Supplement Study Letter Shows How FDA Inspects Clinical Research

The Food and Drug Administration on January 20 posted a warning letter to Prodrome Sciences USA, a Temecula, California company, over a clinical study of its ProdromeNeuro Oil, an omega-3 plasmalogen product. The letter, dated January 8 and issued by the Center for Drug Evaluation and Research's Office of Scientific Investigations, says the company sponsored the study without submitting and having in effect an investigational new drug application, or IND. According to the letter, 29 people received the product between July 2020 and March 2021.

The company had told FDA the product is a dietary supplement that does not require an IND, the letter says. FDA disagreed. The letter came out of an inspection program that most people never see: FDA's checks on the people and companies that run clinical studies.

What the Bioresearch Monitoring program does

FDA established the Bioresearch Monitoring program, known as BIMO, in 1977, according to the agency's compliance program for inspections of sponsors and contract research organizations. Its stated aims are to protect the rights, safety and welfare of people in FDA-regulated studies, to verify the accuracy and reliability of data submitted to FDA, and to assess compliance with FDA's rules on how studies are run.

BIMO inspectors visit clinical investigators, sponsors, sponsor-investigators, contract research organizations and institutional review boards, as well as laboratories running animal studies and bioequivalence studies. The program covers drugs, biologics, medical devices, foods and tobacco products. Separate compliance programs set out what investigators look for at each kind of site. For a sponsor, the rules include 21 CFR Part 312 for drug and biologic studies and 21 CFR Part 812, the investigational device exemption rules, for device studies, along with the human subject protection and review board rules in Parts 50 and 56.

The Prodrome letter describes the usual sequence. An FDA investigator inspected the company between December 17, 2024 and January 10, 2025 and left a Form FDA 483 listing observations. The company responded in writing twice that month. FDA reviewed the inspection report and the responses and then sent the warning letter, which asks for a written reply within 15 business days.

How inspections are rated

Each BIMO inspection is classified. "No Action Indicated" means no objectionable conditions were found, or none serious enough to justify further action. "Voluntary Action Indicated" means problems were found but do not meet the threshold for regulatory action. "Official Action Indicated" means regulatory action should be recommended, for example because subjects were exposed to an unreasonable and significant risk, their rights or safety were seriously compromised, or data integrity was compromised, the compliance program says.

A warning letter is one possible result. Others listed in the program range from an untitled letter for less serious violations to rejection of study data, a clinical hold, seizure of the investigational product, injunctions, civil money penalties and prosecution.

When a supplement study needs an IND

The dispute in the Prodrome case turned on intent. Under federal law a dietary supplement marketed only to affect the structure or function of the body is not treated as a drug. FDA's 2013 guidance on when studies can be run without an IND says the same test applies to research: a study meant only to evaluate a supplement's effect on structure or function does not need an IND, but a study intended to evaluate its ability to "diagnose, cure, mitigate, treat, or prevent a disease" does. A note on the document says parts of that section have been stayed since 2015.

The letter says the study protocol described a safety and tolerability study in people with age-related cognitive decline, but its inclusion criteria expressly included people with mild to moderate dementia, and its outcome measures included the Montreal Cognitive Assessment and the Quick Dementia Rating Scale. "Whether an investigational article is a drug depends on the intent of the investigation," the letter says. FDA concluded the oil was used as a drug in the study. The agency said the company's corrective plan, which included staff training and audits by a consultant, did not explain how it would decide in future whether a study needs an IND.