Ralph Harkin, Ph.D.
CONTENTS Introduction, Dr. Carolyn Tylenda
Comments by Dr. David Kessler, Commissioner, FDA 8
Amalgam Update, Dr. Lee Joseph, FDA/CDRH 15
Dr. Martin Siegel 27
Dr. John C. Baar 30
Dr. Benedict B. Kimmelman 33
Dr. N.J. McDonald 36
Dr. Emanuel Ploumis 39
Dr. A. Joseph Venneri 41
Dr. John Rigby 46
Dr. Joseph D. Maggio 48
Dr. William Fentress 57
Dr. Ken Burrell 60
Dr. Mark Piacine 64
Dr. Newell H. Yaple 71
N2 Universal Products Corporation
Mr. Charles Raubicheck 75
Dr. Alvin H. Arzt 100
Dr. Ramon A. Werts 110
Background Information, Dr. Paula Botstein, FDA 115
Dr. Clarence Gilkes, FDA 121
Consultant's Review, Dr. Sheila McGuire 133
Statistical Review, Dr. Ralph Harkin, FDA 141
Panel Response to FDA Questions 171
PROCEEDINGS DR. ROBERTSON: Welcome to the Dental Products Panel meeting. I am Paul Robertson, the Chairman, and I would like to introduce Dr. Carolyn Tylenda, the Executive Secretary.
DR. TYLENDA: Thank you, Dr. Robertson.
Welcome to the meeting of the Dental Products Panel. Anyone desiring a transcription or an executive summary of today's proceedings may obtain one. A handout is available at the reception desk providing information.
I request that everyone attending this meeting sign the attendance sheet. If you have not already done so, please stop by the registration desk.
I will now introduce the members of today's Panel. Starting at the far end of the table is Dr. Jean Frazier, our consumer representative. She is from Philomath, Oregon. There are two industry representatives for this two-day Panel meeting because we are discussing both dental device and dental drug issues. Miss Mary Edwards is from W.L. Gore & Associates, Flagstaff, Arizona. Dr. Frederick Curro is from Block Drug Co., Inc., Jersey City, New Jersey.
There are three consultants to the Panel present today. Dr. Sheila McGuire is a consultant to the Panel. She is on the faculty of the Harvard University School of Dental Medicine. Dr. Charles Bertolami is also a consultant. He is Professor and Chairman of the Section of Oral and Maxillo-facial Surgery, Center for the Health Sciences, University of California, Los Angeles. Dr. Carlos del Rio is Professor and Chairman, Department of Endodontics, University of Texas Health Science Center at San Antonio.
The remaining Panel members are voting members for today's meeting. Dr. Joel Sandak is a general dentist in practice in White Plains, New York. Dr. Burton Rosan is Professor of Microbiology, School of Dental Medicine, University of Pennsylvania. Dr. Benjamin Gerson is Professor of Pathology and Professor of Pharmacology and Experimental Therapeutics at Boston University, School of Medicine. Dr. Paul Robertson, the Panel Chairperson, is Dean of the School of Dentistry, University of Washington. Dr. Richard Norman is Professor of Restorative Dentistry at Southern Illinois University. Dr. Deborah Greenspan is Clinical Professor of Oral Medicine in the Department of Stomatology, School of Dentistry, University of California at San Francisco. Dr. Larz Spangberg is Professor and Chairman, Department of Restorative Dentistry and Endodontology, the School of Dental Medicine, University of Connecticut Health Center. Dr. Julianne Glowacki is senior investigator in the Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School.
On my right are Dr. David Kessler, Commissioner of the Food and Drug Administration; Dr. Paula Botstein, Acting Director, Division of Medical Imaging, Surgical and Dental Drug Products and Deputy Director, Office of Drug Evaluation I; Dr. Clarence Gilkes, senior reviewing dental officer, Division of Medical Imaging, Surgical and Dental Drug Products; and Dr. Ralph Harkin, group leader, Division of Biometrics.
Five of the voting members, Drs. Robertson, Greenspan, Glowacki, Norman and Rosan, each have a four-year term as a voting member of this Panel. Pursuant to the authority granted under the medical devices advisory committee charter, dated October 27, 1990, I appoint the following people as voting members for today's, February 12, 1993, meeting: Dr. Benjamin Gerson, Dr. Larz Spangberg and Dr. Joel Sandak.
For the record, these people are special government employees and are either a consultant to this Panel or a consultant or voting member of another panel under the medical devices advisory committee. They have undergone the customary conflict of interest review. They have reviewed the material to be considered at this meeting.
FDA is concerned about conflict of interest and I would like to read the following announcement which addresses the issue of conflicts of interest, and is made part of the record to preclude even the appearance of such at this meeting. The conflict of interest statutes prohibit federal executive branch employees, including special government employees, from participating in matters in which the employee, his or her spouse, minor child, partner, employer or employing institution has a financial interest. This includes any firm whose product is being reviewed or discussed by this panel or committee or any firms with which the employee is negotiating employment, grants, contracts, payments in kind or other gifts.
This also means the employee must not discuss competing products or competing technologies of other firms, or discuss generic or class action matters that affect the firm with which they or their employer are associated. However, waivers may be granted where the need for the individual's services outweighs the potential for a conflict of interest created by the financial interest involved, or the interest is not so substantial as to be deemed likely to affect the integrity of the services which the government may expect from such employee. Therefore, waivers have been granted to the following special government employees: Dr. Paul Roberts, for his interest in the University of Washington; Dr. Deborah Greenspan, for her interest in the University of California at San Francisco; Dr. Julianne Glowacki, for her interest in the Brigham and Women's Hospital; Dr. Burton Rosan, for his interest in the University of Pennsylvania; Dr. Richard Norman, for his interest in Southern Illinois University; Dr. Larz Spangberg, for his interest in the University of Connecticut; Dr. Carlos del Rio, for his interest in the University of Texas; Dr. Benjamin Gerson, for his interest in Boston University; Dr. Jean Frazier, for her interest in the University of Minnesota; Dr. Charles Bertolami, for his interest in the University of California at Los Angeles, and Medchem Products, Inc; Dr. Sheila McGuire, for her interest in the Harvard School of Dental Medicine.
At this time, I am pleased to introduce Dr. David Kessler, Commissioner of the Food and Drug Administration, who would like to address the Panel. Dr. Kessler?
COMMENTS BY DR. DAVID KESSLER
DR. KESSLER: Good morning. I am here today for two reasons. First, I want to express my sincere appreciation to all the members of this Advisory Panel. I know that you all have very busy schedules and I appreciate, indeed, everyone at FDA appreciates your sharing your expertise with us.
My main reason for being here today is that I want to discuss how FDA can work more effectively with the dental community; how we can promote the type of information exchange that facilitates the practice of good dentistry and the availability of better drugs and devices. I am talking about better communications. We need to forge stronger communication links, the kind of communication that allows us to predict where potential problems may occur with dental products, and to address them before they become major health concerns for the dental clinician and the consumer; the kind of communications that allow us to resolve issues like dental handpiece sterilization, the use of dental lasers and the safety of TMJ implants before they become headlines. And we need to start now.
I believe that the first step may be as simple as making sure that the dental community understands the role of the FDA in the approval of drugs and devices used in the practice of dentistry. I am not fully convinced that practicing dentists know that the drugs and devices that they use to treat patients need to be approved and regulated by the FDA; that under the law it is FDA's responsibility to, one, determine the legality of products marketed for use in dentistry and, two, to help make sure that those products are safe and effective for their intended use.
In part, today's agenda shows the need for better communications. There is no better evidence than the fact that today you will be talking about a drug that this Advisory Committee will comment upon that has not been approved. Yet, some dentists have been using similar types of products for many years.
There are other examples that suggest that the dental community is not fully aware of FDA's mandate to help assure that dental products are safe and effective, as well as legally on the market. Furthermore, there is evidence that dental devices are being promoted for purposes beyond those for which they are approved. An example is the promotion of dental lasers for hard tissue applications.
Let me digress for a moment to say that some products are promoted and advertised in such a manner that a dentist may not be able to tell that they are not approved for their intended use, and that is a practice that we are now addressing.
We will be focusing on companies that make false advertisements and promotion for dental devices, and we will take appropriate regulatory action before they get too far on in making misleading claims to the dental community. But, again, this underscores the need for us to do a better job of communicating with the dental community at large, not just to tell dentists that FDA approves drugs and biologics and devices they use in their practice, but to let them know where they can get accurate information on the use of such products and, more importantly, to give them a meaningful understanding of the product approval process, the kind of scientific data that are required in our decision making, and why.
We need to enlist the dental community's assistance in evaluating new products, and to tell them why they should promptly report to us adverse events and medical device failures, and how to report them.
One of the first messages to the dental community is for them to understand the basis on which we approve products and the importance of the dentist's role in assuring the integrity of those products. Simply put, to approve a drug or a new device for marketing, we need data collected on the performance of the new product in comparison with either an approved therapy or with a placebo, if appropriate. We need to know that the product works as intended, and we need a thorough analysis of its successes and its failures, its risk versus its benefit. We learn this information from looking at the scientific studies.
For drugs the law is clear. These data must come from adequate and well-controlled clinical trials. I want to emphasize those words—adequate and well-controlled. The trials should compare one group receiving the investigational therapy with a control group, and should report incidence of adverse reactions and assess effectiveness.
For devices requiring premarket approval, the law is slightly different but the general rule of valid scientific evidence still applies, including well-designed clinical trials when appropriate.
These requirements exist for new drugs and devices in all areas of medicine, not just dentistry. These are the rules that you will apply to the product under evaluation today. We want to hear your discussion of the scientific data in the NDA for this drug and your answers to the questions we have asked you about these data. Your recommendations will aid us in deciding whether the data are sufficient and whether the NDA should be approved.
I am not here to take any position on the application under consideration today. What I am committed to do is to bring this product, as well as all other dental products, into the Agency's regulatory purview and, further, into the realm of science. We need the dental community to be a part of this process. FDA needs to establish a closer relationship with the dental community, to have them involved at the outset in our scientific evaluation of products by being investigators in clinical trials, as well as serving on advisory committees.
We also need them involved throughout the process because often we do not find out about a problem, particularly with dental devices, unless the dental community provides that information to us. There are currently reporting requirements to dental device manufacturers, distributors and user facilities, such as hospitals and nursing homes. Most adverse events associated with dental devices, however, occur outside these facilities. As a result, FDA depends on dentists to voluntarily report problems with regulated products to us or we may not know of the problem in a timely manner.
Our medical device reporting records for dental products show that we need, all of us, to do more in this area. Really the need for this kind of data will increase with the development of new technologies that are becoming available in dentistry. We already are seeing an explosion with regard to dental technology, certainly with regard to endosteal implants and dental lasers. It is an explosion that reinforces FDA's belief that clinicians cannot individually assess every technology with which they come into contact, or make certain that those products function both safely and effectively for their patients.
The Congress has assigned that role to the FDA so that clinicians can focus on providing patient care rather than assessing new products before using them. But it is absolutely critical that the dental community be willing to report to FDA the earliest information available on the performance of these devices and all dental products.
This is the second message that we need you to take to the dental community. The FDA needs to know about serious adverse experiences with drugs and devices. We need your colleagues to report them.
Let me say two things about the reporting process before I conclude. First, we hope that it will be a long-term collaborative effort between the practicing community and the Agency, and that will cover all products whether they are new or have been on the market for a long time. The shared responsibility has to be long range because problems can crop up years later.
Second, you need to know where to report problems, and today we will provide you with information that you can disseminate to assist dentists in the reporting of adverse events. I strongly encourage those of you who represent organizations to share this information with your membership and to enlist their participation in the program.
I recognize the many difficult professional issues that dentists have to confront in their offices every day. I am aware of the new OSHA regulations and the EPA guidelines. We are also aware that our Agency may also be seen as complicating the practice of dentistry. What we are now talking about is forging partnerships that will allow us both to do our jobs better.
FDA has traditionally had a strong relationship with the dental community through its cooperation with the American Dental Association and its many councils. We have worked together on many issues and we need to do even more. We need to deal with the consequences of new technologies head on.
The dental community needs to recognize that the law requires us, at the FDA, to regulate the safety and efficacy of dental products.
Once again, my thanks for your willingness to serve on this very important Panel. I look forward to the results of your deliberations and our continued working relationship.
DR. TYLENDA: Thank you, Dr. Kessler.
Each Panel member has been provided with materials on the product problem reporting program. There are some extra copies at the registration desk. Copies may also be obtained by calling 1-800-638-6725. Let me repeat that number, 1-800-638-6725.
Dr. Lee Joseph, from the Center for Devices and Radiological Health, FDA, will now make a presentation to the Panel.
PRESENTATION BY DR. LEE JOSEPH
DR. JOSEPH: Good morning. I spent half of the night trying to think of a line to say when you follow Dr. Kessler on a program, and I could not come up with anything other than behind every great man there is a great woman!
But I would like to thank you for the opportunity to talk with you this morning and to discuss some of our recent activities in regard to dental amalgam restorative material.
It is your role as a conduit to your various representative organizations and to the FDA that provides us with a two-way communication channel, to which Dr. Kessler was referring, that assists us in making some informed decisions about the management of some of our dental products. So my presentation serves a couple of purposes:
One, to update for the Panel our activities relative to dental amalgams since there does exist some recent history of the Panel's consideration of the safety of dental amalgams, and, two, to call your attention to the possibility that if we need to, we may confer with the Panel regarding some of the dental amalgam recommendations that we may implement in the future.
First of all before I continue, I want to acknowledge that the report, which I understand you have a copy of, took a cast of thousands to produce and there are several people in this room who worked very diligently on this. I would like to mention them. One is Dr. Carolyn Tylenda; Dr. Greg Singleton. Behind me we have Dr. Robert Collins, who is Chief Dental Officer in the Public Health Service, and Dr. Bill Kahn, who is with the National Institute for Dental Research. If I have missed anyone, hold up your hand.
It is instructive to describe the process, and you have a handout on that, by which this project was developed so that the recommendations contained in the Public Health Service interagency report, developed by the Committee to Coordinate Environmental Health and Related Programs—we will call it CCEHRP—can be placed in perspective. CCEHRP conducts its business through a variety of committees, such as those that were used to develop this final report.
In 1990, a "60 Minutes" report and various media stories led CCEHRP, chaired by the Assistant Secretary for Health, to undertake a review of dental amalgam safety.
The basic question faced by CCEHRP was do we have a problem with amalgam? Two subcommittees were charged to examine various aspects of dental amalgam. The first was the subcommittee on risk assessment, which as asked to assess the risk, obviously, associated with dental amalgam. The second was an adhoc committee on the benefits of dental amalgam, which was chaired by Dr. Harold Loe of the National Institute for Dental Research. That committee was instructed to examine the benefits of dental amalgam and the benefits relative to alternative dental materials.
Also during 1991, an FDA Dental Products Advisory Panel, your predecessor, and a panel of experts convened at an NIH technology assessment conference and examined the risks posed by dental amalgam.
Both of these panels concluded that based on the scientific evidence available there was no demonstrated causal link between dental amalgam and health risk.
The risk assessment and benefit subcommittees took approximately a year to complete their charge, and concluded that the current research data do not demonstrate a health risk for the vast majority of individuals exposed to mercury vapor at levels commonly encountered from dental amalgam restorations.
Specifically, the risk assessment subcommittee acknowledged that amalgam restorations release small amounts of mercury vapor that can be absorbed by the body, but concluded that available data are not sufficient to indicate that health hazards can be identified in non-occupationally exposed persons— I am quoting—health hazards, however, cannot be dismissed.
The benefits subcommittee, noting that amalgam use has been on the decline with the decreasing incidence of dental caries and the availability of improved alternative materials, yet, noted that there are, and remain, substantial oral benefits that accrue to individuals and the population from the use of dental amalgam.
Each of these groups addressing the risks and the benefits questions recommended the need for additional research before the possibility of amalgam-caused and alternative-caused dental material risks can be dismissed.
Well, the reports of the risk assessment and the benefits subcommittees have been provided to the CCEHRP risk management subcommittee. That group was chaired by the Food and Drug Administration. Those two reports served as the basis for the recommendations and proposed strategy for the management of dental amalgam.
The Assistant Secretary for Health charged the risk management subcommittee to develop a plan that addressed the research needs, the educational needs for the public and the health professions, and to identify options for increased regulatory oversight of this product.
The strategy developed by the risk management subcommittee was the use of three FDA-chaired inter-agency groups focused on research, education and regulation. Using all the materials available to the groups, those contained in the reports, the biotechnology assessment conference, proceedings from the dental panel, and two additional pieces of information which became available during their deliberations and that was the proceedings from a symposium by the Society for Toxicology, as well as proceedings from the Swedish Medical Council—using all those data, they developed recommendations that were incorporated into the strategy document.
That draft document was reviewed by a total of 60-70 people, including about a dozen dental and toxicology experts within the United States and abroad. Generally speaking, the reviews were very positive. Additional comments were made and were incorporated into the final report.
Moving on to the recommendations—there is a big board down here you can follow—the research work group recommended that the National Institutes of Health, in conjunction with the Centers for Disease Control and Prevention and the Food and Drug Administration, develop a research agenda targeted towards amalgam and non-amalgam restorative dental materials based on priority endpoints that were identified by the risk assessment and benefits subcommittee reports.