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WARNING LETTER

Evolutionary Biologics Inc. MARCS-CMS 681586 —

Delivery Method:
VIA EMAIL AND UNITED PARCEL SERVICE
Reference #:
CBER-24-681586
Product:
Biologics
Recipient:
Recipient Name
Jim Morrison
Recipient Title
CEO
Evolutionary Biologics Inc.

14 Penn Plaza West 34th Street Floor 9
New York, NY 10122
United States

admin@evolutionarybiologics.com
Issuing Office:
Center for Biologics Evaluation and Research

United States

WARNING LETTER

December 30, 2024

Warning Letter #: CBER-24-681586

Dear Mr. Morrison:

The United States Food and Drug Administration (FDA) has reviewed your company’s website at the internet address www.evolutionarybiologics.com/rx (last visited November 2024), as well as other information available to the Agency. FDA has determined that you sell the following products in the United States: EXO RNA™ (exosome product), EVO JEL™ (an umbilical cord-derived product), and EVO HYBRID™ (a cellular product derived from umbilical cord, “placental tissue,” and amniotic membrane) (collectively, “your products”). This letter is to advise you that your products are unapproved new drugs and are also unlicensed biological products. The introduction or delivery for introduction of your products into interstate commerce, or the causing thereof, is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. § 331(d).

Based on information and records reviewed by FDA, including your website at www.evolutionarybiologics.com/rx (last visited November 2024), your products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or conditions in humans and/or are intended to affect the structure or function of the body. For example, your website contains the following statements:

EVO JEL™
• “EVO JEL™ is especially effective in orthopedics because it provides cushioning and structural support for tissue and joints while addressing widespread inflammation and modulating an abnormal immune response.” • “EVO JEL™ … can be used as an alternative to assist with musculoskeletal injuries, ailments involving tissue and joints in both acute and chronic settings.”
• “EVO JEL™ is ideally suited to repair, rebuild and regenerate tissue while reducing inflammation”
• Under “Advantages of EVO JEL™”, you list, “Decreases Inflammation” and “Non-surgical orthopedic option for patients”
• Under “Applications of EVO JEL™”, you list, “Large joints (Knee, Hip, Shoulder & Ankle)”…”Chronic partial rotator cuff tears”…”Persistent partial tendon tears (Tennis Elbow)”…”Plantar fasciitis/Bone Spurs”…”Quadriceps and patellar tendon tears”…”Muscular tears”…”Meniscus and cartilage tears”…”Intervertebral disc and spinal facet joints”…”Radicular and Sacroiliac nerves”…”Osteoarthritis”

EVO HYBRID™
• “EVO HYBRID helps restore and improve your internal wellness by reducing inflammation, regenerating tissue, lengthening telomeres, stimulating neuronal growth, modulating the immune response, and other important factors contributing to homeostasis, longevity, and quality of life.”
• “EVO HYBRID™ is ideally suited to repair, rebuild and regenerate tissue while reducing inflammation”
• “SOME KEY GROWTH FACTORS PRESENT IN EVO HYBRID™...
    • “TGFß3 Transforming Growth Factor Beta 3: Most important anti-inflammatory protein; converts inflammatory T cells into anti-inflammatory regulatory T cells...
    • HGF Hepatocyte Growth Factor: Involved in organ regeneration and wound healing
    • PDGF-AA: Regulates proliferation and migration of myocytes and supports angiogenesis
    • VEGF Vascular Endothelial Growth Factor: A protein involved in both angiogenesis and vasculogenesis. Its most important role is to help in the creation of new blood vessels following an injury
    • TIMP -1 and 2 Tissue Inhibitor of Metallopeptidase 1 & 2: Blocks Cartilage and Extracellular Matrix Degradation, Important for Cartilage Repair
    • IGF-1 Insulin-Like Growth Factor: Mediates many of the actions of GH, stimulates the growth of bones and other tissues...
    • B-NGF Beta Nerve Growth Factor: involved with the maintenance, growth and proliferation of target growth neurons”

EXO RNA™
• “Can EXO RNATM Benefit Neurodegenerative Diseases? Research has shown that MSC Exosomes can penetrate the blood-brain barrier and stimulate neuronal differentiation, neuronal growth, and suppress inflammatory processes within the brain tissue.”  
• “NEUROBIOLOGICS; SOME KEY GROWTH FACTORS PRESENT IN EXO RNA™ . . .
    • HGF Hepatocyte Growth Factor: Involved in organ regeneration and wound healing
    • PDGF-BB Platelet Derived Growth Factor Sub-Unit B: Growth factor used to stimulate healing in soft and hard tissues
    • VEGF Vascular Endothelial Growth Factor: A protein involved in both angiogenesis and vasculogenesis. Its most important role is to help in the creation of new blood vessels following an injury
    • GDF-15 Growth Differentiation Factor 15: Regulates inflammation, apoptosis, cell repair, and growth
    • TGFß3 Transforming Growth Factor Beta 3: Most important anti-inflammatory protein. Converts inflammatory T cells into anti-inflammatory regulatory T cells...
    • HGF Hepatocyte Growth Factor: Involved in organ regeneration and wound healing
    • MIP-1 Macrophage Inflammatory Protein 1: Also known as CC1-4, recruits mononuclear cells to the treatment area”

Therefore, your products are drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) 42 U.S.C. § 262(i).

Your product derived from umbilical cord (EVO JEL™) and your cellular product derived from umbilical cord, “placental tissue,” and amniotic membrane (EVO HYBRID™) are also human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d) and are subject to regulation under 21 CFR Part 1271, issued under the authority of section 361 of the PHS Act, 42 U.S.C. § 264. HCT/Ps that do not meet all the criteria in 21 CFR 1271.10(a), and when no exception in 21 CFR 1271.15 applies, are not regulated solely under section 361 of the PHS Act, 42 U.S.C. 264, and the regulations in 21 CFR Part 1271. Such products are regulated as drugs, devices, and/or biological products under the FD&C Act and/or the PHS Act, and are subject to additional regulation, including applicable premarket review.

Based on the review of the materials described above, your firm does not qualify for any exception in 21 CFR 1271.15, and your EVO JEL™ and EVO HYBRID™ products fail to meet all the criteria in 21 CFR 1271.10(a).

For example, your umbilical cord derived product, EVO JEL™, fails to meet the criterion in 21 CFR 1271.10(a)(2) that the HCT/P be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.” This product is not intended solely to perform the same basic function or functions of the umbilical cord in the recipient as in the donor, such as serving as a conduit. Rather, using this product for the treatment of diseases or conditions, such as inflammation, joint tears, tendon tears, muscle tears, cartilage tears, osteoarthritis, plantar fasciitis, and bone spurs is not homologous use as defined in 21 CFR 1271.3(c).

In addition, your umbilical cord derived product, EVO JEL™, fails to meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) and defined for structural tissue in 21 CFR 1271.3(f)(1) because the umbilical cord undergoes processing that alters the original relevant characteristics of the umbilical cord related to its utility for reconstruction, repair, or replacement. Information available to the Agency indicates that EVO JEL is offered in a “flowable” form. The processing of the umbilical cord from the form of a tube into a flowable form is more than minimal manipulation because such processing alters the original relevant characteristics of the umbilical cord relating to the tissue’s utility to serve as a conduit by effectively altering or eliminating its physical integrity and tubular form.

Additionally, EVO HYBRID™ fails to meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) and defined for structural tissue in 21 CFR 1271.3(f)(1) because the umbilical cord and amniotic membrane undergo processing that alters the original relevant characteristics of those tissues related to their utility for reconstruction, repair, or replacement. For example, the processing of umbilical cord from the form of a tube into a flowable form is more than minimal manipulation because the processing alters the original relevant characteristics of the umbilical cord relating to the tissue’s utility to serve as a conduit by effectively altering or eliminating its physical integrity and tubular form, and the processing of amniotic membrane from the form of a sheet into a flowable form alters the original relevant characteristics of the amniotic membrane relating to its utility to serve as a barrier by effectively eliminating its physical integrity, tensile strength and elasticity.1

In addition, your product derived from umbilical cord, “placental tissue,” and amniotic membrane, EVO HYBRID™, fails to meet the criterion in 21 CFR 1271.10(a)(2) because this product is not intended solely to perform the same basic function or functions of umbilical cord and amniotic membrane in the recipient as in the donor, such as serving as a conduit (for umbilical cord) or serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero (for amniotic membrane). Rather, use of this product for reducing inflammation, tissue regeneration, organ regeneration, bone growth, tissue growth, cartilage repair, and wound healing, for example, is not homologous use as defined in 21 CFR 1271.3(c).

Therefore, these products are not regulated solely under section 361 of the PHS Act, 42 U.S.C. § 264, and the regulations in 21 CFR part 1271.2 See 21 CFR 1271.20. In addition to being regulated under section 361 of the PHS Act and 21 CFR part 1271, your EVO JEL™ and EVO HYBRID™ products are regulated as drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i), as stated above.

Your exosome product, EXO RNA™, also meets the definition of a drug and biological product under section 201(g)(1) of the FD&C Act and section 351(i) of the PHS Act, as discussed above, and is subject to premarket review and approval requirements. We direct your attention to FDA’s Public Safety Notification on Exosome Products, at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification-exosome-products. FDA issued this public safety notification following multiple reports of serious adverse events experienced by patients who were treated with exosome products.

To lawfully market a drug that is a biological product, a valid biologics license must be in effect under section 351(a)(1) of the PHS Act, 42 U.S.C. § 262(a)(1). Such licenses are issued only after showing that the product is safe, pure, and potent. A biological product for which a BLA has been approved under section 351(a) is not required to have an approved application under section 505 of the FD&C Act. 21 U.S.C. § 355; 42 U.S.C. § 262(j). Otherwise, with certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act. Your products are not the subject of an approved biologics license application (BLA) or an approved application under section 505 of the FD&C Act. Based on our review, your products are both unapproved new drugs and unlicensed biological products, and you cause their introduction or delivery for introduction into interstate commerce in violation of section 301(d) of the FD&C Act, 21 U.S.C. § 331(d).

This letter addresses certain issues regarding the above-described products and is not intended to be an all-inclusive review. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations. 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.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address these matters may result in action without further notice, including, without limitation, seizure and/or injunction.

Please submit your response in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to address any violations and prevent their recurrence. Include any documentation necessary to show that the matters have been addressed. If you cannot address these matters within fifteen working days, please explain the reason for the delay and the timeframe for completion. If you believe that your products are not in violation of the FD&C Act or applicable regulations, include your reasoning and any supporting information for our consideration.

In addition, we have concerns with your products EXO RX, EXO ELIXIR™ and EXO PERIO™, which are other products described on your websites www.evolutionarybiologics.com/rx and www.evobiologics.com. Your websites (last visited November 2024), make statements indicating these products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or conditions in humans and/or are intended to affect the structure or function of the human body, for example:
• “EXO RX™ expresses 30 forms of collagen and is ideally suited to repair, rebuild and regenerate tissue while reducing inflammation”
• Under “WHY EXO RX™…”, you list, “Anti-Fibrotic”… “Increases epidermal thickness and dermal collagen”…”Reduces scarring in cosmetic procedures and burns”…”Has been known to reduces [sic] acne”
• “EXO ELIXIR is designed to regenerate your skin at a cellular level, with exceptional wound healing and anti-inflammatory growth factors that promote tissue engineering and regeneration.”
• Under EXO ELIXIR “Advantages” you describe, “Modulating Inflammation…Promoting healing of wounds...”
• “EVO PERIO™ Is a Wharton’s Jelly product rich with Mesenchymal Stem Cell exosomes. MSC exosomes induce bone, cartilage, dentin, mucosa, and pulp tissue formation while enhancing oral and craniofacial tissue engineering and regeneration.” 
• “EXO PERIO has demonstrated unique biological properties including being angiogenic, anti-inflammatory, antifibrotic, antimicrobial and immune privileged. The product has shown a strong tendency to accelerate healing and wound repair."
• “Exo Perio can offer solutions for problems like craniofacial, osteochondral, periodontal tissue, nerve, pulp, or endodontics injuries.”

FDA has not identified approved BLAs in effect for your EXO RX™, EXO ELIXIR™ and EXO PERIO™ products. In your response, please explain the basis of your determination regarding whether these products require FDA premarket review. For example, if you believe these products meet the criteria in 21 CFR 1271.10(a) for regulation solely under section 361 of the PHS Act, 42 U.S.C. 264, and 21 CFR part 1271, please explain that determination.

Your response should be emailed to CBERDCMRecommendations@fda.hhs.gov. If you have any questions regarding this letter, please contact the Division of Case Management, CBER at (240) 402-9156.

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

______________________

1 You market EVO HYBRID as being derived from “placental tissue,” in addition to umbilical cord and amniotic membrane. It is unclear what you mean by “placental tissue” in this context, as the mature placenta is composed of multiple tissues. Regardless, your EVO HYBRID product is regulated as a drug and biological product for the reasons described in this letter.

2 Because your EVO JEL™ and EVO HYBRID™ products fail to meet at least one criterion in 21 CFR 1271.10(a), this letter does not evaluate all other criteria in 21 CFR 1271.10(a).

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