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WARNING LETTER

Dear Dr. Goodenowe:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between December 17, 2024, and January 10, 2025. The investigator representing FDA reviewed the role of Prodrome Sciences USA, LLC (Prodrome Sciences) as the sponsor of a clinical investigation (Protocol Pro‐040‐Plasm‐01, “ProdromeNeuro: An Open-Label Study of Omega 3 Oil Nutritional Supplementation for Aging-Related Cognitive Decline”) of the investigational drug ProdromeNeuro™ Oil (Omega-3 Plasmalogens).

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, the FDA investigator presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your written responses to the Form FDA 483, dated January 23 and January 31, 2025.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated January 23 and January 31, 2025, it appears that Prodrome Sciences 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 312.2.¹ Prodrome Sciences failed to comply with these requirements. Specifically, Prodrome Sciences initiated and conducted Protocol Pro‐040‐Plasm‐01, a clinical investigation of the investigational drug ProdromeNeuro™ Oil, subject to section 505 of the FD&C Act [21 U.S.C. 355], without submitting and having in effect an IND.

In Prodrome Sciences’ January 31, 2025, written response to the Form FDA 483, you indicated that the objective of Protocol Pro‐040‐Plasm‐01 was to evaluate the safety and tolerability of ProdromeNeuro™ Oil as a nutritional supplement. Additionally, during the inspection you stated that the investigational product, ProdromeNeuro™ Oil, is a blend of naturally occurring alkylglycerols composed of docosahexaenoic acid (DHA) [22:6], docosapentaenoic acid (DPA) [22:5], and eicosapentaenoic acid (EPA) [20:5] fatty acids. You further stated that these dietary alkylglycerols are found naturally in shark liver oil, which makes ProdromeNeuro™ Oil a dietary supplement that does not require an IND.

For the reasons described below, we conclude that the evidence collected during the inspection shows that ProdromeNeuro™ Oil was intended for use as a drug, not as a dietary supplement, for the clinical investigation conducted under Protocol Pro‐040‐Plasm‐01. Therefore, Prodrome Sciences 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….” Although Protocol Pro-040-Plasm-01 stated that the primary objective was to evaluate the safety and tolerability of ProdromeNeuro™ Oil in subjects with age-related cognitive decline, the inclusion criteria for the study expressly included subjects with mild to moderate dementia, and the protocol stated that one outcome of the study was to provide subjects with some improvement in their cognitive status. The outcome assessments for Protocol Pro-040-Plasm-01 included various validated neurocognitive assessments at baseline, and at follow-up visits at months one through five after baseline. These outcome assessments included the Standardized 25-foot Timed Gait Test, the Nine Hole Pegboard Test, the Montreal Cognitive Assessment, and the Quick Dementia Rating Scale, all of which are instruments used to assess neurocognitive status. Therefore, Protocol Pro-040-Plasm-01 collected study data to assess the effect of ProdromeNeuro™ Oil on cognitive status – as measured by changes in gait and changes in the severity of dementia, as determined by cognitive and functional abilities – of individuals with mild to moderate dementia.

Whether an investigational article is a drug depends on the intent of the investigation. Based on the study design of Protocol Pro-040-Plasm-01, the investigational product, ProdromeNeuro™ Oil, as used in the clinical investigation, was a drug as defined in section 201(g)(1) of the FD&C Act, because ProdromeNeuro™ Oil was studied for use in the treatment of mild to moderate dementia.

Thus, before initiating the clinical investigation of ProdromeNeuro™ Oil conducted under Protocol Pro-040-Plasm-01, under 21 CFR 312.40, Prodrome Sciences was required to submit an IND to FDA and to have an IND in effect. FDA’s records indicate that Prodrome Sciences failed to submit an IND before conducting Protocol Pro-040-Plasm-01, in which 29 human subjects were enrolled and received investigational drug between July 2020 and March 2021.

In your January 23 and January 31, 2025, written responses, you stated that Prodrome Sciences has hired a consulting partner to assist with remediation and resolution of the Form FDA 483 observation, and to provide ongoing FDA compliance support.

In your written responses, you also outlined a corrective and preventive action plan that includes the following: (1) a comprehensive review of standard operating procedures and training programs to identify and address gaps; (2) employee training overseen by your consulting partner on the FDA requirements for dietary supplements, and the differences between clinical studies involving dietary supplements and clinical studies involving investigational drugs; and (3) regular audits conducted by your consulting partner to monitor the effectiveness of these actions.

While we acknowledge the corrective and preventive actions you have taken and plan to take, your written response is inadequate because your corrective action plan did not include sufficient information to address how Prodrome Sciences, as a sponsor, will prevent similar violations in the future. For example, your response does not include sufficient details on how Prodrome Sciences, as a sponsor, will determine whether IND regulations apply to future clinical investigations of products regulated by FDA, as required under 21 CFR part 312.2(a). Additionally, your corrective and preventive action plan does not include sufficient details about developing and implementing procedures to comply with IND regulations, if Prodrome Sciences should decide in the future to initiate another clinical investigation for which an IND is required. Without this information, we are unable to determine whether Prodrome Sciences 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 Prodrome Sciences’ responsibility, as a sponsor, to be aware of and to follow all applicable FDA regulations. Prodrome Sciences’ failure to submit, and to have in effect, an IND before initiating Protocol Pro-040-Plasm-01 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 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 about 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

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1 Protocol Pro-040-Plasm-01 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 during the inspection and in your January 31, 2025, written response, ProdromeNeuro™ Oil is marketed as a dietary supplement, not as a drug product.