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WARNING LETTER

Date: October 24, 2023

Warning Letter #669353

Dear Mr. Ford:

This is to advise you that the United States Food and Drug Administration (FDA) has reviewed your company’s websites at www.abbottnutrition.com, www.abbott.com, and www.pediatricproconnect.com in October 2023 and your company’s marketing materials for Similac® Probiotic Tri-Blend (hereinafter Similac Probiotic Supplement or your product), which contains instructions on where to buy your product. The marketing materials FDA reviewed include one handout that bears the heading “Probiotics and Preterm Infants: Clinical Evidence” and another that bears the heading “The Promise of Similac Another Innovation Only From Similac,” which your sales representatives provided together to hospital staff. You refer to your product as a probiotic and offer it for sale to health care professionals in the United States. Your product is labeled as containing, among other ingredients, Bifidobacterium infantis (Bb-02) and Streptococcus thermophilus (TH-4®), otherwise known as B. infantis (Bb-02) and S. thermophilus (TH-4®), and you sell it for use in preterm infants.

Based on the statements on your website and your marketing materials, your product is an unapproved new drug and unlicensed biological product that you 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)]. Your Similac Probiotic Supplement is also adulterated under section 402(a)(2)(C)(i) and (f)(1)(B) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i) and (f)(1)(B)] because it contains B. infantis (Bb-02), an unsafe food additive within the meaning of sections 201(s) and 409(a) of the FD&C Act [21 U.S.C. §§321(s) and 348]; and S. thermophilus (TH-4®), a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury, when used in preterm infants. These violations are described in more detail below.

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 “Probiotics and Preterm Infants: Clinical Evidence” handout provided by your sales representative to hospital staff has a section with the heading “Probiotics in the NICU: Clinical Evidence” that states, “Probiotics have shown to significantly improve outcomes” for “All-cause mortality,” “Necrotizing enterocolitis (NEC),” “Late-onset sepsis,” and “Feeding tolerance,” and that represents “Benefits of probiotics on NEC,” as “significantly reduc[ing] incidence of NEC in clinical studies.” The other marketing handout with the heading “The Promise of Similac Another Innovation Only From Similac” states that Similac® Probiotic Supplement undergoes safety testing to “ensure the probiotic is ready for hospital use,” (emphasis omitted).

Your website at www.pediatricproconnect.com (last visited in October 2023), includes a link to an Abbott infographic entitled “The Microbiome & The Preterm Infant: Gut Immaturity & Dysbiosis,” which states, “Importantly, giving probiotics to preterm infants can reduce the incidence of NEC.” As noted above, your www.abbottnutrition.com website and documents accessed from it further state that your product is available for “Hospitals and institutions,” and your Pediatric Product Nutrition Guide categorizes the product as for “Premature/ Low-Birth-Weight Infants.”

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 Dietary Supplement

In addition to your Similac Probiotic Supplement being an unapproved new drug and unlicensed biological product, your product is adulterated within the meaning of section 402(a)(2)(C)(i) and (f)(1)(B) of the FD&C Act [21 U.S.C. § 342(a)(2)(C)(i) and (f)(1)(B)].

Unsafe Food Additive: Bifidobacterium infantis (Bb-02)

Your Similac Probiotic Supplement 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, when used in food for preterm infants, B. infantis (BB-02) is an unsafe food additive within the meaning of sections 201(s) and 409(a) of the FD&C Act [21 U.S.C. §§321(s) and 348(a)].

Food additives require premarket approval based on data demonstrating safety. Any substance added or intended for addition to food must have premarket approval by FDA as a food additive 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 section 402(a)(2)(C)(i) of the FD&C Act [21 U.S.C. 342(a)(2)(C)(i)]. There is no food additive regulation that authorizes the use of B. infantis (Bb-02). In addition, as discussed below, 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. infantis (Bb-02) in dietary supplements or in conventional foods, nor are we aware of a basis to conclude that any use of B. infantis (Bb-02) in dietary supplements or otherwise in food for preterm infants is generally recognized as safe (GRAS).

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. infantis (BB-02) in dietary supplements or in conventional foods. Section 201(s) of the FD&C Act [21 U.S.C. § 321(s)] exempts dietary ingredients used in dietary supplements from the food additive definition. However, non-dietary ingredients intended for use in dietary supplements are not exempt from the food additive definition and must meet the same requirements as substances added to conventional foods. The label of your Similac Probiotic Supplement declares B. infantis (Bb-02) as a dietary ingredient. However, the ingredient B. infantis (Bb-02) does not meet the definition of a dietary ingredient. Under section 201(ff)(1) of the FD&C Act [21 U.S.C. § 321(ff)(1)], a dietary ingredient is a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any dietary ingredient from the preceding categories. B. infantis (Bb-02) does not fall within any of these categories. Therefore, the ingredient B. infantis (Bb-02) used in your product is a non-dietary ingredient added to a dietary supplement and must be used in accordance with a food additive regulation or be GRAS for its intended use, unless it qualifies for another exception to the food additive definition.

We are not aware of a basis to conclude that any use of B. infantis (Bb-02) in dietary supplements or food for preterm infants 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”), such as B. infantis (Bb-02), 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.”

Although your Similac Probiotic Supplement label states that the product is “not intended for infants with compromised intestinal permeability,” and your Pediatric Product Nutrition Guide states that your product is “not intended for infants with intestinal permeability,” other marketing materials of yours directly contradict these statements. For example, your infographic titled, “How Probiotics Can Help My Preterm Infant, Infancy is an Important Time in Developing a Healthy Gut Microbiome,” acknowledges that the “[g]ut is not fully developed” in many preterm infants and nonetheless recommends your product be administered to this population because probiotics “increase the number of good bacteria in the gut, promoting a healthy microbiome.” Moreover, you categorize your product as a dietary supplement for premature/low-birth-weight infants in your Pediatric Product Nutrition Guide, and in your “Probiotics and Preterm Infants: Clinical Evidence” marketing handout that your sales representatives distribute to NICU dieticians, you have indicated that this product is designed specifically for preterm infants. Furthermore, statements on the product page of your website indicate your product is available for “Hospitals and institutions” and your “The Promise of Similac: Another Innovation Only From Similac” information sheet describes product testing to ensure it is “ready for hospital use.” 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.

B. infantis (Bb-02) is not GRAS for use in food for preterm infants. Because B. infantis (Bb-02) is not a dietary ingredient and is not GRAS or otherwise exempt from the food additive definition, and because your Similac Probiotic Supplement is intended to be added to food for preterm infants, your Similac Probiotic Tri-Blend product is adulterated under section 402(a)(2)(C)(i) of the FD&C Act because B. infantis (Bb-02) is an unsafe food additive for use by premature infants within the meaning of sections 201(s) 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)].

Section 402(f)(1)(B) Adulteration: Streptococcus thermophilus (TH-4®)

The label of your Similac Probiotic Supplement declares S. thermophilus (TH-4®) as a dietary ingredient. S. thermophilus (TH-4®) is a dietary ingredient under section 201(ff)(1)(F) of the FD&C Act [21 U.S.C. § 321(ff)(1)(F)]. S. thermophilus (TH-4®) is also a new dietary ingredient under section 413(d) of the FD&C Act [21 U.S.C. § 350b(d)], in that it is a dietary ingredient that was not marketed in the United States before October 15, 1994.

A dietary supplement is adulterated under section 402(f)(1)(B) of the FD&C Act if it contains a new dietary ingredient for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury. The available scientific information regarding the safety of S. thermophilus (TH-4®), when intended for consumption by preterm infants, indicates that there is inadequate information to provide reasonable assurance that S. thermophilus (TH-4®) does not present a significant or unreasonable risk of illness or injury. In fact, as noted above, available information on the use of microorganisms in products intended for preterm infants raises serious safety concerns. Therefore, your Similac Probiotic Supplement is an adulterated dietary supplement under section 402(f)(1)(B) of the FD&C Act [21 U.S.C. § 342(f)(1)(B)] because it contains a new dietary ingredient, S. thermophilus (TH-4®), for which there is inadequate information to provide reasonable assurance that such ingredient does not present a significant or unreasonable risk of illness or injury when used in preterm infants. Introduction of this product into interstate commerce is prohibited 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.

We advise you to comprehensively review your website, product labels, and other labeling and marketing materials to ensure that you are lawfully marketing your product 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.

Sincerely,
/S/

Melissa J. Mendoza
Director, Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

/S/

Ann M. Oxenham
Director, Office of Compliance
Center for Food Safety and Applied Nutrition

Cc:
(b)(4)