEL CHAIR LoCICERO:  Let's start with Dr. Ewing.

            DR. EWING:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  I would kind of say no.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Newburger.

            DR. NEWBURGER:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  Yes.

            PANEL CHAIR LoCICERO:  And  Dr. Doyle.

            DR. DOYLE:  Yes.

            PANEL CHAIR LoCICERO:  So the majority answer to Question 2 is yes.

            MS. SHULMAN:  Okay.  Number 3, does the device present a potential unreasonable risk of illness of injury?

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  No.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  No.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  No.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  No.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  No.

            PANEL CHAIR LoCICERO:  And for the record, Dr. Yaszemski is not part of this panel.  So the answer to Question 3 is no.

            MS. SHULMAN:  Okay.  Number 4, did you answer yes to any of the above questions?  The answer is yes.

            We go to six.  Is there sufficient information to establish special controls in addition to general controls to provide reasonable assurance of safety and effectiveness? 

            And it's a yes/no.  We don't have to name them yet.

            PANEL CHAIR LoCICERO:  Okay.  We're just looking to see is there sufficient information to make a document.

            Dr. Leitch?

            DR. LEITCH:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Newburger?

            DR. NEWBURGER:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Lewis?

            DR. LEWIS:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  Yes.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  Yes.

            PANEL CHAIR LoCICERO:  So the answer to this question is yes.

            MS. SHULMAN:  Okay.  Number 7, if there is sufficient information to establish special controls to provide reasonable assurance of safety and effectiveness, identify below the special controls needed to provide such reasonable assurance for a Class II device.

            And that choice is a guidance document of performance standards, device tracking, testing guidelines, other, committee recommendations, sterility, biocompatibility, and others such as patient registries, et cetera.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  I think a guidance document.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Newburger.

            DR. NEWBURGER:  Agree.

            PANEL CHAIR LoCICERO:  Guidance document.  Dr. Lewis.

            DR. LEWIS:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  Agreed.

            PANEL CHAIR LoCICERO:  Blumenstein.

            DR. BLUMENSTEIN:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  Agree.

            PANEL CHAIR LoCICERO:  Okay.  So the guidance document is the suggestion by the panel.

            MS. SHULMAN:  Okay.  Again, we can skip Number 8 and 9 again, performance standards, and we can skip Number 10 because it's only for Class III devices.

            Okay.  Identify the needed restrictions, and the first one is the prescription statement and then the others are in addition to:  only used in certain facilities and used by persons with specific training or experience in its use, and any others.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I think that the first one will qualify the other two.  So I would just go with the first one.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Lewis.

            DR. LEWIS:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Agree.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Miller.

            DR. MILLER:  Agree, I think, but I don't think it's typical to give training on how to properly used medicinal maggots.  So I suppose that would be okay, just the first one.  Someone could read about it, I guess, and do it.

            PANEL CHAIR LoCICERO:  Dr. Leitch?

            DR. LEITCH:  I think the first is fine.

            PANEL CHAIR LoCICERO:  Dr. Bartoo?

            DR. BARTOO:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein?

            DR. BLUMENSTEIN:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  Agreed.

            PANEL CHAIR LoCICERO:  The recommendation of the panel for 11 is prescription.

            MS. SHULMAN:  Thank you.

            Okay.  Now we move on to the next sheet, the supplemental data sheet, and again Question 1 is the generic type of device and Number 2, the Advisory Panel, and then three is device and implant, and Mr. Melkerson had said this morning that the implant is defined as being in the body 30 days or longer.

            PANEL CHAIR LoCICERO:  Dr. Leitch?

            No.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Miller?

            DR. MILLER:  No.

            PANEL CHAIR LoCICERO:  Dr. Newburger?

            DR. NEWBURGER:  No.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  No.

            PANEL CHAIR LoCICERO:  So it is not an implant.

            MS. SHULMAN:  Okay.  Indications for use in the device labeling, and again, we can say as presented in this morning's presentation.

            PANEL CHAIR LoCICERO:  Does anyone want an additional indication other than what was discussed this morning?

            (No response.)

            PANEL CHAIR LoCICERO:  Hearing no objection, the recommendation will be as discussed.

            MS. SHULMAN:  Thank you.

            Notify the identification of any risk to health presented by the device. 

            Again, we can say as presented or if you wanted to name any others, you're welcome to.

            PANEL CHAIR LoCICERO:  Does the panel have any additional recommendations concerning risk to health that we should list?

            Dr. Leitch.

            DR. LEITCH:  I think just the things Dr. Bartoo mentioned as well, the environmental risk, you know, and whether that's appropriate to put here, but I think we do need to make some statements about that.

            PANEL CHAIR LoCICERO:  Okay.  Anyone else want to suggest an additional?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  So we would identify environmental risk in addition to what was discussed this morning.

            MS. SHULMAN:  Okay, and the favorite question, the recommended advisory class is Class II and the priority, high, medium or low.

            PANEL CHAIR LoCICERO:  Okay.  Rather than go around the room, would everybody agree with low?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  A consensus that the priority should be low.

            MS. SHULMAN:  Thank you.

            And in this case we can skip Number 7 because it is not an implant or life sustaining or life supporting from the general device questionnaire where we answered no to Question 1, is it life sustaining or life supporting.  So we can go on to eight.

            The summary of information, including clinical experience or judgment upon which the classification recommendation is based, and again, we can say the information is presented at the panel meeting or if there's anything else you wanted to add, that's fine.

            PANEL CHAIR LoCICERO:  Does anyone want to add additional comments to this, other than what was discussed this morning?

            (No response.)

            PANEL CHAIR LoCICERO:  There are no additional comments.  So we will list it as discussed.

            MS. SHULMAN:  On Question 9, identification of any needed restrictions on use of the device.  We have identified the prescription statement, but if there is anything else that can be added at this time.

            PANEL CHAIR LoCICERO:  Dr. Ewing, are there any additional restrictions?

            DR. EWING:  I have nothing to add.

            PANEL CHAIR LoCICERO:  Dr. Lewis?

            DR. LEWIS:  None.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  None.

            PANEL CHAIR LoCICERO:  Dr. Miller?

            DR. MILLER:  None.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  None.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  None.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  There are no additional.

            MS. SHULMAN:  Okay.  On the next page, Question 10 we can skip because that only applies to Class I devices.

            Number 11, it's devices recommended for Class II.  Recommend whether FDA should exempt it from premarket notification, meaning we would not receive 510(k)s for this device, but it would be subject to all of the other general and special controls that were identified.

            DR. NEWBURGER:  Does that means just of this genus, this species of fly or would that be for all types of maggots in the future?

            MS. SHULMAN:  If we have not identified it but we're classifying right now, then anyone who would come in after it would need to submit a 510(k) because they would have what we call tripped the limitations to be an exempt device.  However, if we found the first one substantially equivalent, ones after that would also be exempt.

            So it kind of expands the way the device regulations work.  So any new technology or indication or anything like that would have to come as a 510(k), but only the first.

            Does that make sense?

            DR. NEWBURGER:  Actually maybe I wasn't as clear as I intended.  I'm sorry.  This refers to this particular species, medical maggot.  If it's exempt, then does that mean that a maggot manufacturer can come along just with different farms of these same animals, or does it mean that any other normal form of fly can be used?

            MS. SHULMAN:  The ones that will be exempt was anyone who has the -- the same one would be exempt or you continue with --

            DR. DURFOR:  Now, I'm not sure I know the answer,b ut I think what Ms. Shulman said was appropriate, which is that if you were to determine this was exempt, then that would determine that -- then someone came in with a new species and genus.  If they were found to be exempt, then anyone after them would also be exempt.

            So it could, indeed, move beyond just the identified species and genus to almost any species and genus of insect at this time.

            DR. NEWBURGER:  Thank you.

            PANEL CHAIR LoCICERO:  Okay.  Let's vote on this with a show of hands, starting with nonexempt.  How many are in favor of nonexempt status?

            (Show of hands.)

            PANEL CHAIR LoCICERO:  One, two, three --

            DR. MILLER:  Could I ask a question before?

            PANEL CHAIR LoCICERO:  Yes. 

            DR. MILLER:  I'm sorry, but I'm not sure I fully understand yet.  To me changing the species would be like changing a device in a significant way.

            MS. SHULMAN:  Right.

            DR. MILLER:  Like using a new polymer or something like that.

            MS. SHULMAN:  I'm sorry.  Yes, that's what we were trying to say.  The first person to change that would have to come in with a 510(k), but then ones after that who used that same category would then be exempt.

            DR. MILLER:  Okay.  So any new person could come with this same identical species of maggot and start a new company and not have to report that.

            MS. SHULMAN:  And they would be exempt.

            DR. MILLER:  But if they came with a new species, they would have to go through the whole process.

            MS. SHULMAN:  Correct.

            DR. MILLER:  And so what we're talking about here is only same species, exempting a new company with the same identical species.  They just want to get into the market.  We exempt them from having to notify you.

            DR. DURFOR:  Right.  I just want to make a point that the risks to health in my mind extend beyond the genus and the species; that, for example, the patients in the past that developed tetanus from use of this product developed it not from -- they developed it because of the lack of control of the facility and the way the material was made.

            So I think there are risks to health beyond just the species and genus itself, and that the whole thing kind of has to be considered.

            DR. MILLER:  Okay.  I guess just one more question, and I want to make sure I understand the implication of this, and I don't -- looking at this device, is it the type of device that the FDA would prefer to know if somebody new got into the market and be informed of this or are you comfortable with this?  Is that a fair question to ask of a panelist?

            DR. DURFOR:  No, it's a good question.  It's an excellent question, and I'll give you my understanding, and if I am incorrect, Mr. Melkerson or Mr. Rhodes will help.

            If they determine that they want to market, they're going to have to register at their establishment independent of submission of 510(k).  The issue becomes really a question in my mind of the risks to health that we've identified and are they taking the adequate controls for the risks to health in terms of making sure that the product is safe.

            And so I'm not sure that answers your question totally, but the point would be that we would know through registration and establishment, but they would be distributing probably about within a very short time with no application review.

            MR. MELKERSON:  I'd just like to follow on if I could.  The exempt from pre-market notification does not exempt you from having adequate design controls and quality systems.  So the questions being asked, you're not exempting them from those controls that are applicable to the manufacturing process, but exemption from pre-market notification, as Dr. Durfor has identified, relates to FDA actually reviewing that information to see if that information is correct.

            So that's your question of exempting from pre-market notification.  In other words, is it appropriate to have a firm identify that we meet the special controls information in the guidance document? 

            They would make that judgment, whereas if you're saying it's not exempt, FDA would make the judgment of whether or not they have adequately addressed the risk to health in the review process.  So that's the question you're being asked of exempt or nonexempt.

            DR. LEWIS:  Okay, but it's correct you're stating that if they were exempt they still have to meet all of the controls on the manufacturing process.

            MR. MELKERSON:  They have to meet quality systems or good manufacturing practices, but that is something that would be done post market only for cause or if that facility was inspected, whereas the pre-market notification determination of what they're doing adequate is done prior to marketing.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  Can I add a bit further comment on that from the industry perspective?  It is that if it is an exempt classification, then really it's reliant upon the compliance audits and inspections from FDA to show that the product conforms to all of the requirements.

            Typically, you know, companies don't get inspected, you know, right away after they've filed, and sometimes it can be quite a while until that happens.  So the pre-market notification gives FDA a chance to see what evidence the company feels they have or at least the statements that they make, that they are compliant with all of the things in the guidance documents and things like that.  So it's just a question of do we want to have FDA review that paper work before it goes on the market as opposed to waiting until, you know, when the next scheduled inspection might be.

            DR. MILLER:  Or a problem happens.

            DR. BARTOO:  Yeah, or a problem happens.

            PANEL CHAIR LoCICERO:  So because of all the discussion, let's go through everybody individually.  Dr. Newburger, how do you vote?

            DR. NEWBURGER:  I vote for nonexempt.

            PANEL CHAIR LoCICERO:  Vote for nonexempt status.

            Dr. Miller?

            DR. MILLER:  I vote nonexempt.

            PANEL CHAIR LoCICERO:  Nonexempt.  Dr. Leitch?

            DR. LEITCH:  I vote nonexempt on the idea that it's sort of new coming back into the market, it seems like to me, and then there are the issues of the type of dressing that it's related to, not just the maggots, but how it's contained and some of these environmental issues that I think we want to be certain are addressed.  So I think for the time being, since it is kind of new back to the market, it would be a good idea.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Bartoo.

            DR. BARTOO:  Nonexempt.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  Nonexempt.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  Nonexempt.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  Just one other question.  When you have a new product that comes on the market and it goes through the FDA scrutiny and then becomes approved and then a second company puts a very similar product on the market; the only difference is it's a brand name; in general are those nonexempt or exempt products?

            MR. MELKERSON:  If you are talking about a product, a second manufacturer wanting to market a product, they would be required to have their own 510(k) submission for their product.  It would not be -- the only classification of not having to make a premarket notification submission would be it's an exempt product and the products then as you read the classification, your product meets that definition.  You attest in your files that you are equivalent to that product.  Therefore, you would then go through listing and registration and notify the agency  that you were marketing that product, and then whatever level of control, Class I, Class II, Class III, you're meeting it, and for that there's no exempt Class III.  So it would be Class I or Class II.

            DR. EWING:  Is that the general rule or the exception?

            MR. MELKERSON:  That is --

            DR. EWING:  I'm just trying to get a feel for it.

            MR. MELKERSON:  That is the general rule.

            DR. EWING:  Okay.  So I would go nonexempt.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Lewis.

            DR. LEWIS:  Nonexempt.

            PANEL CHAIR LoCICERO:  Okay.  It's unanimous that we would go nonexempt.

            MS. SHULMAN:  Okay.  Question No. 12, existing standards applicable to the device subassemblies or components, device materials, parts, and accessories, if any are known.

            PANEL CHAIR LoCICERO:  Okay.  I think it's probably safe to say there are none, but do all agree with that?

            And I see nodding of heads.  So there are no --

            MS. SHULMAN:  Okay.  That's the end of the questionnaires, and then you will vote on the questionnaires as a whole, as filled out as being a Class II device requiring 510(k) subject to the guidance document.

            PANEL CHAIR LoCICERO:  Okay.  Let's do this by a show of hands.  This will be voting in favor of the proposal as we filled out on the work sheets.

            All in favor?

            (Show of hands.)

            PANEL CHAIR LoCICERO:  And the vote is unanimous.

            MS. SHULMAN:  Thank you very much.

            PANEL CHAIR LoCICERO:  Dr. Krause.

            DR. KRAUSE:  Yes, if everybody could pass the filled out form to the center, please, I appreciate it.

            PANEL CHAIR LoCICERO:  At this time we will begin a discussion of the classification of medicinal leeches.  As we have no industry presenters, we will go directly to the FDA presentation, which will be followed by a general panel discussion of this topic, followed by a more focused panel discussion aimed at answering FDA's questions.

            Following the panel discussion, we will complete the reclassification work sheet and supplemental work sheet.  The vote on these work sheets will constitute the panel's recommendation to the FDA. 

            There will also be time for public comment before the vote.  I would like to remind public observers at this meeting that while this portion of the meeting is open to public observation, public attendees may not participate except at the specific request of the panel.

            Let us begin with the FDA presentation.  Dr. Durfor.

            DR. DURFOR:  Thank you very much again for your time.  Some of the aspects of this presentation will be very similar to the other only because both are living systems, and they have a lot of similarities.  So what we are looking for, again, is your recommendation for classification of medicinal leaches as a medical device, and as discussed previously, medical devices are categorized based on risk, and today we're seeking your recommendation on that issue.

            A little bit of history.  Clearly leeches are a medical device with a long history and considerable clinical experience.  Last year in 2004, the FDA cleared their first 510(k) for a medicinal leech, and it was classified as an unclassified medical device.

            As before, I'd like to walk you through some of the review issues that were involved in clearing this medical device.

            Once again, as with maggots, there are issues in terms of controlling the facility to make sure that you keep pathogens, parasites, other things out of the leech growing environment, and in this particular application, these leeches were grown in a controlled facility.

            Of interest, you may or may not know leeches are a protected endangered species, and so consequently -- at least the medicinal leech that is used -- and consequently, when they are manufactured, if you will, then they usually are done in a controlled facility, and they don't go out and harvest them from the local swamp.

            Leech feed is important.  In this particular application, the leech feed involved avian blood, and so clearly there are concerns, once again, infectious disease concerns, and as you know from the material you were given, there are no digestive enzymes in the gut of a leech, and so there is concern about the source of avian blood, review of the application, since it was a French application, required us to get in contact, have the manufacturer get in contact with the French facility and show that the blood that they were using in propagation was pathogen free, and that it also required a follow-up with the USDA to make sure there were no concerns about importation of leeches in this situation and that had been propagated on French avian blood.

            So, once again, the growth conditions are important.

            Packaging and shipping are also important, not only once again to be pathogen free, but also to make sure that the device arrives in a functional and operational state.

            I've already mentioned that if it's coming into the U.S. from outside the U.S., there will have to be some level of documentation that they're dealing with, the fact that it's an endangered species.

            As with maggots, application and disposal are critical issues, and we looked at that very much because there are some adverse events associated with application and very much so human blood inside the leech could be potentially pathogen containing.  So this is the biohazard that has to be disposed of in an appropriate manner.

            The application that came in from the French company did have some level of clinical experience, and they provided that for us, and that was particularly important, and I'll show you some of the concerns that's related to.

            Once again, it's a 2004 application.  So we have not received any medical device reports to date in our adverse event system, but once again, leeches are pretty well understood.

            There is a symbiotic bacterial infection in the gut of many leeches, and consequently there have been reports sometimes as high as 20 percent of infection that is occurring when you use leeches.  Septicemia, pneumonia, and gastroenteritis have been reported as associated with use of leeches, and in fact, the labeling needs to inform people of that, and it's an important issue in terms of facility control because depending on where you grow it, you may have different symbiotic bacterial infection in the gut.

            Leech migration is an issue.  There are reports that if you don't put on the gloves, then the health care provider will get the leech instead of the patient.

            You also need to drape the wound appropriately to make sure that you hit the right area and that the leech does not migrate to a better profused area, and as I've mentioned before, removal is a biohazard for a single use device.

            So as the FDA looked at this product and felt that we would propose Class II regulation, we then began to think about issues associated with how we would want to control this type of product and control the risks associated with the product, and as before, we feel that there are some risks, the first being infection, sterility and disinfection.  There would be a section in the guidance document about that.  You clearly cannot sterilize a living organism, but there have been people who have looked at ways to disinfect the gut of the leech to try and reduce the issue of the bacterial infection.

            Clearly you would want to have a sterile transport system, and whatever you can do to sterilize or disinfect the feed materials, of course, is important.

            Facility control is important not only for safety, but consistency of the product.  Clearly, infection or other things for the animal could change its ability to function.  So facility control is very important.

            Traceability of the animal, in fact, that was an issue that came up in the 510(k) review, was they were able to trace the animals from start to finish so that they knew if something were to go wrong or something was to turn up in the feed or some other issue were to come up, they had a tracing possibility through facility control.

            I've already discussed the issues associated with mammalian derived blood.  That's probably no surprise.  Clinical data is, of course, important because the incidence of infection associated with leech use has been reported to vary, and so if there are data, it's not a requirement, but if there are data, then the FDA would welcome the presence of it in a 510(k) document.

            Labeling is important for infection control, once again, given the fact that many animals had this symbionic bacterial infection as well as appropriate disposal of the organism, of the leech when it's done.

            At risk tissue reactions can occur.  Biocompatibility can be an issue if there is something in terms of the way that the animal is packaged or its final environment, but probably more importantly it would be the issue of whatever drapes or whatever else is used, once again, to keep the animal at the site of application.

            Once again, adverse tissue reactions could be anticipated if somehow manufacturing got a little bit out of control.  Similarly, with clinical data and labeling, these are important to control how the animal behaves when it's on a human body.

            So with that in mind, the FDA is proposing a Class II classification for medicinal leeches.  The definition is before you, that is, that they are fresh water worms intended for use as an adjust to graft tissue healing, with one of our problems of venous congestion, or to overcome the problem of venous congestion created by prolonged  localized bleeding.

            We believe that Class II is appropriate and that an appropriate special controls guidance document can be prepared such that it would be entitled special controls guidance document for industry and FDA for 510(k)s associated with medicinal leech products.

            With that in mind, I thank you for your time.  I'd be happy to answer what questions I can, and I have these classification questions that I hope you will be able to comment on.

            Thank you.

            PANEL CHAIR LoCICERO:  Thank you, Dr. Durfor.

            The panel will now entertain questions for Dr. Durfor.  Let's go with Dr. Lewis.

            DR. LEWIS:  You have in the material that was mailed to us under Section 5, Device  Description, you have five different areas there and the description of the genus, the species, methods, identification of other contact materials, such as special pouches and so forth.  You haven't addressed those here.

            DR. DURFOR:  No.

            DR. LEWIS:  Should they be included as part of the description?

            DR. DURFOR:  I think it's important information to have in an application to define the product.  I think generally the classification reg. can be a little bit broader and a little more succinct.

            However, at the same time, I would very much appreciate hearing what this panel has to say on that topic.  So what I lay before you is what I think could work, but we come to listen to you, and so I would appreciate whatever comment you have.

            DR. LEWIS:  it seems the method of application, the method of handling, how transported and subsequently used, are all important things that should be considered.  I'm not sure where the most important place to put that is in terms of a description or other parts of the application, but I think that should be included.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Ewing.

            DR. EWING:  Two concerns. One, medical leeches are on the endangered species list, and the manufacturer, whatever their participation in not using an endangered species; I mean, what are they giving back for conservation of this creature?

            The second question was do they make recommendations on how you dispose of this creature in a humane manner?

            DR. DURFOR:  Right, yes, good questions.  I did not go into the issue of what the criteria were for them receiving the permission to export the animal as much as just making sure they had addressed that issue.  I felt it was outside my jurisdiction.

            I would suggest that because these are propagated in a defined area that they are not adversely affecting the environment, and that was my approach.

            I'm sorry.  Please.

            DR. LEITCH:  I mean, that's what I would say, too.  If they're farmed for the purpose of medical use as opposed to, you know, they go out in the swamp and collect them, I mean, in fact, I think it's good, you know, if agencies farm animals for use as opposed to selecting from the environment.

            DR. EWING:  I guess my question was are they participating in any conservation program.  I know it's --

            DR. DURFOR:  It's a good question, and I'm not sure it's within our --

            DR. EWING:  -- the farm animals back into the wild.

            DR. DURFOR:  Yeah, it's a good question, and I'm not sure it's within my purview to determine that as much as to make sure that they have addressed that with other regulatory agencies.

            With regards to disposal, yes, the instructions for use were very, very appropriate in terms of telling how to dispose of the animal to make sure that you didn't have a problem with blood contact to other persons.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  For the wording, and maybe Dr. Miller can help with this intended for use as an adjunct to graft tissue healing.  I mean, you would want that type tissue as opposed to a, quote, skin graft, right?  I mean would that be misconstrued?

            DR. MILLER:  I mean, there are some specific words which can be chosen which as a plastic surgeon I'd be more comfortable with.  I don't know how important it is to do that here, but just like you said, I mean, it's not to be used for a graft of tissue.  It's really to be used for a tissue transfer is what we'll call it, a flap.  For a more technical term it would be a tissue transfer.  I've been trying to think about how to say this, and it would be something like medicinal leeches or fresh water annelid worms intended for use as an adjunct to facilitate healing of tissue transfers that are threatened by inadequate venous drainage, something like that.

            DR. DURFOR:  This is very helpful.  I mean, the indication that we used in this particular proposal is drawn from what we perceived within the literature, and so if you have a better way to say it this truly would be helpful.

            PANEL CHAIR LoCICERO:  We'll address that specific issue in the questions in a little while.

            Dr. Newburger, any questions?

            DR. NEWBURGER:  Is it planned to be in the labeling as to the maximum time of contact or is that not in the purview of this discussion?

            PANEL CHAIR LoCICERO:  I would think we'd do that in the guidelines or in the labeling.

            DR. DURFOR:  Yeah.  There's some variability as with any living system depending on the size of the leech, depending on how long it has been since their last blood meal, but there are some general ideas in terms of contact.  So that sort of information needs to be in the product labeling within a range of what the product manufacturer does.

            In the one application we saw the last blood meal, I believe, for the animals was maybe as much as three months.  And so consequently they had very tightly defined sort of specifications, if you will, as to how large the leach was and how effective it would be given the fact that they controlled when the animals had eaten last.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  Maybe you can help clarify for me.  According to the wording here, there's medical leeches or freshwater annelid (phonetic) worms.  Is that a specific genus and species or are there multiple types.  I'm not quite sure of --

            DR. DURFOR:  My understanding is that there is a particular genus and species that has been used, and it's the European leech, and the medical name is -- I can give it to you, and I apologize for not having it, but, for example, American leeches are not used.

            DR. BARTOO:  Okay.

            DR. DURFOR:  And that's why.  So there is a genus and species, and I'm sorry if it's not in the definition, but it should be probably.

            DR. BARTOO:  So I mean my question was do we want to make it specific to that particular type because if in the future they find some other type of leech that happens to have similar properties, you know, this wouldn't apply, I guess in that case.

            So my question would be would we want to potentially expand that to be a little bit more broad just to be leeches, and some would work.  If they don't work, then obviously there wouldn't be anything in the application to put in.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  My understanding is that the only leech which really is suitable is a single species.  I think it's  Hirudo medicinalis or something.

            DR. DURFOR:  Thank you.

            DR. MILLER:  Any other candidate leech I think you'd have to really scrutinize as to whether it was suitable.  This is the one that has been used for centuries, I believe, and the one that's used today.  I don't think you can just casually switch species.

            So I don't know.  I defer to your judgment whether that's essential to say that in this identification, but it is that specific leech.

            DR. DURFOR:  Okay.  Thank you.

            PANEL CHAIR LoCICERO:  Okay.

            DR. DURFOR:  Thank you.

            DR. KRAUSE:  Yes, from my records Hirudo medicinalis is the genus/species, and the annelid worms are fairly broad.  That's a phylum.  So I don't know if you want to include a whole phylum.

            DR. DURFOR:  Well, I think what I've heard in this discussion is that we should limit it to genus and species.  That's what has been used.  That's what is well understood, and the definition that's provided is too broad.  So message received.  Thank you.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Blumenstein, any comment?

            DR. BLUMENSTEIN:  No comment.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  No comment.

            PANEL CHAIR LoCICERO:  I have two questions.  Since these are coming in from Europe and most animals require quarantine, are there special rules concerning quarantine with this animal?

            DR. DURFOR:  Not that I'm aware.  In general, the infectious disease controls were done by means of controlling the feed and the environment that the animal is in.

            I'm not sure at this point, and it doesn't mean that I'm right.  It means that I would appreciate an education as to what additionally might be obtained by quarantining animals on the way in.  What would you look for or how long would you want it to be?

            PANEL CHAIR LoCICERO:  Okay.  It's maybe something that's going to require interagency negotiation because you can't keep the animal unfed for too long a period of time.

            DR. DURFOR:  Right.  I actually did spend some time with the Department of Agriculture on this issue.  I want it to be very clear because they do regulate the importation of any animal or plant material, and so it was important to talk to them about this issue to see what their regulations were because just because we said it was okay doesn't mean USDA was buying off.

            In my discussions with the Animal and Plant Health Inspection Service of USDA, I was informed that because this is a living animal that they did not have any concern about its importation through their regulations.

            I mean, the one issue that did come up -- I actually contacted them as well at the same time about the French avian blood -- their one concern was about their compliance with the Endangered Species Act.

            So there has been -- clearly, the product would not have reached the market if these initial discussions had not already taken place.  It doesn't mean there isn't more that we can do, but we have spent some time talking to USDA.  Just in my experience with other biological type of products, you always have to talk to USDA because just because FDA says it's okay to come in doesn't mean the USDA will agree to let it into the United States.

            PANEL CHAIR LoCICERO:  Okay, and you said that there is clear instructions on disposal.  Does that include euthanasia?

            DR. DURFOR:  I'm not aware of that issue being addressed.  So, no, I don't think that's an issue in terms of that has not been discussed in terms of terminating the leech.

            PANEL CHAIR LoCICERO:  Okay.  Are there any additional questions from the panel?

            (No response.)

            PANEL CHAIR LoCICERO:  Thank you, Dr. Durfor.

            DR. MILLER:  Can I ask a question?

            PANEL CHAIR LoCICERO:  Yes, yes.

            DR. MILLER:  So am I to understand that there's one source in the world?  But I think there's a couple of companies that you can call to get them.  Are the different distributors getting their animals from the same source or --

            DR. DURFOR:  My understanding is that there's not one source, but multiple sources.  There's a source in the U.K. as well.

            DR. MILLER:  Right.

            DR. DURFOR:  And that source, I believe, and we have not confirmed, but I'm pretty sure that company is a pre-amendments product.  I have very strong suspicions they were selling before '76.  So that would make them a pre-amendments device.

            I have not confirmed that, but I do know that there is an exporter from the U.K., as well as from France.

            DR. MILLER:  So these have been available for longer than last year.  So the circumstances under which they were available were totally unregulated.  Is that how that works?

            DR. DURFOR:  Yeah.  I mean, well, to the best of my knowledge.

            DR. MILLER:  So if we classified them and this company alone has submitted the documentation, does that mean that they will be the only company that is permitted to market the leeches in the U.S.?

            DR. DURFOR:  Well, the way the medical device amendments work, it's my understanding that if you were commercially distributing before 1976, you are permitted to continue to distribute it, but you are required to register your establishment and undergo inspection.

            DR. MILLER:  I see.

            PANEL CHAIR LoCICERO:  Okay.  At this time we begin to focus on the discussion of the FDA questions.  Now, we have the FDA questions on the board.  At this time we will not refer to the reclassification questionnaire.  We will do that after the discussion on these questions is complete.

            Please consider medicinal leeches while responding to the question.

            The first question is:  please discuss the proposed classification of medical leeches for use as an adjunct to graft tissue healing and to overcome problems of venous congestion.

            Let's start with Dr. Miller.

            DR. MILLER:  I think the words of the identification could be, you know, massaged a little bit, and I think you could say medicinal leeches or freshwater annelid worms of the species Hirudo medicinalis intended for use as an adjunct for healing, tissue transfers, threatened, you know, with failure by venous congestion or venous insufficiency or something like that.  I think that would be a good definition.

            DR. DURFOR:  If I could ask for clarification, the way the definition worked, it actually had two indications.  One was the rescue of a graft and the other was to overcome the problem of venous congestion just created by prolonged localized bleeding.

            So in your revised statement you've only addressed the first one.  Do you feel the second is inappropriate or do you wish to change that in any way?

            DR. MILLER:  Oh, you mean the second from the problem of venous congestion?

            DR. DURFOR:  Yes.

            DR. MILLER:  That's fine.

            DR. DURFOR:  Okay.

            DR. MILLER:  That's how they work from my understanding.

            DR. LEITCH:  That is the mechanism.

            DR. MILLER:  The mechanism is that it makes the flap bleed.

            DR. DURFOR:  Right, but it becomes a broader indication than just tissue transfer rescue.

            DR. MILLER:  Well, yeah.

            DR. LEITCH:  But he's saying the reason for the problem of the needs rescue is the venous congestion, right?

            DR. MILLER:  Right.

            DR. LEITCH:  And that's why it's in trouble.

            DR. DURFOR:  I understand.

            DR. LEITCH:  It's for that reason, and so his definition says something about it, but it doesn't have it as an "or."  It's inherent in the problem.

            DR. MILLER:  And it comes down in a way to how you define "graft," and my view on this is that graft is a term which shouldn't be used for a piece of tissue transfer that has a blood supply, you know.  So you wouldn't need to use a leech on a graft because it doesn't have blood supply, and so the jargon is "flap" for a tissue transfer with a blood supply, but that's a little bit, you know, informal maybe.  So you can call it tissue transfer or something.

            But I think it's good to be more specific because the idea is that the reason you're using the leech is because you've moved a piece of tissue somewhere or replanted it.  You can say plus a replant.

            DR. DURFOR:  Right.

            DR. MILLER:  Tissue transferred or replanted tissue.

            DR. DURFOR:  Right.

            DR. MILLER:  That is threatened with failure because of a venous congestion.

            DR. DURFOR:  Thank you.

            PANEL CHAIR LoCICERO:  Let me restate this now, if I have this correct.  Medicinal leeches are freshwater annelid worms of the species Hirudo medicinalis intended for use as an adjunct to transferred or replanted tissue where healing is jeopardized by venous congestion.

            DR. MILLER:  I like that.

            PANEL CHAIR LoCICERO:  Okay.  Yes?

            DR. NEWBURGER:  Just a small question.  This one is called medicinal leeches whereas the previous one was called medical leeches, and I was just wondering if there was any --

            PANEL CHAIR LoCICERO:  Medical maggots.

            DR. NEWBURGER:  -- or do we want to keep them consistent between the two.

            DR. LEITCH:  It's probably because it's Hirudo medicinalis, is the name of it, you know.

            PANEL CHAIR LoCICERO:  Rolls off the tongue easier.  I don't know.  Do we want to make a distinction or lumping?

            It sound like we're going to stick with the different names.  Okay.  So I'm going to read it one more time.  Medicinal leeches are freshwater annelid worms of the species Hirudo medicinalis intended for use as an adjunct to transferred or replanted tissue where healing is jeopardized by venous congestion.

            DR. LEITCH:  That doesn't sound quite right because when they're using adjunct, it's the adjunct to healing, is what the adjunct part is.

            PANEL CHAIR LoCICERO:  Okay.  Adjunct to --

            DR. LEITCH:  It's wordsmithing you've got to work on a little bit there is all.

            PANEL CHAIR LoCICERO:  Okay. 

            DR. LEITCH:  It's not -- but you've got the main elements in there.

            PANEL CHAIR LoCICERO:  Well, we could really word split and say that it's not the healing.  It's the survival.

            DR. MILLER:  It is the survival.  I like that even better.

            DR. LEITCH:  Yeah, yeah, yeah.  That would be okay.

            DR. MILLER:  Yeah, it's the survival of the tissue threatened by venous congestion.

            PANEL CHAIR LoCICERO:  So adjunct to the survival of transferred or replaced tissue.

            DR. MILLER:  To facilitate the survival or something.  Now, you probably have like medical writers who are like just authorities on saying things just right.

            DR. LEITCH:  But I think you've expressed what the sense of the issue is, that it is to permit the survival of a transferred tissue flap or a replanted tissue that is threatened by venous congestion.  I mean, that's -- and it's not this either/or thing.  It's kind of one thing.  I think that's the point that needs to be clear.

            PANEL CHAIR LoCICERO:  Okay.  Mr. Melkerson, has this answered Question 1?

            MR. MELKERSON:  I believe we can take your guidance and do a little wordsmithing.

            PANEL CHAIR LoCICERO:  Great.  Thank you.

            Question No. 2:  please discuss what descriptive information and intended use should be included in the proposed classification identification.

            Dr. Bartoo.

            DR. BARTOO:  I think we just did that when you go back to the first question.

            PANEL CHAIR LoCICERO:  Okay.  All right.  So we went through that.  So go back to Question 1.  So I'm getting the sense out of everybody that this is probably Class II.  We're not going to get by with anything other.

            Okay.  So Class II.  Does this sufficiently answer the FDA's question?

            MR. MELKERSON:  Thank you.

            PANEL CHAIR LoCICERO:  Okay, and now to number three.  Please discuss the risk to health during use of these devices.

            Dr. Ewing.

            DR. EWING:  I think both issues were brought up, specifically the infection that can occur when using animals.

            My only other bothersome thing about this is, you know, destroying an animal that's on the endangered species list.  I know it has nothing to do with our review here, but is there any way that we can address that?

            Can these animals be harvested or --

            DR. MILLER:  Well, I think the endangered animals are the wild ones.

            DR. LEITCH:  Well, these are endangered, too, because --

            DR. MILLER:  Well, but these are --

            DR. LEITCH:  They're grown for the purpose.

            DR. MILLER:  They can produce.

            DR. EWING:  I know, but is there any way that the two can be wedded together somehow?  I mean, if they're growing these animals on a farm, once the animal was used does it have to be destroyed I guess is my question.

            DR. BLUMENSTEIN:  Maybe they could be given the job of eating up the maggots.

            (Laughter.)

            DR. EWING:  There you go.

            DR. LEITCH:  Well, I think the practicality, I suppose, of things is, you know, once the animal has taken the human blood, then you have all the issues of the human blood borne diseases that could be transferred, and  then if you have to have personnel that, you know, have to work with getting these things back to the ocean or the fresh water again, I think you introduce risk to the health care worker then that's more than is probably warranted for the issue would be my thought on that.

            I mean that's a concern I have, is, you know, getting the things off, you know, and then getting bit, and then having the health care worker be injured.

            So I guess I just think you have to deal in some practicality, and I think that would be -- I would think it would be hard to do easily.  I would get them back to a nice pond in England.

            DR. EWING:  You know, the little retirement pond.

            (Laughter.)

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  I'm having trouble here.  They're leeches.

            PANEL CHAIR LoCICERO:  Please use your microphones.

            Thanks.

            Dr. Lewis.  No additional.

            Dr. Miller, anything additional?

            DR. MILLER:  Nothing additional.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I think the subject has been well covered.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  No more comments.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  So based on Dr. Leitch's comments, should we add like another environmental risk in addition to the infection and adverse --

            DR. LEITCH:  I mean, I think like to me that has to be addressed somewhere, is the environmental risk once they've been used.

            PANEL CHAIR LoCICERO:  And I think we've communicated that to the FDA, that they become a biohazard after application.

            So does this answer the FDA's third question?

            MR. MELKERSON:  Yes, I believe so.

            PANEL CHAIR LoCICERO:  Great.

            DR. LEWIS:  Excuse me.  That would then be added as an additional risk, not in units, but as a risk to other personnel.

            PANEL CHAIR LoCICERO:  Yes.  We'll now proceed to the open public hearing session regarding medicinal leeches.  All persons addressing the panel are asked to speak clearly into the microphone as the transcriptionist is dependent upon this means of providing an accurate record of this meeting.

            Do we have anyone who wishes to address the panel concerning medicinal leeches?

            (No response.)

            PANEL CHAIR LoCICERO:  Since we have no public comment, we will now fill in the classification questionnaire and supplemental data sheet.  Ms. Shulman of the Office of Device Evaluation will assist us as we go through our process.

            We will vote on the completed questionnaire and supplemental data sheet.  It will become the panel's recommendation to the FDA, and we'll hand out the sheets.

            MS. SHULMAN:  Okay.  Here we go again.  The panel name, petitioner, generic type of device, and the date.  So we'll go for the first question.

            Is the device life sustaining or life supporting?

            PANEL CHAIR LoCICERO:  I'm getting shaking heads that this is not life sustaining.  So the answer to the first question is no.

            MS. SHULMAN:  Okay.  Thank you.

            Number two, is the device for use which is of substantial importance in providing empowerment of human health?

            PANEL CHAIR LoCICERO:  And Dr. Miller is shaking his head yes.  Do we have a general agreement?

            It looks like we have general agreement that this answer is yes.

            MS. SHULMAN:  Okay.  Number three, does the device present a potential unreasonable risk of illness or injury?

            PANEL CHAIR LoCICERO:  I'm getting some head shaking.  Is there anybody who thinks that this should be yes?

            (No response.)

            PANEL CHAIR LoCICERO:  Okay.  So the answer to this one is no.

            MS. SHULMAN:  Okay.  Number four, did you answer yes to any of the above three questions?  Yes, we did so we go to Number 6.

            Is there sufficient information to establish special controls in addition to general controls to provide reasonable assurance of safety and effectiveness?

            PANEL CHAIR LoCICERO:  And I think everybody is in agreement that we can.  So the answer is yes.

            MS. SHULMAN:  Okay.  Thank you.

            Number seven, if there is sufficient information to establish special controls to provide reasonable assurance of safety and effectiveness, identify the special controls needed to provide such reasonable assurance for Class II, and they are listed below, and there's always the other recommendations:  sterility, biocompatibility, et cetera.

            PANEL CHAIR LoCICERO:  Just a question on this.  Does this also include guidance for disposal?

            MR. MELKERSON:  The answer to that would be yes.

            PANEL CHAIR LoCICERO:  Okay.  All right.  So we need to consider everything from manufacturing practices through use to disposal.

            Okay.  Dr. Leitch.

            DR. LEITCH:  Yes, I think the guidance document if it covers those elements would be fine.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  The guidance document.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            Dr. Lewis.

            Dr. Ewing.

            DR. EWING:  I'm going to abstain.

            PANEL CHAIR LoCICERO:  Abstain.  Okay.

            Dr. Doyle.

            DR. DOYLE:  Yes.

            DR. BLUMENSTEIN:  Yes.

            PANEL CHAIR LoCICERO:  And Dr. Bartoo.

            DR. BARTOO:  Agreed.

            PANEL CHAIR LoCICERO:  Okay.  So we have one abstaining, but everyone else agrees that a guidance document would be sufficient to answer this question.

            MS. SHULMAN:  Thank you.

            Number eight, again, we get to skip as well as number nine because it has to do with performance standards, and number ten is only for Class III devices.  So we can move on to the next page.

            This is the needed restrictions question.  The first question, only upon the written or oral authorization of a practitioner licensed law to administer use of the device.  In addition, you can have use only by persons with specific training or experience in its use; use in only certain facilities or any other.

            PANEL CHAIR LoCICERO:  I think everybody is going to agree to number one.  The question will be if there are additional ones.  Dr. Bartoo.

            DR. BARTOO:  It was brought up in the presentation earlier that traceability is currently required for the devices, you know, from France.  So is that what you would consider a restriction?

            MS. SHULMAN:  I believe we would consider that a special control.  We can amend the first page if you wanted to add that.

            DR. DURFOR:  I want to be very clear because there's a track device and there's traceability, and tracking I don't believe is what we're talking about.  That's where you have an implant and you follow it until patient death.  So you're not talking about tracking.

            What you're more talking about is good manufacturing practice of knowing how to follow traceability.  So I just want to clarify the difference between tracking and traceability.

            MS. SHULMAN:  So in answer to the question, too, if you wanted that to be of note would amend the first page to say that it wouldn't be one of the restrictions under the prescription under number 11.

            DR. BARTOO:  So it sounds like traceability though is just part of general quality system regulations; is that correct?  So that there are no other specific controls.

            PANEL CHAIR LoCICERO:  Okay.  So that makes that.

            Dr. Blumenstein, any additional?

            DR. BLUMENSTEIN:  No.

            PANEL CHAIR LoCICERO:  Dr. Doyle?

            DR. DOYLE:  No.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  No.

            MR. MELKERSON:  Dr. LoCicero, the transcriptionist is having difficulty hearing.  People need to speak in the microphones, please.

            PANEL CHAIR LoCICERO:  They're going up and down.  If we could try to get that regulated, that would help.

            Dr. Newburger has a question.

            DR. NEWBURGER:  The question is in terms of needed restrictions I'd like some clarification about specific training or experience in its use.  This seems to be a little bit trickier in that there is risk to the individual places and removes the animal.

            And just as we have from OSHA requirements for training to avoid needle sticks, might there not also be for this particular mix specific training in terms of at least having something a little bit more sophisticated other than reading a label and having to remove these animals, especially since they will likely be biohazards after use?

            PANEL CHAIR LoCICERO:  Well, let's have a little discussion about that.  Do you feel that this should have some additional training, albeit maybe a short time, instructions from the universe of precautions, instructions as a short course?  Should that be part of this?

            Dr. Miller.

            DR. MILLER:  I don't know.  This is an unusual thing to use, but it's not very difficult really.  I mean, you know, you become very comfortable handling them very quickly and a patient even can manage them themselves.  So it sounds -- it's unusual, but I don't know that special training is necessary.  It's not really complicated.

            DR. NEWBURGER:  May I ask how you achieved your comfort level with these animals?

            DR. MILLER:  Well, just by using them.  I mean, they don't move very fast, and you put them where you want them and just sort of herd them around and let them tumble in and this type of thing.  I mean, if you read some of the concerns about being treated as a biohazard for disposal and that type of thing, they're not dangerous.  I don't think they're dangerous to the healthcare workers using them.  It may be a little disconcerting if a leech tries to go for you, but it's not -- even if it's successful, it's not going to harm you.

            DR. NEWBURGER:  Even though it has already taken the blood of the other person?

            DR. MILLER:  Well, the thing about that is once the leech attached to the flap of the person, it doesn't let go.  You know, as long as it's getting blood, you can't get it off.  If it latches on, it tends to stay there until it has finished, and then it just lets go.  It's not going to bother anything else.  Once it lets go, it's full and it's finished.  It doesn't try to bite anything else.

            PANEL CHAIR LoCICERO:  They're quite lethargic when they're full.

            DR. MILLER:  If you're not familiar, it may not be self-evident; however, whether that means someone needs special training, I mean, to me that sounds like a little more elaborate than --

            PANEL CHAIR LoCICERO:  Maybe I can relate a story.  Some years ago we had an opportunity to do this in a human in a significant replantation situation, and it took one instructor ten minutes to teach the nurse how to do it, and then that propagated until we were no longer using them.  So the training really was not a big deal.

            DR. NEWBURGER:  I ask since I have no experience with leeches whatsoever.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I think that anyone that's training in a plastic program that would be doing lab transfers, pre-implementation, that would just be part of their training as any other surgical skill that we pick up.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  I would agree.  I don't think additional training is necessary.  I think it would be part of the medical preparation of the people who would be doing this.

            PANEL CHAIR LoCICERO:  Okay, and Dr. Leitch.

            DR. LEITCH:  Yes, I think just the prescription.

            PANEL CHAIR LoCICERO:  Okay.  Should we list this as restricted to certain facilities?

            DR. MILLER:  I don't think so.

            PANEL CHAIR LoCICERO:  All right.  So after discussion, our recommendation is that this be by prescription only.

            MS. SHULMAN:  Okay.  Thank you.

            We can move on to the supplemental data sheet.  And again, the first question there, the type of device and the Advisory Panel, and then three is device and implant.  Again, that's 30 days or longer.

            PANEL CHAIR LoCICERO:  This clearly is less than 30 days.

            MS. SHULMAN:  Yes, okay.  Number four, the indications for use in the device labeling, we can say as presented and as amended during the discussion.

            PANEL CHAIR LoCICERO:  I think everyone will agree to that.

            MS. SHULMAN:  The identification of the risk to health presented by the device, again, we can say as presented or if there's any others you would like to add at this point.

            DR. BARTOO:  So in that one it's as presented as well as environmental risks?

            PANEL CHAIR LoCICERO:  I would think that since we discussed it earlier and we included the environmental risks, that we can just say as discussed.

            MS. SHULMAN:  Correct.

            PANEL CHAIR LoCICERO:  I'm not sure where the right point is to bring up the issue of disposal.

            MS. SHULMAN:  I think this would be a good please to, identification of the risks under --

            PANEL CHAIR LoCICERO:  Okay.  These are potential biohazards after use, and we don't have a clear definition of termination or just throw it in a red beg.  So I'd like to have some discussion at this point on the panel's thoughts concerning disposal.

            Dr. Leitch.

            DR. LEITCH:  Oh, man, I think they should be killed.  That's what I think.  I mean, I just think you're in a situation where, I mean, this is hospitals all across the country, and you know, granted they'll probably be in bigger cities where there's more access to how to do things, but I think, you know, the idea of trying to save them and send them back live somewhere else and deal with it that way, I think, is a process that's fraught with difficulties.

            PANEL CHAIR LoCICERO:  I'm sorry.  You would recommend language concerning termination and disposal as a biohazard?

            DR. LEITCH:  Yes, you know, similar to how tissues are destroyed when they're ultimately destroyed.

            PANEL CHAIR LoCICERO:  Okay.  Dr. Miller?

            DR. MILLER:  I agree with that.  They should be killed.  I think if you put them in a solution of some kind, I think it's an alcohol solution, they die instantly, and then they are treated like a blood soaked, you know, sponge or something like that because that's essentially what they are.  They're just a device soaked with blood, and so they're treated as other devices like that.  That's how we have done it, and I think continue to do it.  So these guidelines would be appropriate.

            PANEL CHAIR LoCICERO:  Dr. Newburger?

            DR. NEWBURGER:  I agree.

            PANEL CHAIR LoCICERO:  Okay.  Agreed.

            Dr. Lewis.

            DR. LEWIS:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I just have one question.  In the guidelines there is a description of how they are to be destroyed?

            MS. SHULMAN:  Yes.

            DR. EWING:  Do they use alcohol or is it ‑- I wouldn't want them to toss live animals in the incinerator, that kind of thing.

            MS. SHULMAN:  Right, right.  There are two different things.  One would be the guidelines that you're talking about, which would be the special controls document that you're helping us write, and the other is the 510(k). 

            I don't remember the specifics of how they disposed of it, but they did not incinerate live animals, no.  So with that said, I think the value of your comments to me is how we want to write the special controls guidance or whatever guidance, whether -- I don't want to lead you in any one direction, but your comments are good for the guidance document in terms of what you would like to see.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Blumenstein.

            DR. BLUMENSTEIN:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Bartoo.

            DR. BARTOO:  Nothing to add.

            PANEL CHAIR LoCICERO:  Okay.  It looks like we're going to say as discussed with appropriate language concerning termination and disposal after use.

            MS. SHULMAN:  Perfect.

            PANEL CHAIR LoCICERO:  Okay.  Question six, the recommended Advisory Panel classification and priority.  The classification recommended was two, and the priority, again, is high, medium or low.

            PANEL CHAIR LoCICERO:  All right.  How does everybody feel about the guidance here?  Maybe Dr. Bartoo will start there.

            DR. BARTOO:  Well, first of all, I think we all agree it's Class II, and in terms of high, medium or low, I think this might be more of a medium because if it sounds like there's no guidance out there for people for how to terminate and dispose at this present time, so maybe you know, having that guidance document out there so that the manufacturers can produce the appropriate labeling might be of a little bit more urgency than maybe some of the other things we talked about today.

            PANEL CHAIR LoCICERO:  So medium.  Okay.  Dr. Blumenstein.

            DR. BLUMENSTEIN:  I concur.

            PANEL CHAIR LoCICERO:  Dr. Doyle.

            DR. DOYLE:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Ewing.

            DR. EWING:  I agree.

            PANEL CHAIR LoCICERO:  Dr. Lewis.

            DR. LEWIS:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Newburger.

            DR. NEWBURGER:  Agree.

            PANEL CHAIR LoCICERO:  Dr. Miller.

            DR. MILLER:  Agreed.

            PANEL CHAIR LoCICERO:  Dr. Leitch.

            DR. LEITCH:  Agree.

            PANEL CHAIR LoCICERO:  Medium.

            MS. SHULMAN:  Medium.  Thank you.

            Number seven we may skip because there's not an implant or life sustaining or life supporting.

            Number eight, the summary of information including clinical experience or judgment upon which classification recommendation is based.  Again, we can say as presented during the panel meeting or anything else you wanted to add.

            PANEL CHAIR LoCICERO:  I think we can safely say as discussed, unless anyone wants to add something, and it looks as though nobody wants to add anything.

            MS. SHULMAN:  Thank you.

            Number nine, the identification of any metered restriction besides the prescription statement that we have already chosen on the general questionnaire.  If there's anything to add there?

            PANEL CHAIR LoCICERO:  Does anybody want to add additional restrictions?

            (No response.)

            PANEL CHAIR LoCICERO:  No additional restrictions.

            MS. SHULMAN:  Thank you.

            Number ten we get to skip because it's for Class one devices.

            Number 11, if the device is recommended for Class II, recommend whether FDA should exempt it from pre-market notification.

            PANEL CHAIR LoCICERO:  I take it everybody is going to say not exempt here.

            And that is what we have, nonexempt.

            MS. SHULMAN:  Thank you.

            And number 12, any existing standards that are applicable to this device or subassemblies, components, device materials, parts or accessories.

            PANEL CHAIR LoCICERO:  That is pretty clear from our discussion earlier that there is no standard.

            MS. SHULMAN:  Okay.  Thank you.

            Now I'll take one final vote on the two sheets as they stand as a Class II device subject to the special control guidance document, non-510(k) exempt, nonexempt.

            PANEL CHAIR LoCICERO:  Okay.  Let me finish writing here.

            MS. SHULMAN:  Oh, sorry.

            PANEL CHAIR LoCICERO:  The document that we'll vote on.

            MS. SHULMAN:  Thank you.

            PANEL CHAIR LoCICERO:  Okay.  We have our documents concerning medicinal leeches.  We're voting for approval of this document as we just put it together.

            All in favor.

            (Show of hands.)

            PANEL CHAIR LoCICERO:  And it's unanimous.

            MS. SHULMAN:  Thank you very much.

            DR. KRAUSE:  Please pass me your documents.

            PANEL CHAIR LoCICERO:  I want to thank everybody for today's work.  It was intense, but short.  Mr. Melkerson, do you have any final comments?

            MR. MELKERSON:  I'd just like to thank the panel and actually I'm impressed that you have gotten through the classification process.  This is one of the processes that panelists struggle with quite a bit, and you've shown great vigor in getting through them.

            PANEL CHAIR LoCICERO:  So this concludes our meeting for today.  The meeting of the General and Plastic Surgical Devices Panel is adjourned, and we will meet again tomorrow morning at 8:00 a.m.

            Thank you.

            (Whereupon, at 2:01 p.m., the meeting was adjourned, to reconvene at 8:00 a.m., Friday, August 25, 2005.)