RAAS Nutritionals, LLC/Rare Antibody Antigen Supply, Inc.

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted from March 15 to 23, 2021. Investigator Stuart W. Russell, representing FDA, reviewed the role of RAAS Nutritionals, LLC (RAAS) as the sponsor of the following clinical investigations:

(b)(4)1, 2, 3, 4, 5

(b)(4)

(b)(4)6

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 Russell presented and discussed with you and your staff the Form FDA 483, Inspectional Observations. We acknowledge our receipt of RAAS’s April 7, 2021, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and RAAS’s April 7, 2021, written response to the Form FDA 483, we conclude that RAAS 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:

FDA regulations require a sponsor to submit, and to have in effect, an investigational new drug application (IND) before initiating a clinical investigation of a drug subject to 21 CFR 312.2(a) in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2 (see 21 CFR 312.20 and 312.40(a)). RAAS failed to comply with these requirements. Specifically, RAAS initiated and conducted the following clinical investigations of investigational drug products subject to section 505 of the FD&C Act without submitting and having in effect an IND7:

The clinical investigation of the investigational drugs (b)(4) and (b)(4) conducted as part of the (b)(4) described above

The clinical investigation of the investigational drug (b)(4) conducted as part of the (b)(4) study described above

The clinical investigation of the investigational drug (b)(4) conducted as part of the (b)(4) study described above

In RAAS’s April 7, 2021, written response to the Form FDA 483, RAAS argued that it was not obligated to submit an IND before initiating these clinical investigations because the articles under study are dietary supplements and not drugs.

To support this argument, RAAS described previous written communications it had sent to the National Institutes of Health (NIH); the Biomedical Advanced Research and Development Authority under the U.S. Department of Health and Human Services; and the former Commissioner of Food and Drugs Stephen Hahn, M.D., regarding the use of its “non-pharmaceutical products” (b)(4). In addition, RAAS also described written communications with the (b)(4).

RAAS stated that it proceeded without an IND because it believed that if it was legally able to sell its nutritional supplements to the general public, it should be able to test and observe the effects of those supplements without an IND. RAAS believed that as long as it did not advertise in direct conjunction with a product sold in the market, the products could continue their designation as dietary supplements.

RAAS also asserted that it took steps to operate within FDA’s rules and to seek required authorization. RAAS stated that it delayed large-scale public introduction of the products pending FDA approval and did not advertise its products for use as drugs. In addition, RAAS stated that it was never its intention to sell or investigate the products as drugs. RAAS claimed that it received a communication from FDA stating that one of its compounds did not qualify as a drug, and that explicitly indicated that the sponsor did not need to proceed with an IND. In further arguing that the investigational products should be classified as dietary supplements, RAAS stated that its products are Generally Recognized as Safe (GRAS) and are not new drugs, and that it had completed all legal steps to sell these products as dietary supplements. RAAS argued that it conducted a “medical observation in order to ascertain the extent of the beneficial properties of the supplements in order to apply for health claims or for qualified health claims.”

For the reasons described below, we conclude that the evidence collected on inspection shows that (b)(4) were intended for use as drugs, not as dietary supplements, in the three clinical investigations named above.

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 in man or other animals . . . .” RAAS studied the efficacy and safety of the investigational products ((b)(4)) to cure, mitigate, and/or treat disease as described below:

As shown by a draft manuscript intended for publication, the objective of the COVID-19 Study was to evaluate the safety and efficacy of (b)(4) and (b)(4) to cure, mitigate, and (b)(4) effect on symptom improvement, (b)(4) on (b)(4).

As shown by the protocol, the objective of the (b)(4) Study was to evaluate the safety and efficacy of (b)(4) effect on the (b)(4).

As shown by the protocol, the objective of the (b)(4) Study was to evaluate the safety and efficacy of (b)(4) to cure, mitigate, and treat (b)(4) effect on the (b)(4).

In fact, in its response to the Form FDA 483, RAAS stated that “our hopes were that the botanicals could have drug-like impact on the participant’s health (i.e., curing or preventing disease)[.]”

Whether an investigational article is a drug or a dietary supplement depends on the intent of the investigation. Based on the designs of the (b)(4) studies, the investigational products as used in these clinical investigations were drugs as defined in section 201(g)(1) of the FD&C Act, because, respectively, (b)(4) and (b)(4) were studied to cure, mitigate, and treat (b)(4); because (b)(4) was studied to cure, mitigate, and treat (b)(4); and because (b)(4) was studied to cure, mitigate, and treat (b)(4).

Thus, before initiating the clinical investigations of (b)(4) and (b)(4) conducted under the studies referred to above as the (b)(4) study, the (b)(4) study, and the (b)(4) study, RAAS was required to submit INDs to FDA and to have these INDs in effect under 21 CFR 312.40. FDA records indicate that RAAS failed to submit INDs before conducting these clinical investigations. From the records collected on inspection, it appears that (b)(4) human subjects were enrolled at one clinical site for the (b)(4) study, (b)(4) human subjects completed the (b)(4) study, and (b)(4) human subjects completed the (b)(4) study.

RAAS’s claims that the FDA explicitly indicated that the sponsor did not need to proceed with an IND are unfounded. First, the referenced communication attributed to FDA was, in fact, from a representative of the NIH, a different government agency. Second, in this referenced communication, the NIH representative did not suggest that RAAS’s product was not considered a drug for purposes of the FD&C Act, or that an IND was not required. Rather, they merely stated that the product could not be tested for antiviral activity because it was an extract and not a pure compound – a determination very different from an opinion on whether the product at issue was a drug for purposes of the FD&C Act. We also note that RAAS’s communications with the (b)(4) regarding the legality of studies to be conducted there are immaterial to the question of the legal status of clinical investigations conducted in the United States.

Similarly, the purported GRAS status of RAAS’s products and the methods of its marketing of those products are very different from a determination on whether RAAS could conduct these studies without having an IND in effect. As discussed above, (b)(4) were considered drugs for the purposes of these studies. The purported GRAS status of an article for one or more uses in a dietary supplement does not exempt that same article from IND requirements when it is being investigated for use as a drug. In other words, an article may be a drug as used in a clinical trial even if it is considered a food or a dietary supplement as used in other contexts.

RAAS assured in its response that it “will use its best efforts to comply with the recommended use of IND . . . guidelines in the future based on our enhanced understanding of the rules provided by [FDA’s Office of Regulatory Affairs]”; however, RAAS also indicated that they would like to maintain their products’ designation as dietary supplements and will follow whatever advice or ruling the FDA offers to maintain this designation.

RAAS’s response is inadequate because it did not provide a corrective action plan explaining how it would comply with IND regulations. Without this information, we are unable to determine whether RAAS’s stated intent to comply with IND regulations is adequate to prevent similar violations in the future.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical studies of investigational drugs. 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.

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 adequately address this matter may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant FDA regulations, please include your reasoning and any supporting information for our consideration.

If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S. Branch Chief (Acting) 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 5219 10903 New Hampshire Avenue Silver Spring, MD 20993