Safety of Topical Human Biosignals in Skincare – Part 2 (Including information re: FDA regulatory notifications) | BareFacedTruth.com

Safety of Topical Human Biosignals in Skincare – Part 2 (Including information re: FDA regulatory notifications)

Two decades have passed since the first skincare product containing human cell-culture-derived biosignals was launched in 2001. TNS Recovery Complex by SkinMedica was the pioneer that established a new class of topical skincare products. TNS and other products in the class contain cytokines & growth factors harvested from laboratory culture of human cells. Whereas TNS contains biosignals obtained from cultured fibroblasts (skin cells from human infant foreskins), most other products are based on the culture of stem cells obtained from bone marrow, adipose tissue (fat), umbilical cord, and even (shocking to us!) human embryos. These products contain bio-signals in the form of “conditioned media” which is the nutrient broth in which cells are cultured after it has undergone ultrafiltration to remove all cells, cell parts, and other debris. Conditioned media contains all the biosignals produced by the specific cell type during culture. The biosignals produced are reflective of the genetic machinery of the cell cultures and identical to what they produce naturally within the human body.  There are at least two products we are aware of that contain bio-signals in the form of lysed (“ruptured” or “exploded”) cells. These products therefore contain cells or cell parts in their formulation.

BFT has written extensively about the pros, cons, and ethics of different types of cells used to produce biosignals for these products and invites the reader to use the search function on this blogsite, or click on the links below, to acquaint themselves with prior posts.

Cytokines in Dermal Regenerative Medicine (Part 1 of a Series)

Cytokines in Healing and Rejuvenation (Part 2 of a Series)

Stem Cells and Skin Part 3: It’s the Cytokines

Stem Cytokine “Tissue of Origin” Issues (Part 4 of a Series)

“Cytokine Facts” & Actual Products (Part 5 of a Series)

Do you know that fat stem cells and bone marrow stem cells are really, really different?

Unsure about Growth Factor and Cytokine Products for Skin Care & Microneedling?

Safety of Topical Human Biosignals in Skincare – Part 1

What?! CSC14 Cells Actually Come from Human Embryos?

 

NO REPORTED ADVERSE EVENTS FROM TOPICAL BIOSIGNAL PRODUCTS

With a twenty-year history and multiple manufacturers producing topical skincare products containing human biosignals, it is not unreasonable to assume millions of applications of such products have occurred. Some of these products have also been used as topical adjuvants with a variety of controlled traumatic aesthetic procedures including microneedling, radiofrequency microneedling, IPL, laser resurfacing, peels, and others. To be candid, we are aware that our brands, AnteAGE and AnteAGE MD, have been used in such procedures many thousands of times. We are unaware of any significant adverse events with any of our products when used alone or in conjunction with aesthetic procedures. Similarly, we have provided substantial quantities of private label versions of our products to other brand names and have not been informed about any significant adverse event with their usage. Again, this is after many, many thousands of such uses. We are convinced our products under all brand names are exceedingly safe. We are also convinced of the safety of other products in this class. Past and current internet searches confirm this conclusion.

Google Scholar, PubMed, and MedWatch (the FDA adverse event reporting system) searches using keywords – skin, skincare, topical, injury, adverse event, growth factors, cytokines, healing, wound, photodamage, aging – produce innumerable references supportive of the use and benefits of topical human biosignals and none that raise concern. Empirically, many hundreds of thousands, if not millions on uses over two decades, attest to the safety of this technology in skincare.

FDA REGULATIONS 

Skincare products containing biosignals are regulated as cosmetics, for which there is a specific definition. Simply put, a cosmetic is a product used to beautify or alter appearance. The Federal Food, Drug, and Cosmetic Act (FD&C Act) defines cosmetics by their intended use, as products “intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body…for cleansing, beautifying, promoting attractiveness, or altering the appearance”

In the United States, the FDA does not pre-approve cosmetic products or ingredients, with the important exception of specific color additives. Firms producing cosmetics are responsible for marketing safe, properly labeled products, avoiding the use of prohibited ingredients; and adhering to limits on restricted ingredients. This all changes in the event of reports of significant adverse events and safety concerns.

This contrasts with regulations pertaining to drugs which the FDA defines “by their intended use, as articles for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals”.

AFTERMARKET MONITORING

Aftermarket monitoring (Post-Market Drug Safety Monitoring) is required for drugs and medical devices in all regulatory markets because Phase I, II, and III testing may be insufficient to uncover rare or idiosyncratic detrimental responses. Adverse event reporting systems are therefore necessary to monitor and tabulate untoward events. Drug approvals may also be rescinded if efficacy in use is not predictable or significant. As data accumulates, approval of a drug or device may be rescinded based on revelations occurring during aftermarket monitoring.

Historical examples of approved drugs that were removed from the market include:

Accutane (isotretinoin), Baycol (cerivastatin), Bextra (valdecoxib), Cylert (peoline), Darvon (proposyphine), DES (diethylstilbestrol), Duract (bromfenac), Ergamisol (levamisole), Hismanal (astemizole), Lotronex (alosetron), Meridia (sibutramine), Merital/Alival (nomifensine), Micturin (terodiline), Mylotarg (gemtuzumab ozogamicin), Omniflox (temafloxacine), Palladone (hydromorphone hydrochloride, extended-release), Permax (pergolide), Pondimoin (fenfluramine), Posicor (mibefradil), Propulsid (cisapride), PTZ/Metrazol (pentylenetetrazol), Quaalude (methaqualone), Raplon (rapacuronium), Raptiva (efalizumab), Raxar (grepafloxacin), Redux (dexfenfluramine), Rezulin (troglitazone), Selacryn (tienilic acid), Seldane (terfenadine), Trasylol (aprotinin), Bioxx (rofecoxib), Xigris (drotecogin alfa), Zelmid (zimedlidine), Zelnorm (tegaserod maleate)

FDA PRONOUNCEMENT AND SUBSEQUENT CONFUSION AMONG PROFESSIONALS

The FDA recently announced pending policy changes pertaining to products that meet the definition of an HCT/P in 21 CFR 1271.3(d). HCT/Ps are defined as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples of HCT/Ps include “bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.” Excluded from this definition are “secreted or extracted human products, such as milk, collagen, and cell factors [….].”

Biosignals (cytokines and growth factors) secreted by cells into nutrient broth during laboratory culture are consistent with the excluded substances designation. Furthermore, conditioned media obtained through ultrafiltration to remove all cells, cell parts and other debris does not meet the definition of “consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” Based on definitions alone, it seems clear that the recent FDA notification is not applicable to biosignal containing topical skincare products devoid of cells or tissue. Potential exceptions to which the FDA notification may apply are those mentioned above that contain lysed cells within their formulations.

The primary mission of the FDA is to ensure drugs and devices are efficacious and safe prior to being marketed to the public, and that food is also safe. Regulations stipulate that cosmetics do not require premarket approval but must be safe and properly labeled so as not to endanger or deceive the public.

LONG HISTORY OF SAFETY AND EFFICACY OF BIOSIGNAL CONTAINING TOPICAL PRODUCTS

Human biosignal containing skincare products have been used for years in a variety of clinical settings, by physicians and estheticians. In addition to being resold to patients and clients for daily home use, thousands of practitioners have regularly and routinely used these products in their practices.  These products have proved valuable in promoting improvements in appearance following a variety of minimally invasive and controlled traumatic procedures. Safety and efficacy of this class of products has been confirmed in many published studies, and as recounted above, in countless instances of use over the course of twenty years. It is your BFT hosts’ opinion that the recently proposed FDA policy implementation is not relevant or applicable to this class of topical skincare products.

References:

 

An Assessment of Microneedling with Topical Growth Factors for Facial Skin Rejuvenation: A Randomized Controlled Trial. J Clin Aesthet Dermatol. 2020 Nov; 13(11): 22-27

Skin rejuvenation using cosmetic products containing growth factors, cytokines, and matrikines: a review of the literature. Clin Comet Investig Dermatol. 29016; 9:411-419

The potential of topical and injectable growth factors and cytokines for skin rejuvenation. Facial Plast Surg. 2014 Apr;30(2):157-7

 

10 Comments

  1. Matthew D says:

    Thanks for the summation, gentlemen! I read about the “new” FDA guidelines as well. Do you know if this applies to autologous PRP/PRF treatments in aesthetics? Or is that excluded as well?

    • drgeorge says:

      “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: MinimalManipulation and Homologous Use”, recently issued as guidance for industry and FDA staff pertains to HCT/P, shorthand for “human cells, tissues, and cellular and tissue-based products.” “HCT/P are defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” Contained within the FDA guidance is language that specifically states PRP (platelet-rich plasma) is not considered within the HCT/P classification.

      Specifically (as copied directly from the published guidance):

      REGULATORY SCOPE AND COMPLIANCE POLICY
      A. Scope of FDA’s Regulation of HCT/Ps
      As noted in the Background section of this guidance, this guidance only applies to products and establishments that are subject to FDA’s regulations in 21 CFR Part 1271. Establishments that meet the same surgical procedure exception in 21 CFR 1271.15(b) are not subject to FDA’s regulations in 21 CFR Part 1271. This guidance also does not apply to products that fall outside the definition of HCT/P in 21 CFR 1271.3(d). For example, platelet rich plasma (PRP, blood taken from an individual and given back to the same individual as platelet rich plasma) is not an HCT/P under 21 CFR Part 1271 because it is a blood product. Accordingly, FDA does not apply the criteria in 21 CFR 1271.10(a) to PRP, and PRP is outside the scope of this guidance.

      • Rima says:

        Why isn’t taking autologous bone marrow and injecting it into the hip consistent with the FDA definition of autologous use? It hasn’t been more than minimally manipulated. Do you have any thoughts on that?

        • drgeorge says:

          The FDA regulatory Guidance Letter of July 2020 pertaining to use of tissues / cells that are “minimally manipulated” is complex and detailed. We cannot give any information upon which you should rely since the particulars and specifics are so important. We suggest you refer to the Guidance Letter, itself, which can be retrieved at the following URL:

          https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulatory-considerations-human-cells-tissues-and-cellular-and-tissue-based-products-minimal

          As to the specifics of your question, we can refer you to a few references from the literature that are on point. Note they discuss “bone marrow concentrate” which would include much more than just bone marrow-derived stem cells. Good question. Complex answer requiring someone with extensive regulatory experience and expertise in a labyrinth of regulations. Sorry, we are not competent resources for the picayune world of FDA regulatory directives.

          Whitney KE, Briggs KK, Chamness C, Bolia IK, Huard J, Philippon MJ, Evans TA. Bone Marrow Concentrate Injection Treatment Improves Short-term Outcomes in Symptomatic Hip Osteoarthritis Patients: A Pilot Study. Orthop J Sports Med. 2020 Dec 9;8(12):2325967120966162. doi: 10.1177/2325967120966162. PMID: 33344667; PMCID: PMC7731709.

          Rodriguez-Fontan F, Piuzzi NS, Kraeutler MJ, Pascual-Garrido C. Early Clinical Outcomes of Intra-Articular Injections of Bone Marrow Aspirate Concentrate for the Treatment of Early Osteoarthritis of the Hip and Knee: A Cohort Study. PM R. 2018 Dec;10(12):1353-1359. doi: 10.1016/j.pmrj.2018.05.016. Epub 2018 May 29. PMID: 29857166.

          Anz AW, Hubbard R, Rendos NK, Everts PA, Andrews JR, Hackel JG. Bone Marrow Aspirate Concentrate Is Equivalent to Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis at 1 Year: A Prospective, Randomized Trial. Orthop J Sports Med. 2020 Feb 18;8(2):2325967119900958. doi: 10.1177/2325967119900958. PMID: 32118081; PMCID: PMC7029538.

  2. Peter says:

    Are AnteAge products suitable for rosacea?
    I have read some articles that people who are at high risk at skin cancer should avoid products like TNS from Skinmedica.

    • drgeorge says:

      You pose two questions: one about rosacea and AnteAGE, and one about TNS-like products and the risk of skin cancer.

      DrGeorge was guinea pig number one for our concept skincare products containing growth factors and cytokines produced by bone marrow mesenchymal stem cells. Based on our knowledge of the secretome of BMSCs, we anticipated an anti-inflammatory effect. On July 1, 2011, he began his own personal test of our two-part system – AnteAGE Serum & Accelerator, which continues to be marketed as our consumer/aesthetician version. DrGeorge had a decades-long history of rosacea flareups for which he applied Metrogel topically, took 10mg doxyclycline each morning, and applied steroids whenever flareups occurred, despite his daily meds. He was victim to the usual triggers – heat, cold, spicy foods, alcohol, sun, anxiety, etc. It annoyed the hell out of him but it all stopped the day he started using our products. No flareups since and he applies AntAGE products almost daily. So, yes, AnteAGE can be helpful for rosacea – red flareups. Pustular and ocular rosacea have had reported improvements but on a purely anecdotal basis.

      As to increased cancer risks with TNS-like products, we say balderdash! We have written two posts on the safety of such products so you can start there. We also once again recently performed searches about the safety of this kind of product (ours are also in this class) and could not find a single adverse event documented in Google Scholar, PubMed, and the FDA adverse event reporting system. Please understand that all complex multicellular life forms employ biosignals in intercommunication between cells. No biosignals = no complex multicellular life. If one wants to pursue this concept to other aspects of cancer, one could impugn the safety of glucose and oxygen also, as both are necessary for cancer to grow. I’ve used these products daily for the past decade. Not a wink of sleep has been lost worrying about cancer risks. Not a wink.

  3. Todd says:

    The body seeks homeostasis and I assume the skin is no different. Should products like AntAGE or any topical for that matter be cycled, i.e. discontinued for a period of time and then restarted, to prevent tolerance/loss of efficacy?

    • drgeorge says:

      The concept of “tolerance/loss of efficacy” is applicable to certain types of compounds, and most commonly applies to certain classes of drugs, especially ones that act upon the nervous system. As you may know, the nervous system functions essentially as an ultralow current electrical system, one that is powered at its most basic level by differences in voltage within and without excitable cells as a result of the the transmembrane transport (an energy consuming process) of ions of sodium and potassium. The most notable excitable tissues are nerve and muscle. The signaling molecules that cause these tissue to “fire off” are known as “neurotransmitters”. The 7 major neurotransmitters are acetylcholine, dopamine, gamma-aminobutyric acid (GABA), glutamate, histamine, norepinephrine, and serotonin. Other molecules with neuro effects include oxytocin, cannabinoids and endorphins. Many pharmaceutical compounds used in psychiatry and medicine impact how this complex signaling network functions, including sensitizing and desensitizing receptors, enhancing or inhibiting transmitter release and/or transmitter synthesis and re-uptake.

      The term tachyphylaxis is used to describe desensitization to drugs or molecules that occurs very rapidly, sometimes with the initial dose. The term tolerance is used to describe a more gradual loss of response to a drug that occurs over days or weeks. Discontinuation of a drug for a period of time can result in increases sensitivity at a later point. It’s difficult to definitively attribute this type of loss of sensistively to other substances such as hormones, growth factors, cytokines, vitamins, etc. We therefore cannot state with certainty that stopping our products or any others of similar type is necessary or desirable. On the other hand, we do know that individuals may have a period of skin acclimatization when true actives are applied to naive skin. When redness, eruptions, or other signs of sensitivity occur, discontinuation and slower reintroduction usually resolve the issue.

  4. kkdaycare says:

    Hi, I am interested in trying out the AnteAGE Serum and Accelerator, but I am worried about the Salicylic Acid in the Serum formula drying out my skin, and the Sodium Hyaluronate in the Accelerator causing more inflammation. I have used HA products for the past 5 years and seen my skin go downhill ever since. I also did 4 picosure treatments 1 month apart in 2021 and 2 months later , I did 3 under eye microneedling treatments. I am concerned I messed up with all of the aftrcare, and my skin is now ruined forever. Also are your products safe for the eye area or those who may have connective tissue disorders?

    • drgeorge says:

      All ingredients in our products use concentrations within recommended limits so as to minimize side effects. Dry skin has not been reported as an issue. With regards to salicylic acid, it is part of the preservative system and comprises an extremely small amount of the product, on the order of 0.09% of the formula. The HA we use in our products is of the high molecular weight variety, making it unlikely to be pro-inflammatory. Like any cosmetic, we want consumers to avoid getting our products into the eye but have had good reports of their use on eyelids and undereye areas. Just use caution when applying. Our products have no contraindication against use with connective tissue disorders but we would caution their use on a trial and error basis. In other words, if there is a problem when they are used, they should be discontinued out of an abundance of caution. That said, some people with sensitive skin may need a period of acclimatization to become used to the many active ingredients. We recommend the time between applications be increased for a few days and then revert to recommended usage. That usually resolved the issue.

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