is scheduled for November 12, 1975, and have invited both the opponents and proponents of these drugs to present their views before this committee. A memorandum setting out the questions on which we are seeking the advice of the committee is submitted here for the record. You may be assured that we are anxious to resolve this matter as rapidly as possible. However, our first responsibility is to assure that the ultimate decision is legally and scientifically correct and in the best interests of the public health. We, therefore, believe it is appropriate to take the time necessary to accomplish this. We will be happy to keep you abreast of our actions as they occur. My colleagues and I will be pleased to answer any questions you may have. Mr. FOUNTAIN. I am placing into the record pertinent documents from the files of the Food and Drug Administration. [The documents follow:] MEMORANDUM OF CONFERENCE (September 21, 1971, 9 a.m. to 9:45 a.m.) Between: Dr. Angelo Sargenti, D.M.D., Locarno, Switzerland and William J. Subject: N-2 root canal sealer. Dr. Sargenti thanked us for the opportunity to meet. He mentioned that he has just completed a tour during which he had lectured on his technique on the use of N-2. (Some of the places mentioned were Chicago, Philadelphia, Delaware, Boston, California.) Dr. Sargenti then spent approximately 5 minutes shuffling papers (and reprints) on to Dr. Gyarfas' desk, on surrounding chairs and on the floor. He then proceeded to read portions of letters from dental organizations and from individual dentists across the country. He said that he realized that this could be considered as mere testimony but added that this country (U.S.A.) is a "dentally underdeveloped nation" in the treatment of root canal problems when compared to Switzerland. He proceeded to give a lengthy dissertation on the need (as he saw it) to correct the problems (as he saw them) and proceeded to quote figures relating to the large number of edentulous people in the U.S.A. as contrasted to the few in Switzerland where his product is widely used. He proceeded to give a long-winded (and somewhat irrational) criticism of the present state of Root Canal Therapy in the U.S. Some of the statements made by Dr. Sargenti were: His material is for the obliteration of the root canal and is a hard material. (He passed around a sample of a hard pink substance in a plastic sac.) That he has a solution for all our problems in root canal work. That approximately 25 different formulations had been used and that they had all produced the same good results. He said that these were basically zinc oxide and that some date back to about 6 years ago. FDA is influenced by falsified information. That he has other connections. He then asked if there were any questions. Dr. Gyarfas gave him copies of the pertinent sections of the Food, Drug and Cosmetic Act and the Federal Regulations. Dr. Sargenti showed some knowledge of the Food, Drug and Cosmetic Act and stated that he knows most of it from memory. He expressed the idea that we are denying the dentists in this country the use of a "new Product" (by these regulations). Since Dr. Sargenti said that the N-2 stayed within the root canal, Dr. Wade asked what purpose the formaldehyde served. Dr. Sargenti's answer was evasive and he could not be pinned down. Dr. Gyarfas explained that we are not denying anything to dentists or to dentistry-that our purpose is to protect the public-that no clinical evidence was presented to show the safety and efficacy of the drug (s) and that this is a New Drug which requires such evidence. Dr. Carr explained (among other things) that the Council of the American Dental Association (as well as many foreign countries) condemns the use of formaldehyde in such preparations. Dr. Sargenti said that we have been misinformed and that he wanted to inform us on this important problem of Root Canal Therapy (no explanation of the formaldehyde was given by Dr. Sargenti). Dr. Gyarfas again expressed the need for well conducted trials in order to demonstrate the safety and efficacy with controlled scientific data-and that he (Dr. Sargenti) would have to abide by the new drug regulations and procedures. Dr. Sargenti got very emotional at this time and it became difficult to follow his line of thought. It appeared that he was threatening some type of legal action. Dr. Gyarfas attempted to restore order and to calm Dr. Sargenti down and adjourned the meeting when Dr. Sargenti became even difficult to understand. Dr. Gyarfas then again reminded Dr. Sargenti that no evidence had been presented to support the product and that the drug cannot be imported into the U.S.A. or be in interstate commerce without an effective Notice. Los Angeles District (HFR-9240), January 14, 1975. JOSEPH M. RENNA, D.D.S. Prescription Drug Compliance Branch (HFD-313), Division of Drug Labeling As we discussed by phone (12/23/74), this memorandum will serve as an update on the status of known N2 type products currently being marketed. The use of root canal filling cements containing zinc oxide, eugenol, phenylmercuric borate, paraformaldehyde, lead tetroxide, prednisolone, and hydrocortisone and the technique used for their administration has become a very controversial issue among the dentists in this country. These type preparations are similar in formula to an original imported product "N2," originally produced by Dr. Angelo Sargenti, a European dentist. The AGSA Distributing Company in New York submitted an NDA for "N2" in June, 1962. Although numerous reviews were made by the FDA of data submitted to this NDA for several years, the drug was never found to be proven safe and effective for the recommended use. The main reason for non-approval of the NDA was that the company never submitted adequate and well-controlled clinical studies to demonstrate that the drug is safe and effective. Most of their data consisted of testimonials, an unacceptable substitute for adequate and well controlled studies. Consequently, the application was withdrawn by the company in June 1967. Since that time, "N2" has had a history of changing composition and/or name depending on the supplying firm and the time the product was purchased. We are currently aware of three firms involved in the production and/or distribution of N2 type products under the name RC-2B; they are Steri Kem (Whittier, Calif.), Shar Don Labs (Thousand Oaks, Calif.) and Mormort, Inc. (Valley Stream, N.Y.). To our knowledge, the product is promoted only by the American Endodontic Society which is an organization formed specifically for this purpose. Their method of promotion consists of conducting seminars at which pre-printed "prescription" blanks are provided the attending dentists. These blanks have the "N2" type formulation printed on them and the dentist simply fills in his name, the amount needed, and mails the pre-addressed card to one of several manufacturers and/or distributors of the product whose name appears on the card. We have no information regarding who is responsible for the printing of these cards. It is our position that distribution of these products in this manner does not constitute dispensing of a drug via a prescription in the traditional sense. In our view, a prescription is a written expression initiated by a licensed practitioner to provide his patient with a specific quantity of a drug to be used under his supervision. Thus, exemptions for pharmacy operations do not contemplate a manufacturing order for goods to be delivered to a licensed practitioner for ultimate dispensing by him. Our dental experts feel the use of paraformaldehyde, lead, hydrocortisone, and/or prednisolone (alone or in combination) in dental products of this type has not been demonstrated to be safe and effective, and therefore these type preparations are still considered new drugs as defined in 201(p) of the Act. On January 7, 1975, a conference was held between our dental experts and two endodontists at their request. They stated that they have copies of studies which demonstrate that N2 has had adverse effects on animals. This material will be reviewed by us and based on the conclusions we will be in a better position to determine what course of action we will pursue in this case. We will inform you of the results of the medical review upon its completion and what course of action to be taken, if any. RICHARD CHASTONAY. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, FOOD AND DRUG ADMINISTRATION, MEMORANDUM To: Deputy Director, Bureau of Drugs (HFD-2), through: Associate Director for From: Acting Director, Division of Drug Labeling Compliance (HFD-310). PROBLEM To determine the most efficient means of regulating certain root canal preparations which are considered new drugs. BACKGROUND The use of root canal filling preparations containing zinc oxide, eugenol, phenylmercuric borate, paraformaldehyde, lead tetroxide, prednisolone, and hydrocortisone and the technique used for their administration has become a very controversial issue among the dentists in this country. These type preparations are similar in formula to an imported product called "N2", originated by Dr. Angelo Sargenti, a European dentist. The AGSA Distributing Company in New York submitted an NDA for "N2" in June, 1962. Although numerous reviews were made by the FDA of data submitted to this NDA for several years, the drug was never found to be proven safe and effective for the recommended use. The main reason for non-approval of the NDA was that the company never submitted adequate and well-controlled clinical studies to demonstrate that the drug is safe and effective. Most of their data consisted of testimonials, an unacceptable substitute for adequate and well-controlled studies. Consequently, the application was withdrawn by the company in June, 1967. Since that time, "N2" has had a history of changing composition and/or name depending on the supplying firm and the time the product was purchased. It has changed formulas over 25 times and has appeared under the names "N2", "R-C", "RC-2A”, “RC-2B", "RET-B", and "EOT" with the ingredients essentially remaining the same but their percentages of the total preparation changing. The Bureau of Drugs dental experts believe the use of paraformaldehyde, lead, hydrocortisone, and/or prednisolone (alone or in combination) in dental products of this type has not been demonstrated to be safe and effective, and therefore these type preparation are considered new drugs as defined in 201 (p) of the Act. Both the proponents and opponents of this drug and its use have been advised repeatedly by this office and HFD-160 that these preparations are "new drugs" and may not be marketed in the absence of an NDA (see Tab A-C). To our knowledge, the product is promoted only by the American Endodontic Society which is an organization formed specifically for this purpose. Their method of promotion consists of conducting seminars at which pre-printed "prescription" blanks are provided the attending dentists. These blanks have the "N-2" type formulation printed on them and the dentist simply fills in his name, the amount needed, and mails the pre-addressed card to one of several manufacturers and/or distributors of the product whose name appears on the card. The manufacturer then in turn sends the drug to the requesting dentist. We understand the amount of material involved is usually 10 gms. which is enough to treat 30-40 teeth. It is our position that distribution of these products in this manner does not constitute dispensing of a drug via a prescription in the traditional sense. In our view, a prescription is a written expression initiated by a licensed practitioner to provide a specific patient with a specific quantity of a drug to be used under his supervision. Thus, exemptions for pharmacy operations do not contemplate a manufacturing order for goods to be delivered to a licensed practitioner for ultimate dispensing by him. We are aware of several firms which are currently marketing and/or have marketed these preparations in the past. (See list on Tab D). One of these firms, Steri Kem has expressed a desire to file for an NDA but as of yet they have not done so. We have recommendations for regulatory action from New York and Los Angeles Districts which involve three of these firms. We have placed these recommendations in temporary abeyance pending consideration of a class action approach on these preparations. On January 7, 1975, a conference was held between representatives from HFD310, HFD-160 and two endodontists at their request. (See Memo of Conference Tab E). They stated that they had copies of studies which demonstrate that N2 has had adverse effects on animals. We have received this submission and it contained statements from various hospitals, state health departments, and 24 U.S. dental schools that they do not endorse N-2 nor do they teach the method. It also contained a survey of foreign countries which showed that 23 countries placed this drug in an unacceptable category and 10 countries said it was not as good as conventional endodontics, but had some merit. In addition the submission contained several papers and abstracts which demonstrated the various cytotoxic, inflammatory, ankylotic and necrotic, effects these pastes could have if the material is extruded into the periapical region. Among these publications is the ADA Council on Dental Therapeutics report on May, 1962 on the hazards of formaldehyde preparations for single treatment procedures in endodontics. The Council concluded that formaldehyde pastes are highly irritating and may present a real hazard if forced through the apex of the root. The ADA Council on Dental Research has just issued a statement that there still is insufficient evidence to judge these abbreviated endontic methods and recommended carefully designed clinical studies to be initiated as soon as possible to provide this evidence (See Tab F). In view of the above and in order to effectively achieve compliance with the new drug regulations with regard to these root canal preparations, we are proposing the following options for your consideration. Option 1 COURSE OF ACTION Based on the possible health hazard involved should these products come into contact with periapical tissue, initiate regulatory class action on these drugs now, commencing with the issuance of a regulatory letter to the responsible firms officially informing them that their product is a new drug, followed by whatever appropriate action is necessary to bring about discontinuance of marketing and their subsequent removal from the market. This option would be based on a possible health hazard and would not involve a Federal Register announcement giving FDA's position on this class of drugs. Option 2 Proceed as we did with the topical fluoride preparations and present the entire class of root canal preparations to the Dental Drug Product Advisory Committee for their recommendation and publish a Federal Register announcement stating FDA's position regarding the use of these drugs. ARGUMENTS Pro. The alleged adverse reaction complaints we are receiving from the dental profession and the ADA position provide an adequate basis to proceed with regulatory action based on section 505 of the Act since the products are clearly not generally recognized as safe and effective. A Federal Register statement would not be required prior to introducing regulatory action and consequently this action would not be delayed. Con.-Initiation of regulatory action without prior notification in the Federal Register would be contrary to the present preferred procedure. Protracted litigation could result as summary judgment would not necessarily be possible in the absence of a regulation, i.e. the contested question would be the safety and efficacy of the drug per se rather than whether the article is in violation of a substantive regulation. RECOMMENDATION Even though the N2 preparations do not present an imminent health hazard, there does appear to be a significant safety question involved. Therefore, we are in favor of foregoing the Federal Register announcement and proceeding with option 1. Should the alternative option be chosen, however, we would recommend that the review and subsequent Federal Register announcement be expeditiously carried out. RUDOLF APODACA. DECISION Option 1 Option 2 Disapproved: Carl Leventhal. Date: August 6, 1975. Approved: Carl Leventhal. Disapproved: Date: August 6, 1975. Prepared by: HFD-313, Chastonay, August 5, 1975, X34206. (1) As agreed above, under Con. RATIONALE (2) The absence of documented rather than hypothetical hazard. (3) We will be in a far better position after expert (Dental Committee) judgment that products are not GRAS and GRAE, which can then form basis for FR statement. (4) I think emergent FR statement can form basis for prompt regulatory action-i.e. issuance immediately followed by regulatory letters to firms. CML. [Additional documents from FDA files and subcommittee correspondence follow:] DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, MEMORANDUM To: Deputy Director, Bureau of Drugs (HFD-2), through: Acting Associate From: Executive Secretary of the Dental Drug Products Advisory Committee. Reference is made to the memo dated August 5, 1975, from HFD-310 and your approval of Option 2 dated August 6, 1975. We request reconsideration of Option I for the following reasons: 1. Hazards are documented in published article in the JADA May 1962 (See Flag A). 2. The following experts feel adequate well-controlled clinical studies are needed : (a) The ADA Council on Dental Research (See Flag B). (b) Departments of Endodontics in 24 dental schools in the U.S. (See Flag C). (c) U.S. Government Agencies (See Flag D). (d) Foreign Countries that place the drug in an "unacceptable" category (See Flag E). |