Systematic literature review to evaluate pH cycling models as an alternative to the animal testing requirements for the over the counter (OTC) anticaries monograph drug products

Yujin Kim, Philadelphia College of Osteopathic Medicine
Keisha Findley
Francisco Martínez-Murillo
Steven Adah

Description

OTC drug products that follow FDA’s OTC monograph regulatory pathway are required to comply with all the conditions stipulated in the OTC drug monograph to be determined as Generally Recognized as Safe and Effective (GRASE) and allowed to enter the market. As required by law under the anticaries monograph (under 21 CFR§355.70) until the implementation of the CARES Act), all anticaries drug products must meet specific testing procedures conditions and requirements, while allowing for alternative testing procedures to be proposed for FDA’s assessment.

Currently, animal caries reduction testing (rat caries model) is the gold standard, which mimics actual conditions in the human oral cavity and conclusively verifying that the final formulations is fully effective and not compromised by different inactive ingredients. Because of increasing resistance to animal testing, manufactures of fluoride toothpastes are seeking alternatives to the rat caries model for testing fluoride dentifrice final formulations. The objective of our literature research described here is to evaluate whether the pH-cycling model is an appropriate alternative testing method to assess the effectiveness of the fluoride-based anticaries products.

Methods

A literature review search was undertaken in the MEDLINE electronic journal database using the intersection of the keywords “pH-cycling”, “demineralization”, “remineralization”, “in vitro”, and “fluoride dentifrice.” Full text articles published between 1988 and 2020 were selected for initial screening. All the articles were imported into EndNote® and data were extracted and tabulated according to parameters of the laboratory pH cycling models.

Results

The dose-response studies demonstrated a strong linear relationship between the mineralization capacity and fluoride dose, showing a dose-response correspondence between treatments regarding surface microhardness and mineral loss. Seven ingredients were identified as inert elements of the formulations. The respective authors concluded that these compounds do not disturb the fluoride’s anticaries effect of the formulations. The systematic literature review also identified several potential concerns relative to the validity of the pH cycling model as adequate alternative testing.

Conclusions

The literature review performed indicates that the pH cycling model can show a good dose-response correlation. However, the assessment is inconclusive in relation to correlating the efficacy of the in vitro model against the gold standard. Hence, additional studies showing direct comparison of the pH-cycling model and the rat caries model are needed.

 
May 3rd, 1:00 PM May 3rd, 4:00 PM

Systematic literature review to evaluate pH cycling models as an alternative to the animal testing requirements for the over the counter (OTC) anticaries monograph drug products

Suwanee, GA

OTC drug products that follow FDA’s OTC monograph regulatory pathway are required to comply with all the conditions stipulated in the OTC drug monograph to be determined as Generally Recognized as Safe and Effective (GRASE) and allowed to enter the market. As required by law under the anticaries monograph (under 21 CFR§355.70) until the implementation of the CARES Act), all anticaries drug products must meet specific testing procedures conditions and requirements, while allowing for alternative testing procedures to be proposed for FDA’s assessment.

Currently, animal caries reduction testing (rat caries model) is the gold standard, which mimics actual conditions in the human oral cavity and conclusively verifying that the final formulations is fully effective and not compromised by different inactive ingredients. Because of increasing resistance to animal testing, manufactures of fluoride toothpastes are seeking alternatives to the rat caries model for testing fluoride dentifrice final formulations. The objective of our literature research described here is to evaluate whether the pH-cycling model is an appropriate alternative testing method to assess the effectiveness of the fluoride-based anticaries products.

Methods

A literature review search was undertaken in the MEDLINE electronic journal database using the intersection of the keywords “pH-cycling”, “demineralization”, “remineralization”, “in vitro”, and “fluoride dentifrice.” Full text articles published between 1988 and 2020 were selected for initial screening. All the articles were imported into EndNote® and data were extracted and tabulated according to parameters of the laboratory pH cycling models.

Results

The dose-response studies demonstrated a strong linear relationship between the mineralization capacity and fluoride dose, showing a dose-response correspondence between treatments regarding surface microhardness and mineral loss. Seven ingredients were identified as inert elements of the formulations. The respective authors concluded that these compounds do not disturb the fluoride’s anticaries effect of the formulations. The systematic literature review also identified several potential concerns relative to the validity of the pH cycling model as adequate alternative testing.

Conclusions

The literature review performed indicates that the pH cycling model can show a good dose-response correlation. However, the assessment is inconclusive in relation to correlating the efficacy of the in vitro model against the gold standard. Hence, additional studies showing direct comparison of the pH-cycling model and the rat caries model are needed.