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WARNING LETTER

FDA Ref. No.: 25-HFD-45-11-01
 

Dear Mr. Patel:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between June 25 and July 12, 2024. The investigators representing FDA reviewed the role of Verdure Sciences, Inc. (Verdure) as the sponsor of a clinical investigation (Protocol 005, “Randomized, Double-Blind Evaluation of Maple leaf extract (Maplifa for Photoaging”) of the investigational drug Maplifa® (1% or 5%).

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 investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 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 July 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(a) and (b) and 312.40(a)] in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. Verdure failed to comply with these requirements. Specifically, Verdure initiated Protocol 005, a clinical investigation of the investigational drug Maplifa®, which is subject to section 505 of the FD&C Act [21 U.S.C. 355], without submitting and having in effect an IND.

In Verdure’s July 24, 2024, written response to the Form FDA 483, you stated that Verdure did not believe an IND was required because Protocol 005 assessed the use of topical Maplifa® skin regimen on the cosmetic appearance of skin photoaging (wrinkles and skin brightness). You further stated that the study ingredient was not being studied for use to affect the structure or function of the body or to prevent, treat, mitigate, cure, or diagnose a disease because Protocol 005’s primary endpoint was to detect change in skin brightness as measured by a skin colorimeter and facial photographic image analysis, which are widely used to study the efficacy of cosmetic formulations. Furthermore, you stated that the study met all the IND exemption requirements as listed in an FDA proposed rule¹ that proposed exemptions for certain clinical investigations of products lawfully marketed as a food or cosmetic when the product is to be studied to evaluate its use as a drug. Finally, you stated that Verdure signed a Clinical Study Agreement (CSA) with a third-party vendor to conduct Protocol 005, and the CSA transferred the obligation of the “sponsor” to this third party.

We address your arguments below.

1. Protocol 005 was a clinical investigation of a drug subject to 21 CFR 312.

Section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)] defines drug, in part, as “articles (other than food) intended to affect the structure or any function of the body of man or other animals….” Whether an investigational article is a drug depends on the intended use of the article in the investigation. Based on Protocol 005 and the final study report, the investiga-tional product, Maplifa®, as used in this clinical investigation, was a drug as defined in section 201(g)(1) of the FD&C Act because Maplifa® was studied for use in the mitigation or treatment of facial wrinkles, skin brightness, skin redness, erythema, and hyperpigmentation.

Specifically, as described in the protocol, the objective of Protocol 005 was to “examine the effects of topical Maplifa® on facial wrinkles, redness, and pigmentation.” The final study report for Protocol 005 also stated that “Maplifa® is a proprietary, standardized, phenolic-enriched A[cer] rubrum extract formula that is intended to whiten skin and reduce wrinkle production, primarily due to its anti-oxidative and anti-glycating properties.” The final study report further stated, “To further understand the influence of applying topical A. rubrum-based products to the skin, we conducted a randomized, double-blind evaluation to explore the influence of [glucitol-core containing gallotannins] on reduction of face redness, hyperpigmen-tation, and wrinkle formation.” According to the protocol and the final study report, to assess the efficacy of Maplifa®, Protocol 005’s outcome measures included changes in skin brightness, pigmentation, erythema, redness, and wrinkles. These outcomes were measured using different methods, including skin colorimeter, image-based analysis, and in-person clinical assessments. Therefore, Protocol 005 collected study data to assess the effect of Maplifa® on the skin, as measured by methods including skin colorimeter and facial photographic image analysis.

Considering the nature of the study, as described above, we conclude that the evidence collected during the inspection shows that Maplifa® was intended to affect the structure or function of the body; it was not merely intended to affect cosmetic appearance. Maplifa® was therefore intended for use as a drug for the clinical investigation conducted under Protocol 005. As a result, you were required to submit an IND before conducting the clinical investigation.

2. The clinical investigation conducted under Protocol 005 does not meet the exemption criteria in 21 CFR 312.2(b)(1) and is subject to the IND requirements under 21 CFR 312.

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) are met.

Protocol 005 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 be lawfully marketed in the United States as a drug product. Verdure’s July 24, 2024, written response claims that Maplifa® is marketed only as a cosmetic ingredient, not as a drug product. However, as described above, the intended use of Maplifa® under Protocol 005 was as a drug, and we are not aware of any basis to conclude that it is a lawfully marketed drug. You also argue that Maplifa® is exempt from the IND requirements based on an FDA proposed rule. However, your response provided no reasoning to support this assertion. A proposed rule, until final, is not binding and does not supersede or otherwise change existing FDA regulations regarding IND exemptions. Your response also did not explain why Protocol 005 would have qualified for an exemption, even if the proposed rule were final and in effect. Moreover, we note that study participants received the study drug and the study was completed before FDA proposed the regulation at issue for public comment. As explained above, the study materials for Protocol 005 establish that Maplifa®’s intended use in the clinical trial was that of a drug. Further, Protocol 005 was not exempt from 21 CFR 312, and Verdure was required to submit an IND before initiating a clinical investigation of a drug in human subjects.

3. Verdure is the sponsor of the clinical investigation conducted under Protocol 005 as defined in 21 CFR 312.3.

FDA regulations define a sponsor as a person who takes responsibility for and initiates a clinical investigation [see 21 CFR 312.3]. Under 21 CFR 312.52, a sponsor may transfer responsibility for any or all of its obligations to a Contract Research Organization (CRO) and must describe any such transfer, including the specific obligations transferred, in writing; however, if all obligations are transferred, a general statement that all obligations have been transferred is acceptable. Both the CSA and the work order collected during the inspection and provided in your written response identify Verdure Sciences, Inc., as the “Sponsor” and the third-party vendor as the “Service Provider.” Neither of these documents describes which of Verdure’s sponsor obligations for conducting this study, if any, were transferred to the third-party vendor. Additionally, the CSA and work order do not contain any general statements that sponsor obligations have been transferred. Your written response refers to a provision of the CSA, which states that the third-party vendor “will conduct the Study according to the provisions of the Protocol and this Agreement and in conformance with all [Applicable Laws].” This provision does not describe, in either general or specific terms, any obligations that transferred from you to the third-party vendor.

In your written response, you stated that as a corrective and preventive action, Verdure will ensure that all third parties, such as a CRO, comply with all applicable FDA regulations, including filing for an IND, unless exempt. However, your written response is inadequate because it does not provide sufficient details of a corrective and preventive action plan for developing and implementing procedures that comply with IND regulations, should Verdure decide in the future to initiate another clinical investigation for which an IND is required. Without this information, we are unable to determine whether Verdure will comply with IND regulations in the future.

As a sponsor, you are responsible for complying with IND requirements, including submitting and having in effect an IND before initiating a clinical investigation, and it is Verdure’s responsibility, as a sponsor, to be aware of and to follow all applicable FDA regulations. Verdure’s failure to submit, and to have in effect, an IND before initiating Protocol 005 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 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 Federal Register Proposed Rule - December 9, 2022.