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WARNING LETTER

Dear Dr. Den Besten:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between September 16 and October 15, 2024. Investigator Dustin R. Abaonza, representing FDA, reviewed your conduct as the sponsor-investigator of a clinical investigation (Protocol 15-18297, “Pilot Study: Oral Microbiome and Dental Plaque Control with Livionex® Dental Gel in Children Undergoing Hematopoietic Stem Cell Transplantation (HSCT)”) of the investigational drug Livionex® Dental Gel.

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 5, 2024, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated November 5, 2024, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312), governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

You failed to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with an investigational new drug that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].

FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation of a drug that is subject to 21 CFR 312.2(a) [see 21 CFR 312.20 and 312.40(a)] in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. You failed to comply with these requirements. Specifically, you conducted Protocol 15-18297, a clinical investigation of the investigational drug Livionex® Dental Gel (Livionex) subject to section 505 of the FD&C Act [21 U.S.C. 355], without submitting and having in effect an IND.

Section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)] defines drug, in part, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease….” You studied the efficacy of Livionex to mitigate, cure, treat, or prevent gingivitis and dental caries. As shown by the protocol, the primary and secondary objectives of Protocol 15-18297 were to evaluate the efficacy of Livionex in plaque and gingivitis reduction in pediatric hematopoietic stem cell transplantation (HSCT) recipients. To assess the efficacy of Livionex, Protocol 15-18297 used various dental parameters, which were also identified as the study efficacy endpoints. These efficacy-related assessments included the change in dental plaque scores and gingival inflammation scores from Day 0 to 7, and Day 44 ±14 days, for each subject, as well as the comparison of plaque scores and gingival inflammation between the test and control groups. In addition, optical coherence tomography was used to image and quantify plaque presence. Plaque staining assessments were also performed, and standardized photographs were taken for plaque distribution mapping. Therefore, Protocol 15-18297 collected study data to assess the effect of Livionex on improving plaque control and gingivitis prevention in pediatric subjects undergoing HSCT.

Based on the study design of Protocol 15-18297, the investigational product, Livionex® Dental Gel, as used in the clinical investigation was a drug as defined in section 201(g)(1) of the FD&C Act, because Livionex was studied for use in the treatment of gingivitis and dental caries. Thus, before initiating the clinical investigation of Livionex under Protocol 15-18297, under 21 CFR 312.40, you were required to submit an IND to FDA and to have an IND in effect. FDA’s records indicate that you failed to submit an IND before conducting Protocol 15-18297, in which 43 subjects were enrolled and received study drug between September 2016 and January 2020, under your oversight as the sponsor-investigator.

We acknowledge that this finding was not included on the Form FDA 483 you received. However, this finding was discussed with you during the inspection, and your written response does in part address this finding.

In your November 5, 2024, written response to the Form FDA 483, you explained that in 2016 the initial principal investigator had consulted with the University of California, San Francisco’s Office of Ethics and Compliance regarding the IND requirements related to the study and had represented that Livionex was an over-the-counter (OTC) toothpaste. In response, the Office of Ethics and Compliance instructed the previous principal investigator to include rationale in the IRB application, confirming that the study meets each of the IND exemption criteria. We note that the rationale for exemption included in the IRB application for this study incorrectly stated that Livionex is an OTC toothpaste, which is lawfully marketed in the United States and does not require FDA approval for its use.

You stated in your written response that it was your understanding at the time that all products used in this study were lawfully marketed, and that the study met all IND exemption criteria. You also stated there was no intention that the study outcomes would be used to support any change or any marketing claims by any toothpaste manufacturers, and as such, this study was not conducted as a clinical trial seeking regulatory approval from the FDA.

As noted above, FDA regulations require a sponsor to submit an IND before conducting a clinical investigation of a drug in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2(b). Under 21 CFR 312.2(b)(1), the clinical investigation of a lawfully marketed drug product in the United States is exempt from the IND regulations for a clinical investigation if all the exemption criteria in 21 CFR 312.2(b)(1) are met.

The clinical investigation of Liovionex Dental Gel conducted under Protocol 15-18297 does not qualify for an IND exemption under 312.2(b)(1) because Livionex is not lawfully marketed as a drug product in the United States. Specifically, Livionex is not the subject of a new drug or abbreviated new drug application approved under section 505 of the FD&C Act [21 U.S.C. 355]. Additionally, Livionex does not contain an active ingredient that is a part of any OTC monograph.

In your written response, you also stated that this FDA inspection had been a learning process, and you are much better informed as to the correct procedures, protocols, and monitoring of any future IND regulated clinical trials. You noted that you and your team have completed training on FDA regulatory requirements and reached out the Office of Ethics and Compliance for additional targeted education. You further stated that you will review internal procedures and resources regarding investigational drug and device determinations to ensure compliance with regulatory standards.

While we acknowledge the corrective and preventive actions you have taken or plan to take, your response is inadequate because you did not include sufficient information about how you will determine whether IND regulations apply to future clinical investigations of products regulated by FDA, as required by 21 CFR 312.2(a). Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.

As a sponsor-investigator, you have ultimate oversight of the clinical investigation and are responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, including submitting and having in effect an IND before initiating a clinical investigation. Your failure to submit, and to have in effect, an IND before initiating Protocol 15-18297 with an investigational drug raises significant concerns about the safety and welfare of enrolled subjects and raises concerns about the validity and integrity of the data collected during the conduct of this clinical investigation.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Should you have any questions or concerns regarding this letter or the inspection, please email FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr, MPH
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Building 51, Room 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993

Sincerely yours,
/S/

David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration