There is a funny thing about the Food and Drug Administration: they really want you to follow their rules. Considering that they are responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices, it's probably best for all of us when companies do follow their rules.
The Federal Regulations
For HCT/P manufacturers to comply with the rules they have to pay careful attention to Section 1271.3 which sets forth the necessary definitions that the agency and HCT/P manufacturers are relying on. There is a carve out in 1271 (1271.10(a)) regarding the regulation and pre-market approval for products that are referred to as 361 HCT/Ps. Broadly speaking, if your product meets the criteria as outlined in 1271.10(a) you've got yourself a Section 361 HCT/P. If you don't meet that criteria (and you don't fulfill some extremely narrow exceptions in 1271.15) you don't qualify as a Section 361 HCT/P and you've got a heavily regulated approval process ahead of you under section 351. Section 361 is important because it allows manufacturers of certain types of biologics to market their products without filing a Biologics License Application (BLA) and seeking express marketing approval from the FDA. If a manufacturer's product is appropriately qualified it literally saves years and millions upon millions of dollars. It is a very useful carve out that relies on the FDA's risk-based approach to the approval process.
The previous policy of enforcement discretion had allowed for manufactures of HCT/Ps to continue marketing products while they worked to formalize the FDA's classification of their particular products as either a 361 HCT/P or to submit a BLA. Generally speaking to comply with the CFRs as a 361 HCT/P the product must be "minimally manipulated" and for "homologous use".
The really important parts of 1271.3 are below(highlight added):
The following definitions apply only to this part:
(a) Autologous use means the implantation, transplantation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered.
(b) Establishment means a place of business under one management, at one general physical location, that engages in the manufacture of human cells, tissues, and cellular and tissue-based products. "Establishment" includes:
(1) Any individual, partnership, corporation, association, or other legal entity engaged in the manufacture of human cells, tissues, and cellular and tissue-based products; and
(2) Facilities that engage in contract manufacturing services for a manufacturer of human cells, tissues, and cellular and tissue-based products.
(c) Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient's cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.
(d) Human cells, tissues, or cellular or tissue-based products (HCT/Ps) means 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, but are not limited to, 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.
The really important parts of 1271.10 are below(highlight added):
(a) An HCT/P is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets all of the following criteria:
(1) The HCT/P is minimally manipulated;
(2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent;
(3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
(4) Either:
(i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
(ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
(a ) Is for autologous use;
(b ) Is for allogeneic use in a first-degree or second-degree blood relative; or
(c ) Is for reproductive use.
(b) If you are a domestic or foreign establishment that manufactures an HCT/P described in paragraph (a) of this section:
(1) You must register with FDA;
(2) You must submit to FDA a list of each HCT/P manufactured; and
(3) You must comply with the other requirements contained in this part.
How Enforcement Discretion Expiration Could Negatively Impact MiMedx
"Despite all of the FDA’s efforts to engage industry, there continues to be broad marketing of these unapproved products for the treatment or cure of a wide range of diseases or medical conditions. Many of these unapproved products appear to be HCT/Ps that are regulated as drugs, devices and/or biological products subject to premarket approval requirements. The wide extent of the marketing of such unapproved products is evidenced by their inappropriate advertisement in various media and by the number of consumer complaints about them submitted to the FDA.These regenerative medicine products are not without risk and are often marketed by clinics as being safe and effective for the treatment of a wide range of diseases or conditions, even though they haven’t been adequately studied in clinical trials. We’ve said previously and want to reiterate here – there is no room for manufacturers, clinics, or health care practitioners to place patients at risk through products that violate the law, including by not having an IND in effect or an approved biologics license. We will continue to take action regarding unlawfully marketed products. Our oversight of cellular and related products has included taking compliance actions, including numerous warning and untitled letters, and pursuing enforcement action for serious violations of the law.Since December 2019, the agency has issued more than 350 letters to manufacturers, clinics, and health care providers, noting that it has come to our attention that they may be offering unapproved regenerative medicine products and reiterating the FDA’s compliance and enforcement policy."
"we have continued to market our micronized and particulate products during the period of enforcement discretion, but must cease to do so after May 31, 2021 until the FDA approves a Biologics License Application for a specific product and indication."
"Amniotic membrane has been used in numerous wound covering and wound healing applications for over 100 years. These applications have been highly publicized over a long period of time and have been repeatedly referenced by the FDA. These references form the basis for MiMedx's position on marketing, labeling and intended use."Why "form a basis" for marketing when you could definitively receive an opinion from the TRG? Perhaps the company was fearful that the TRG would determine that MiMedx products did not meet the standards under section 361 for any one of a number of reasons.
"Several of our products, including OsteoSponge and OsteoWrap, are regulated as HCT/Ps because they meet these four criteria. The FDA’s Tissue Reference Group confirmed this in non-binding recommendations provided to us."[emphasis added]
"Product manufacturers are not required to consult with the TRG or OCP and instead can market their products based on their own conclusion that the product meets the 361 HCT/P criteria. We have not consulted the TRG or sought a formal designation from the OCP, though we have had informal interactions with OCP."
Homologous Use
"Reducing scarring, angiogenesis, and inflammation are potential clinical effects in the recipient but are not basic functions of amniotic membrane in the donor; therefore, they are not considered homologous uses of amniotic membrane."
By MiMedx's own admission(10-K) the "guidance documents confirmed that sheet forms of amniotic membrane generally are appropriately regulated as solely Section 361 HCT/Ps when intended for use as a barrier or covering" [emphasis added], despite subsequently detailing in their most recent 10-Q that:
"Our EpiFix and EpiCord sheet product lines are promoted for external use, such as in advanced wound care applications, while our AmnioFix, AmnioCord and AmnioFill products are positioned for surgical applications, including lower extremity repair, plastic surgery, vascular surgery and multiple orthopedic repairs and reconstructions."[emphasis added]
MiMedx also disclosed in their 2020 10-K that ~20% of their 2020 sales were products they either knew to be subject or believed that they could be subject to enforcement action(micronized products, EpiCord and AmnioCord). Strangely in the 2020 10-K the company seems to paint a target on the back of their umbilical cord derived products:
"Also, the Company currently markets EpiCord and AmnioCord, tissue products derived from human umbilical cord, as providing a protective environment or as a barrier. The Company has become aware that the FDA may view the basic function of human umbilical cord as a conduit, based on warning letters to several companies marketing human umbilical cord derived products for a variety of uses, which raises the risk that the FDA will take the position that MiMedx’s marketing of human umbilical cord products may not be a homologous use. To our knowledge, the FDA has not indicated this publically or to MiMedx however, if FDA determines that EpiCord and AmnioCord do not meet the requirements for regulation solely under Section 361, then pre-market clearance or approval under Section 351 will be required."
Unnecessary Uncertainty
MiMedx's marketing materials however are directed toward advanced wound care applications, with "semi-permeable protective barriers" that "supports the healing cascade and protects the wound bed to aid in the development of granulation tissue" or are directed toward surgical applications such as "tendon, bone or hardware coverage".
In addition to potential action by the FDA, the company's current marketing practices will also put them squarely at odds with the expectations they disclosed to investors in their most recent 10-K.
"Under the Guidance, we expect that the FDA will continue to regulate our amniotic membrane sheet products (AmnioFix, EpiFix, EpiBurn and EpiXL) as Section 361 HCT/Ps so long as the claims we make for them are consistent with the Section 361 framework."[emphasis added]
For the sake of their shareholders, I hope that MiMedx uses their annual meeting to clarify the precise TRG designation status for all of their products, whether they participated in the TRIPs program, as well as the significant changes to their sales and marketing activities which will likely be warranted starting June 1st when enforcement discretion ends. As responsible fiduciaries, if they haven't already done so, the company should immediately take all steps necessary to submit multiple Requests for Designation to the TRG and disclose the outcome of those requests so that the veil of uncertainty surrounding their products can be lifted for the sake of consumers and the company's shareholders.