- Delivery Method:
- VIA UPS and Electronic Mail
Food & Beverages
Recipient NameMichael D. Johnson
- Infinant Health, Inc formerly Evolve Biosystems Inc.
2121 2nd Street, Suite C108
Davis, CA 95618-6567
- Issuing Office:
- Center for Biologics Evaluation and Research (CBER)
Date: September 28, 2023
Lisa Hannan, General Counsel, Corporate Secretary, Chief Compliance & Regulatory Officer
Dear Mr. Johnson and Ms. Hannan:
This is to advise you that the United States Food and Drug Administration (FDA) has reviewed your company’s website at www.evivo.com in September 2023 and your marketing materials, including your Evivo with MCT Oil Product Information sheet, which contains directions for purchasing your product, Evivo with MCT Oil (hereinafter, Evivo with MCT Oil or your product). You refer to your product as a probiotic and offer it for sale in the United States. Your product contains B. longum subsp. infantis EVC001 bacteria, and you market it for use in infants aged 0 to 36 months.
Based on the statements on your website and your Evivo with MCT Oil Product Information sheet, your product is an unapproved new drug and unlicensed biological product, which was introduced or delivered for introduction into interstate commerce in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 331(d)] and the Public Health Service Act (PHS Act) [42 U.S.C. § 262(a)(1)]. These violations are described in more detail below.
Further, your Evivo with MCT Oil product is intended to be added to food for infants, including preterm infants. As described in your Evivo with MCT Oil Product Information sheet, this product is designed specifically for infants in the Neonatal Intensive Care Unit (NICU). Preterm infants are often hospitalized in a NICU. Furthermore, statements on the product page of your website indicate your product is “[e]xclusively for Healthcare Settings” and “made specifically for use in healthcare settings.” The care of infants in a healthcare setting includes care of preterm infants; therefore, this use is further evidence of the intended use of this product for consumption by preterm infants.
Therefore, in addition to your product being an unapproved new drug and unlicensed biological product, your Evivo with MCT Oil product is an adulterated food under section 402(a)(2)(C)(i) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i)], because when intended for consumption by preterm infants, this use of B. longum subsp. infantis “EVC001” is an unsafe food additive within the meaning of sections 201(s) and 409(a) of the FD&C Act.
As explained further below, introducing or delivering your product for introduction into interstate commerce violates the FD&C Act and the PHS Act. You can find the FD&C Act, PHS Act, and FDA regulations through links on FDA’s home page at www.fda.gov.
Unapproved New Drug and Unlicensed Biological Product
Your website at www.evivo.com (last visited on September 28, 2023), through which providers can contact you to purchase your product, includes references to articles that discuss uses for your product in the mitigation, treatment, or prevention of disease, specifically:
- “Bifidobacterium longum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants” (article title);1 and
- “Probiotics containing B. infantis decrease the risk of necrotizing enterocolitis in premature infants” (from opening summary of article titled, “Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut”).2
As noted above, your website further states that your product is “made specifically for use in healthcare settings,” and your Evivo with MCT Oil Product Information sheet describes the product as “[d]esigned specifically for infants in the NICU[.]”
Because these statements indicate that your product is intended for use in the mitigation, treatment, or prevention of disease, your product is a drug under section 201(g)(1)(B) of the FD&C Act [21 U.S.C. § 321(g)(1)(B)]. Additionally, your product is a biological product as defined in section 351(i) of the PHS Act [42 U.S.C. § 262(i)], because it is applicable to the prevention, treatment, or cure of a disease or condition of human beings.
Please be advised that to lawfully market a drug that is also a biological product, a valid biologics license application (BLA) must be in effect [42 U.S.C. § 262(a)]. Such licenses are issued only after a demonstration that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations (21 U.S.C. § 355(i); 42 U.S.C. § 262(a)(3); 21 CFR Part 312). Your product is not the subject of an approved BLA nor is there an IND in effect for its use. Based on this information, your actions have violated the FD&C Act and the PHS Act.
Adulterated Food: Unsafe Food Additive
In addition to your product Evivo with MCT Oil being an unapproved new drug and unlicensed biological product, your product is adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i)] because under its intended use in food for preterm infants, B. longum subsp. infantis “EVC001” is an unsafe food additive within the meaning of sections 201(s) of the Act and 409(a) of the FD&C Act [21 U.S.C. §§ 321(s) and 348(a)].
The label of your Evivo with MCT Oil product declares the ingredient “Bifidobacterium longum subsp. infantis EV C001 (milk, soy)* CFU Count: 8 Billion CFU per 0.5 milliliters.”
Any substance added or intended for addition to food must have premarket approval by FDA for that use unless the use is generally recognized as safe (GRAS) by qualified experts or meets one of the listed exceptions at Section 201(s)(1)-(6) of the FD&C Act [21 U.S.C. § 321(s)(1)-(6)]. Otherwise, the substance is deemed an unsafe food additive, and food that is or contains an unsafe food additive is adulterated under the FD&C Act. There is no food additive regulation that authorizes the use of B. longum subsp. infantis “EVC001.” We are not aware of an applicable exception under section 201(s) of the FD&C Act [21 U.S.C. § 321(s)] for the use of B. longum subsp. Infantis “EVC001” in conventional foods, including infant formula. We are also not aware of a basis to conclude that any use of B. longum subsp. Infantis “EVC001” in food for preterm infants, including infant formula, is GRAS.
GRAS status requires publicly available evidence that the intended use is safe and a consensus among qualified experts that the intended use is safe (21 CFR 170.30). The information on the use of living microorganisms (also referred to as “probiotics”) by preterm infants in the scientific literature raises serious safety concerns. Preterm infants are a highly susceptible, heterogenous subpopulation of varying ages (<37 weeks of gestation) and weight, who are physiologically, developmentally, and metabolically immature compared to healthy term infants, resulting in their having a high risk for morbidity and mortality and requiring specialized care; thus, we have greater safety concerns for this population than we have for a healthy term infant population. Because their gastrointestinal system is not fully matured, preterm infants have more permeable intestinal linings, often referred to as “leaky guts,” and motility problems, which can lead to opportunistic infections and sepsis when ingesting living microorganisms. The current published literature does not show consensus among qualified experts that the use of living microorganisms in preterm infants is safe. For example, the American Academy of Pediatrics does not endorse the routine use of living microorganisms in preterm infants, finding conflicting data on its safety and efficacy in this vulnerable population, particularly those with birth weight <1000 grams.” FDA communicated these safety concerns related to use in food for preterm infants during a meeting between the FDA’s Center for Food Safety and Applied Nutrition (CFSAN), Office of Food Additive Safety’s Division of Food Ingredients and Infinant Health on July 7, 2023. In particular, FDA questioned whether the clinical studies Infinant cited in its presentation to FDA were robust enough to support safety, as the studies were short-term, poorly designed, and difficult to interpret without appropriate controls. FDA also noted that short-term clinical studies, in general, are only supportive evidence of safety for the use of living microorganisms and have not served as the primary basis for safety in any GRAS conclusions to date for the use of living microorganisms that have come through the GRAS Notification program.
Therefore, based on our review, FDA has determined that the intended use in food for preterm infants of B. longum subsp. infantis is not GRAS. As such, your EVIVO with MCT oil product is adulterated within the meaning of section 402(a)(2)(C)(i) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i)] because this use in food for preterm infants of B. longum subsp. infantis “EVC001” is an unsafe food additive within the meaning of sections 201(s) of the Act and 409 of the FD&C Act [21 U.S.C. §§ 321(s) and 348]. The introduction or delivery for introduction into interstate commerce of any food that is adulterated is a prohibited act under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].
The violations cited in this letter are not meant to be an all-inclusive list of violations that may exist in connection with your products. You are responsible for promptly investigating and determining the causes of any violations, correcting them, and preventing their recurrence, and ensuring full compliance with the law.
During a meeting with FDA on September 21, 2023, your firm emphasized to Agency representatives the benefits of B. longum subsp. infantis in Evivo with MCT Oil for preterm infants in neonatal intensive care units, including by reducing the incidence of necrotizing enterocolitis. These statements suggest that similar claims may exist in other labeling or promotional materials that may be inaccessible to FDA.
We advise you to comprehensively review your website, product labels, and other labeling and marketing materials to ensure that you are lawfully marketing your products in full compliance with the FD&C Act, the PHS Act, and their implementing regulations. Failure to adequately address this matter may result in enforcement action without further notice, including, without limitation, seizure and/or injunction.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. If you believe that your product is not in violation of the FD&C Act and the PHS Act, include your reasoning and any supporting information for our consideration in your response to this letter.
Within fifteen working days of receipt of this letter, please notify FDA in writing of the specific steps that you have taken to correct any violations. Your response should include an explanation of each step being taken to prevent the recurrence of violations as well as related documentation. If you cannot complete all corrective actions within fifteen working days, state the reason for the delay and the date by which you will complete the correction.
Your written response should be sent to the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Avenue, WO71-G112, Silver Spring, MD 20993-0002. Please also email your response to CBERDCMRecommendations@fda.hhs.gov.
Melissa J. Mendoza
Director, Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Ann M. Oxenham
Director, Office of Compliance
Center for Food Safety and Applied Nutrition