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WARNING LETTER

FDA Ref. No.: 25-HFD-45-04-02

Dear Timea Ciliberti:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between April 17 and May 3, 2024. Investigator Sheri L. Stephenson, representing FDA, reviewed the role of American Behavioral Research Institute, LLC (ABRI) as the sponsor of a clinical investigation (Protocol ABRI-002, “A Study to Evaluate the Effects of Relaxium in Subjects with Sleep Disorder”) of the investigational drug Relaxium® Sleep.

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 Stephenson presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 24, 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 May 24, 2024, written response, 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 312.2¹. ABRI failed to comply with these requirements. Specifically, ABRI initiated and conducted Protocol ABRI-002, a clinical investigation of the investigational drug Relaxium® Sleep (Relaxium) subject to section 505 of the FD&C Act [21 U.S.C. 355], without submitting and having in effect an IND.

We acknowledge that this finding was not included on the Form FDA 483 you received, and therefore your written response does not directly address this violation as discussed in this letter.

In ABRI’s May 24, 2024, written response to the Form FDA 483, your authorized representative stated, “As is obvious from the formulation, labeling, marketing, and advertising of Relaxium, the article is and is intended to be a dietary supplement, and not a drug.” ABRI’s authorized representative also stated that “whether Relaxium has any effect on subjects with sleep disorders is not evidence that the article is a drug as defined by 21 USC 321(g). Subjects with sleep disorders (as with any medical condition) may also take dietary supplements – and doing so does not cause the supplements to be drugs. Even determining the effect of a dietary supplement on persons with a particular condition does not amount to an intended use of that supplement to treat that condition.” Additionally, ABRI’s authorized representative stated that at no time was Relaxium intended to treat, cure, mitigate, or diagnose a disease, whether as a commercially available finished product or as a supplement, in study ABRI-002.

For the reasons described below, we conclude that the evidence collected during the inspection shows that Relaxium was intended for use as a drug, not as a dietary supplement, for the clinical investigation conducted under Protocol ABRI-002. Therefore, ABRI was required to submit an IND before conducting the clinical investigation.

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….” ABRI studied the efficacy of Relaxium to mitigate and treat insomnia. As shown by the protocol, the primary objective of Protocol ABRI-002 was to investigate the effect of Relaxium on sleep parameters in subjects with insomnia. To assess the efficacy of Relaxium in the study, Protocol ABRI-002 used various sleep parameters, which were also identified as the study efficacy endpoints. These efficacy assessments included wrist actigraphy, to estimate wake/sleep time and to assess sleep variability; the Leads Sleep Evaluation Questionnaire (LSEQ), which measures sleep and daytime effects; and a daily sleep diary that rated the quality of the subjects’ sleep and the quality of the subjects’ day by rating their daily energy. The sleep quality information from the diaries and the LSEQ data collected was used to evaluate the baseline disease severity and to evaluate the treatment’s effect. The wrist actigraphy data were compared from the lead-in period (averaged as a baseline) to Days 8 to 15, with variables measured, including total sleep time and awake time. Therefore, Protocol ABRI-002 collected study data to assess the effect of Relaxium on insomnia, as measured by variability and quality of sleep.

Whether an investigational article is a drug or a dietary supplement depends on the intent of the investigation. Based on the study design of Protocol ABRI-002, the investigational product, Relaxium, as used in the clinical investigation, was a drug as defined in section 201(g)(1) of the FD&C Act, because Relaxium was studied for use in the treatment of insomnia.

Thus, before initiating the clinical investigation of Relaxium conducted under Protocol ABRI-002, under 21 CFR 312.40, ABRI was required to submit an IND to FDA and to have an IND in effect. FDA’s records indicate that ABRI failed to submit an IND before conducting Protocol ABRI-002, in which 40 human subjects were enrolled and received investigational drug.

In their written response, ABRI also stated that because they are in the business of marketing and distributing dietary supplements, and not performing clinical studies, there is no risk of future violations because there is no chance of future studies. We acknowledge your statement. However, ABRI’s written response does not provide sufficient details of a corrective and preventive action plan for developing and implementing procedures to comply with IND regulations, should ABRI decide in the future to initiate another clinical investigation for which an IND is required. As a result, ABRI’s response is inadequate. Without this information, we are unable to determine whether ABRI will comply with IND regulations in the future.

As a sponsor, you are responsible to comply with IND requirements, including submitting and having in effect an IND before initiating a clinical investigation, and it is your responsibility to be aware of and to follow all applicable FDA regulations. Your failure to submit, and to have in effect, an IND before initiating Protocol ABRI-002 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 e-mail FDA at CDER-OSI-Communications@fda.hhs.gov.

Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr-Colón, 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

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1 Protocol ABRI-002 does not qualify for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR 312. To be IND-exempt under 21 CFR 312.2, the investigational product must, among other things, be lawfully marketed in the United States as a drug product. As stated in your May 24, 2024, written response, Relaxium is marketed as a dietary supplement, not as a drug product.