Abstract
I
From a practical standpoint, surgeons have a wide array of building blocks to work with in clinical reconstructive procedures today, including a broad range of tissues in the body that can be grafted, a number of approved biomaterials readily available in the operating room, approved growth factors such as bone morphogenic protein and platelet-derived growth factor, and fibrin glue to serve as a biologic bonding agent. As the limits of technology and technique are being pushed forward, a surgeon has the capability to harvest autologous tissue during a surgical procedure, isolate cellular elements or other tissue components, seed the tissue onto a scaffold that is approved for implantation, and enrich the construct with growth factors that are readily available in the operating room.
Given this expansive pallet of materials available to the surgeon to work with in the operating room, where do the boundaries of standard clinical care lie when it comes to removing and implanting tissues? The answer is found in the United States Code of Federal Regulations Section 21, part 1271 (21 CFR 1271), HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS. This specific code of federal regulations was written by the food and drug administration (FDA) under authority granted by Section 361 of the Public Health Service Act, which empowers the agency to control the spread of communicable diseases. While many surgeons are under the impression that they are free from FDA regulations when performing procedures that involve autologous tissue grafting and that they are simply practicing medicine, 21 CFR 1271 gives the FDA regulatory jurisdiction over any tissue removed from the human body and intended for implantation.
Within this set of regulations, a human cell and tissue product (HCT/P) is defined. “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. (§ 1271.3).” These regulations govern the production and distribution of products such as acellular dermal matrix, demineralized bone allograft, and a host of other tissue products. If an entity is removing tissue from a human, and the tissues fit the definition of a HCT/P, then the entity removing the tissues must register their facility with the FDA, list their products with the FDA, and adhere to a rigorous set of standards for labeling, donor selection, and manufacturing practices. While these rules are most relevant to commercial manufacturers, they can impact all instances where tissues are removed from the human body, and intended for implantation.
For practicing surgeons, this set of regulations is largely invisible to them. This is because surgeons are given an exception to regulation under 21 CFR 1271 for many procedures that are commonly performed. Under the guidelines, “You are not required to comply with the requirements of this part if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure (§ 1271.15).” This has also lead to the misperception that operating room practices are free from FDA regulation, and that surgeons have complete discretion when it comes to working with tissues that they remove from an individual. To exercise this same surgical procedure exception, however, the tissue would otherwise have to be considered an HCT/P that would be regulated under 21 CFR 1271. The criteria for an HCT/P to be regulated under 21 CFR 1271 include two important characteristics: (1) the tissue is minimally manipulated, and (2) the tissue is for homologous use (see complete list of criteria in Table 1, § 1271.1).
HCT/P, human cell and tissue product.
It is important to understand the definitions set forth by the FDA for minimal manipulation and homologous use. Notably, definitions of minimal manipulation, as stated in 21 CFR 1271, are different for tissues that are classified as cellular versus structural. Structural tissues, such as bone, are considered more than minimally manipulated if the biomechanical properties are significantly altered. “For structural tissue, [minimal manipulation is] processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement (§ 1271.3).” Cellular tissues, such as bone marrow aspirate, are considered more than minimally manipulated if the basic biologic properties are changed. “For cells or nonstructural tissues, [minimal manipulation is] processing that does not alter the relevant biological characteristics of cells or tissues. (§ 1271.3).” Homologous use, refers to “like into like,” or that the tissue performs the same function in the recipient as in the donor. “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 (§ 1271.3).” With these definitions being fairly broad, there can be considerable interpretation of how a specific procedure may or may not fit the definition of minimal manipulation. If a clinician would like an official opinion from the FDA as to whether or not a cell or tissue product fits the definition of an HCT/P, they can submit a request to the Tissue Reference Group of the FDA, and a nonbinding opinion will be issued. Tissue Reference Group opinions become public record, and they can be reviewed online.
Given the fact that tissues removed from a human can be broken down very easily and quickly into cellular elements using enzymatic digestion, and the fact that automated devices are now available that can be used directly in the operating room, there is considerable opportunity to apply novel, tissue-based, regenerative therapies in clinical practice. In late 2014, the FDA released three draft guidance documents in quick succession that highlighted their jurisdiction over surgical procedures that involve tissue grafting and clarified their thought process concerning how tissues can be handled in the operating room, as well as conveying specific thoughts on the concept of minimal manipulation and use of adipose tissue. These documents were released in draft form and opened for public comment. At the time of the writing of this editorial, the FDA had not released final guidance documents.
In the first document (Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception, Draft Guidance for Industry), the FDA clarified that they consider the same surgical procedure exception to be a very narrowly applied exception to the rule. They stated that tissues should undergo no more manipulation than rinsing, sizing, and shaping. This certainly raises considerable questions for current surgical practice, and underscores the fact the FDA not only regulates tissue grafting procedures, but wants to ensure that the tissues are not being significantly modified in the operating room. The second guidance document (Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products, Draft Guidance for Industry and FDA Staff) emphasizes differences between structural tissues and cellular tissues relative to definitions of minimal manipulation. Importantly, the FDA points out that a tissue could either be considered structural or cellular, and this categorization has significant implications on how the tissue can be handled and processed. The third guidance document deals specifically with adipose tissue (Human Cells, Tissues, and Cellular and Tissue-Based Products [HCT/Ps] from Adipose Tissue: Regulatory Considerations, Draft Guidance for Industry).
These guidance documents present many limitations for surgeons who are interested in applying regenerative medicine and tissue engineering concepts in the operating room. The guidance on the same surgical procedure exception limits how tissues can be handled in the operating room once harvested, potentially impacting current and future therapies. This guidance document also creates ambiguity surrounding some commonly performed procedures. For example, cartilage grafts or other tissues may be mechanically crushed to soften them before application. Does this constitute more than rinsing, cleansing, or sizing? Additionally, vascular grafts, such as vein grafts, may be irrigated with pharmacologic agents with vasodilator properties. Does this constitute more than minimal manipulation?
In the Guidance Document on Minimal Manipulation, the FDA provided examples of cases when tissues were and were not considered more than minimally manipulated. Skin, a structural tissue, was noted in the draft guidance to have a barrier function in the donor. This property would be retained in decellularized dermal matrix products, and therefore was considered acceptable. Amnion also serves a barrier membrane function in the donor, and would fall under 21 CFR 1271 regulation if it was left intact. However, the FDA gives an example in the draft guidance that if the amnion was lyophilized and converted to a powder form, it would no longer have this barrier function and would be considered more than minimally manipulated. For adipose tissue, the FDA emphasized the fact that fat tissue fell into the category of structural tissue, with properties of padding and cushioning. An example was provided in the draft guidance that decellularized adipose tissue matrix would be considered more than minimally manipulated because the native characteristics of cushioning and padding had been altered. Additionally, the isolation of adipose stem cells from the adipose tissue, by any means, would render those isolated cells more than minimally manipulated because the cell product will have lost the native function of padding and cushioning. Therefore, once cells are removed from adipose tissue, both the cellular component and extracellular matrix component would be considered more than minimally manipulated.
The Adipose Guidance Document reiterated these issues related to minimal manipulation of fat tissue, and also raised the issue of homologous use. Specifically, breast applications of HCT/Ps derived from adipose tissue were considered to not meet the definition of homologous use. The FDA made this argument based on the assertion that the primary function of the breast is lactation, and that lactation is not a function of adipose tissue.
The consequence of a tissue product being more than minimally manipulated or outside of homologous use is that the cell and tissue product would fall into the category of a biologic drug, and would be regulated under Section 351 of the Public Health Service Act, which gives the FDA authority to grant a biologic license. This development pathway requires phase 1, 2, and 3 clinical trials under an FDA Investigational New Drug or Investigational Device Exemption (IND or IDE Protocol), followed by application for a biologic license.
So what is the path forward to facilitate the innovation and application of clinical regenerative therapies based on human tissues? Regarding the FDA's position on minimal manipulation, a potential path forward is to abandon the concept of structural versus cellular tissues, and understand the innate biologic characteristics of the tissue components and how they might be applied. This is especially true of adipose tissue, which has been identified as a rich source of multipotent adult stem cells. Indeed, adipose tissue is not just a passive energy store and source of padding for surrounding tissues, but a fascinating biologically active tissue. Therefore, adipose tissue, along with many other tissues, can have both structural and cellular characteristics that can be capitalized upon for regenerative therapies. In clinical practice, fat tissue can certainly be used as a structural filling agent, in which fat harvested by minimally invasive hollow-bore aspiration cannulas is separated from aqueous and oil layers and then injected into subcutaneous tissue to provide additional padding or volume. Indeed, this application is cited as acceptable in the FDA Draft Guidance on Adipose Tissue. However, adipose tissue and its cellular components have also been used clinically for such nonstructural purposes (via paracrine effects) of improving vascularity and helping to remodel tissues that have been injured from radiation therapy. Additionally, adipose stem cells are well known to have anti-inflammatory effects. Therefore, adipose tissue can have applications befitting both structural tissues and cellular (nonstructural) tissues depending on the specific clinical application. A rational path forward would be the regulatory consideration of the intended use of the tissue product rather than narrowly classifying tissues as either structural or cellular. The finite definitions of structural versus cellular do not fit well with regenerative applications, and this concept could be further modified to recognize structural and cellular properties rather than structural versus cellular.
In the adipose guidance document, the concept of homologous use is narrowly applied based on a single function of the breast (lactation) and single anatomic component, and it actually challenges commonly used procedures for breast reconstruction. The contention that use of fat tissue products in the breast is nonhomologous ignores the fact that the breast is composed largely of fat tissue. Additionally, adipose tissue is commonly used for breast reconstruction, with a decades-long history of autologous tissue from the abdomen being transferred to the chest to rebuild a breast. Lactation is never restored in these situations. Moreover, an important function of the breast is defining the female body shape, and federal legislation mandates a woman's right to insurance coverage for breast reconstruction after mastectomy to restore the female form. No current method of breast reconstruction restores lactation, whether based on adipose tissue or silicone implants. Indeed, restoring functional breast ducts in a patient with a propensity for breast cancer could put the patient at further risk for the disease. Autologous fat transfer, or grafting of fat tissue, is now commonly used for breast reconstruction. It is used as a primary reconstruction method, although most commonly used as an adjunct to other reconstructive methodologies, and the new guidance document could impact this practice. This therapy is highly beneficial for our cancer patients recovering from their disease. Another regulatory quandary created by this guidance document has to do with the use of free tissue transfer for breast reconstruction. This commonly used surgical procedure involves the removal of a mass of adipose tissue, usually from the abdomen, with its major arterial blood supply disconnected from the vascular source. The tissue flap is then transferred to the chest and the arteries and veins connected to the local circulation with microsurgical technique. Interestingly, a free tissue flap, once removed completely from the donor site and separated from the body, would fit the definition of an HCT/P. Therefore, this standard method of breast reconstruction would fall outside of 21 CFR 1271 regulation because of nonhomologous use. How the FDA will approach these issues of autologous fat grafting to the breast and free tissue transfer for breast reconstruction is yet to be seen.
Why the FDA generated these Guidance Documents, especially one focused on adipose tissue, is speculative but may be related to the ready availability of methods to process adipose stem cells from fat tissue. That, combined with the easy collection of fat tissue through minimally invasive hollow-bore aspiration cannulas, sets the stage for widespread applications of cellular therapies by a number of specialists. The positive aspect is that new cell therapies are more available to patients in need. The downside is that the therapies may not always be substantiated by strong evidence and appropriate safety data. It will be important going forward for the FDA and clinicians in different specialties to work collaboratively to establish new regulatory pathways that facilitate the generation of new regenerative therapies that can help our patients, and also maintain patient safety. Additionally, harmonizing the FDA regulations with regulations in Europe and Asia will help standardize approaches across the globe. The FDA is continuing its focus on 21 CFR 1271 with another draft guidance document on homologous use recently released. Moreover, the FDA will be holding public hearings in 2016, and clinicians must have a voice. This is a true crossroads for innovative surgical practice, and the regulatory environment should evolve with new technologies.