Navigating the complex regulatory landscape of some fluoride caries therapies in the United States. The burden to clinicians.

FV entered the US market in 1995 when it received FDA clearance as a class II medical device; that is, a cavity liner or coating to reduce dentin hypersensitivity and protect the pulp in adults. The predicate devices were typically another cavity liner or hypersensitivity agent. Therefore, FVs are not approved in the United States to prevent or control caries. The FDA determined FVs to be of middle risk and thus are subject to a lower level of regulation. The proof required for the sealing effect is based on laboratory bench testing only. Almost without exception, no controlled trials were required before marketing, and today there are dozens of such FVs sold in the United States. Some FVs contain other ingredients, such as casein phosphopeptide–amorphous calcium phosphate and tricalcium phosphate.

Evidence supporting US professional FV recommendations for caries control consists largely of studies conducted on FVs no longer available or sold in the United States. Formulas for FVs are substantially altered from those studied and marketed earlier, particularly related to inactive ingredients, such as the varnish carriers and flavoring agent. The FV market price is low, and if the FDA required greater evidence, few companies could recoup the expense of obtaining approval in a reasonable period. Insurers do not regulate devices or drugs, so insurance coverage is no guarantee of safety or efficacy. The American Dental Association (ADA) Seal of Acceptance does not mean a product approved as a device has met the requirements for a drug. Yet the ADA Seal of Acceptance ensures to consumers that the ADA has independently verified through testing or review that products have met the manufacturers’ claims for safety and efficacy.

Researchers in at least 4 laboratory studies have raised questions about the efficacy of some FVs sold in various countries, including the United States, but it is unknown if or how these laboratory concerns directly translate to clinical concerns.^6-9 Although FVs are recognized and recommended by most professional organizations to manage caries and the results of systematic reviews support their safety and effectiveness,^10,11 in some limited clinical studies, conducted almost exclusively outside the United States, researchers have raised further questions about whether some FVs prevent caries.¹² Neither the FDA nor professional or manufacturers’ organizations police this market. This places an onerous burden on the practicing clinician to understand which products may be most effective and how to best use them.

There are 8 SDF products marketed legally as medical devices in the United States, and 1 nanosilver product that gained FDA clearance in February 2025. SDF is a liquid containing silver, ammonia, and fluoride ions. There are also silver fluoride solutions in the United States that contain silver, fluoride, water, and nitric acid. Silver ions interact with the caries-affected dental tissues, leading to dark staining and the formation of silver phosphate (which is further photoreduced to metallic silver) and black silver sulfide. For clearance, the predicate devices were either existing cleared varnishes or an already cleared SDF product. The first SDF product to enter the US market in 2014 was rigorously evaluated by the FDA and cleared as a class II medical device. Toxicologic studies in animals and human controlled trials were required to show safety and efficacy in adults to treat dentin hypersensitivity, for which it was labeled. Some of these data have been published.^13,14 On the basis of trials conducted outside of the United States, SDF has been recommended by most professional organizations as an effective agent to help manage caries.¹⁵ In the United States, SDF use by dentists to prevent or arrest caries is off label and the responsibility of the dentist; the ADA recommended it be applied biannually to arrest cavitated lesions.¹⁵

In 2025, a US manufacturer of an SDF product is seeking FDA approval for their agent to be classified and approved as a drug labeled for caries lesion arrest in young children with severe early childhood caries. A key difference from earlier regulatory pathways is the premise that the mechanism of action for caries arrest is biological, not simply the mechanical sealing of tubules.¹⁶ This development has been accelerated because the FDA granted Breakthrough Therapy designation to this product in 2016 on the basis of its public health importance and efficacy and safety reported outside the United States. Granting Breakthrough Therapy designation to SDF does not mean that it can now be lawfully labeled to treat caries; rather, it is a process designed to expedite the development and review of the drug. This designation also allowed a major definitive randomized clinical trial of efficacy and safety to be conducted in the United States through a cooperative agreement between the National Institute of Dental and Craniofacial Research, National Institutes of Health, and the University of Michigan, completely independent of the manufacturer. The interim results were published in 2024.¹⁷ As with the previous example of FVs, evidence is either sparse or not available for some SDF products available on the US market, placing the burden of choosing an effective product for off label caries-control use on the clinician.

The dark staining of caries dentin by SDF is often considered undesirable by clinicians and patients. Thus, there has been interest in nanosilver fluoride agents containing silver nanoparticles, chitosan, and fluoride that produce less staining because they do not undergo oxidation.¹⁸ Nanoparticles are particles with at least 1 dimension in the size range of 1 through 100 nm. Their properties, such as reactivity and optical behavior, can differ substantially from those of the same material in bulk form. These products have mostly been developed outside the US regulatory environment, with some encouraging clinical results suggesting efficacy in caries arrest with decreased staining compared with SDF.¹⁹

The FDA has rigorous standards regarding nanosilver products when used as drugs, and the level of proof of safety required is high.²⁰ The reason for this level of rigor is that the safety of these various very small particles is unknown, yet they are known to enter and accumulate in individual cells and organs. Exposure to silver nanoparticles can lead to health complications.^21,22 Researchers comparing the toxicity of silver nanoparticles and silver salts, either in vivo or in vitro, yielded contradicting results, as some showed similar toxicity for silver nanoparticles and salts,²¹ others showed higher toxicity for silver nanoparticles,²³ and others showed higher toxicity for silver ions.²⁴ These differences likely depended on the coating or surface properties of the nanomaterials, the test system (in vitro), and the exposure (eg, oral vs mucosal). A phased approach, as proposed by the European Union’s Scientific Committee on Emerging and Newly Identified Health Risks that includes an evaluation of the potential of the device to release nanoparticles, assessment of the distribution of the released particles and their persistence, and hazard assessment by means of selecting relevant toxicity tests would be required to evaluate the risk of a medical device containing nanomaterials.²⁵ Besides the effects of potentially released particles, possible local effects at the site of application should be considered.

One nanosilver fluoride product has been cleared by the FDA as a medical device using existing approved SDF products as predicate devices. As discussed above, there is no doubt that manufacturers prefer to have such products cleared as devices rather than drugs because the burden of proof and cost for the device regulatory pathway is lower than that for a drug. Thus, clinicians should look for evidence of efficacy and safety, particularly when used in children.

John Timothy Wright serves as the Editor in Chief for JADA. Dr. Wright was not involved in decisions about the article he wrote, and peer review was handled independently.