FDA AND ADA GUIDELINES FOR TOPICAL FLUORIDE PRODUCTS

A Brief History of Clinical Trials with Topical Fluoride Products

by Robert T. Zahradnik, PhD

In response to the success demonstrated by the early clinical studies, topical application of aqueous sodium fluoride began to be used routinely by the dental profession at large beginning in the late 1940s. As supporting clinical data became available in the 1950s, dentist also started applying freshly-prepared 8-10% solutions of stannous fluoride. By the 1960s, continued fluoride research resulted in the development of a new topical preparation, acidulated phosphate fluoride (APF). Soon after this discovery, dental manufacturers began supplying the profession with solutions containing 1.23% fluoride ion in a 0.1 molar phosphoric acid buffer with a pH between 3.0 and 4.0. The traditional "paint-on" technique, where only one or two quadrants at a time are isolated, dried and treated was found to be time-consuming. For this reason, other vehicles for APF were sought that could be more easily applied in a program of professional topical fluoride application. Eventually, APF became available commercially as a gel. Gels had the advantage of being used in disposable trays so that the entire mouth could be treated in a single application. Clinical studies in the late1960s provided support for the anticaries effectiveness of these new fluoride gels.

In a parallel fashion to the evolution of in-office fluoride preparations, procedures for the self application of fluoride were developed in the early 1960s. The investigation of self-application techniques was prompted b their need in public health programs. It was recognized that not all children had access to fluoridated water supplies, and that office treatments can be costly and time-consuming for certain other patient groups. Significant caries reduction with the self application of topical sodium fluoride gels, delivered by either mouth trays or tooth brushing, was adequately demonstrated in a number of school-based programs. Also, the anti-caries benefit of sodium fluoride mouth rinses was extensively documented. In total, a wide variety of fluoride gels and rinsing solutions, with different treatment regiments, were evaluated. The most efficacious formulations included a high frequency 1-2% sodium fluoride gel, delivered by mouth trays or by tooth brushing, and a daily (0.05%) and a weekly (0.2%) neutral sodium fluoride mouth rinse. In the public health studies, the fluoride formulations were generally prepared by the clinical investigators. The anti-caries success of such preparations, however, led to the commercial development of comparable products for regular home use by individual patients. It should be noted that, at this point, the major emphasis of public health officials, and the dental profession, was on the control of dental caries in children and not on plaque or periodontal disease control.

FDA APPROVES CERTAIN TOPICAL FLUORIDES
BY DRUG MONOGRAPH

By the early 1970s, a substantial amount of research had been performed on the caries inhibiting effect of direct application of specific fluoride preparations to the surfaces of teeth. Several manufactures, relying on these clinical database, commercialized topical fluoride preparations for both in-office and home use. However, none of these formulations were ever the subject of an approved new drug application to the Food and Drug Administration (FDA). In order to rectify this situation, the FDA, in the mid-1970s conducted a review of available safety and efficacy data from sodium and stannous fluoride preparations intended for professional application or on a prescription basis. Seven specific formulations were judged to have sufficient clinical evidence of anti-caries efficacy and thus were approved for the U.S. dental market by a mechanism known as an "Old Drug Monograph". Similarly the FDA, in the early 1980s, approved an additional five formulations, including three types of dentifrice, and grouped these new fluoride topicals with two of the previously approved formulations into an OTC (over-the-counter) category. Companies may manufacture and market any of the listed preparations provided that they (1) register as a drug manufacturer, (2) submit labeling and a list of ingredients to the FDA for all fluoride products (drug product listing), and (3) insure that each manufactured lot of products complies with all requirements and conditions of the appropriate FDA monograph.

A compilation of fluoride drug monographs can be found in the official publication of "The United States Pharmacopoeia" (USP), which is updated periodically. A monograph includes a description of the drug formulation, the standards that determine the drug's strength, quality and purity, appropriate test methods, and the requirements for packaging and labeling. In order to be in full compliance with the monographs, any fluoride-containing product must meet all specifications and labeling requirements, including the correct percentage of active fluoride, pH and viscosity. If it does not, then this formulation is considered misbranded by the FDA. Any company wishing to market a fluoride drug product, with a strength and dosage form that falls outside a monograph, must obtain an FDA approval as a new drug prior to U.S. distribution.

All products manufactured and marketed under the same Old Drug Monograph share a common base of clinical efficacy and safety data. At the time of the review, the FDA did not have sufficient clinical evidence to include additional claims (e.g., detin sensitivity or anti-gingivitis) under the list of approved indications for use. In the 20 years since the first fluoride monographs were released, however, additional clinical information has been published which provides a better understanding of the mechanisms of topical fluoride action with tooth surfaces and bacterial plaque. The dental professional, therefore, should carefully with this new evidence, and the recommendations of clinical experts, when designing an appropriate fluoride program for their patients.

ADA ACCEPTANCE PROGRAM AND SEAL

The Council on Dental Therapeutics of the American Dental Association has responsibility for an Acceptance Program covering fluoride products. Under this program, the Council first recognized fluoride dentifrices in the 1960s as effective agents in reducing the incidence of dental decay. In the early 1970s, several other types of topical fluoride products were approved and permitted to carry the ADA Seal on their labels.

In order to be considered for the Acceptance Program, manufacturers must submit several lost of product, final labeling, advertising/promotional matter and sufficient manufacturing information so that the Council may form and educated opinion regarding product acceptance. At present, such formulations as 1.23% APF gel, 0.2% and 0.05% sodium fluoride rinses, and 0.4% stannous fluoride gel are eligible for review by the Council. The ADA has not recognized several commercial fluoride preparations because the Council feels that, at this time, there is not sufficient clinical documentation to support either (1) a new dosage (e.g., 1.23% APF foam), (2) a change in the instructions for use, such as a one minute application time for APF gels versus te recommended four minutes, or (3) and additional claim other than that for protection against dental caries. Laboratory data can be useful but, because of the complexity of the oral environment, the ADA recognizes that in vitro results cannot serve as a substitute for well-controlled clinical trials.

Both the FDA and the ADA have reviewed the safety database for fluoride products and have concluded that topically-applied fluoride, in an approved dosage form and application frequency, is safe. These agents are intended to be applied topically in the oral cavity and are only inadvertently ingested. Nevertheless, the safety review included chronic and acute toxic effects resulting from excessive fluoride ingestion. Accumulated evidence from numerous studies shows that the prolonged use of fluoride at recommended levels does not produce harmful physiological effects resulting from excessive fluoride ingestion. Accumulated evidence from numerous studies shows that the prolonged use of fluoride at recommended levels does not produce harmful physiological effects in humans. Chronic ingestion of home care products can lead to dental fluorosis, but this effect is primarily cosmetic and of little consequence after teeth are formed. Epidemiological and clinical findings indicate that the formative state of teeth of children six years of age and older (excepting third molars) are too advanced to be affected by excessive fluoride ingestion. However, acute toxicity form excessive fluoride ingestion can occur if a small child were to swallow the entire contents of a high strength fluoride product. The lethal dose, when taken orally, is 35070 mg of fluoride per kg body weight or about 1to 2 grams of sodium fluoride for a small (15 kg) child. Amounts less than this may cause nausea and vomiting. Dentist and hygienists need to caution their patients that, as with all medications, fluoride-containing products should be kept out of the reach of small children.

WHAT TO LOOK FOR IN A FLUORIDE PRODUCT LABEL

The dentist or hygienist should be able to look at the front panel of a product label and easily identify the product type. Company trade names can be confusing among office staff, so the generic name of the topical formulation should be dominant on the label; (e.g., 1.23% APF Topical Gel). Check to see if the fluoride products are safety-sealed and that a lot number and expiration date are clearly displayed on the primary package. These numbers can provide a tracking mechanism if a problem develops with the product. Companies are required to have data on file to substantiate a product's shelf life. As a rule, offices should not accept a product with less than one year remaining on its stamped expiration date.

The FDA requests that a National Drug Code (NDC) number be placed on all drug labels, preferably located in the top third of the primary label. This number is made up of a 10-character code preceded by either "NDC" or "N". The first four or five numeric characters identify the manufacturer and the remaining digits identify the drug formulation and the package size and type. With certain product categories in a fluoride line, and ADA Seal may appear on the front label; the Seal serves to demonstrate a company's support for the ADA's Acceptance Program.

Indications for home use should be limited to the prevention of dental caries and, in some cases, dentin sensitivity. Although clinical evidence is growing to support the use of fluorides in supra-gingival and sub-gingival plaque control, neither the FDA nor the ADA currently recognizes specific periodontal claims for any of the approved topical fluoride formulations. The directions for use must be clear, direct and provide the user with sufficient information to permit safe and effective use of the product. Clear instructions are especially important for home care products.

As with all drugs, there are certain cautionary statements which should be communicated to the user by appearing prominently on the label. Examples of such statements include "Do Not Swallow", "Federal Law Prohibits Dispensing Without Prescription", "Not A Dentifrice", and "This Product May Produce Surface Staining Of Teeth". These statements are generated by the FDA, and the absence of specific statements on a given product label should not be taken as an indication that this brand is somehow different; more likely, it constitutes a regulatory oversight on the part of the manufacturer.

ARE ALL BRANDS IN A SPECIFIC
FLUORIDE CATEGORY EQUAL?

It's difficult for dental professionals to assess the effectiveness of using or prescribing a particular fluoride product for his/her patients. The therapeutic benefit of the treatment is not immediately self-evident in the same sense, for example, as the easily recognizable effectiveness of aspirin in relieving pain. It is for this reason that the FDA reviewed and approved only the most efficacious topical fluoride preparations. Unfortunately, manufacturers do not always meet the full standards and requirements of the specific fluoride monographs.

Taste is an important factor in patient acceptance and compliance with fluoride therapy. There are pharmaceutical formulation techniques that can be used to significantly mask the acid bite of APF products or the astringency of stannous fluoride preparations. The basic composition and the potency of the drug, however, should never be compromised to improve taste. In this regard, the occasional practice of reducing acid bite by arbitrarily formulating APF topicals with a more neutral pH produces a product with questionable efficacy, especially if used to treat patients at high risk for dental disease.

The question of product stability is also an important consideration when choosing among available topical fluoride product lines. A drug product must meet the minimum requirements for potency throughout is assigned shelf life. Inactive ingredients, such as flavors or thickening agents, and potentially react with a drug agent over time to reduce its activity; improper or inappropriate packaging can also contribute to less active formulations. On a more practical level, flavor impact can decrease significantly with time, especially for liquid formulations in plastic containers; this factor alone may effectively limit the practical lifetime of a fluoride product. The FDA requires that manufacturers generate sufficient data to support any assigned expiration date for their drug products. Shelf life is generally determined through a validation program which combines normal (long-term) and accelerated (high temperature) aging studies.

In-office and home care fluoride products have a long history of safety and effectiveness, and represent an important adjunct to better patient care. Not all commercial brands of fluoride, however, met the same manufacturing standards. When choosing a brand of fluoride, therefore, price should not be the sole consideration. In fact, the difference in cost per single fluoride application is typically small among major brands. Other points must be considered in the selection process, and attention should be paid to the total support package offered by a manufacturer. One important factor includes the quality and completeness of the product line. Also, there should be and expressed concern for the safety and effectiveness of each formulation; this can be demonstrated by a visible commitment to ADA and FDA manufacturing and labeling requirements. Finally, a company's technical and professional staff should be easily accessible to provide up-to-date information and support, whether for specific products or for your total fluoride therapy program.