Four Food and Drug Administration draft guidance documents and the REGROW Act: A litmus test for future changes in human cell‐ and tissue‐based products regulatory policy in the United States?

Abstract Modern regenerative medicine research has expanded well past the development of traditional drugs and medical devices with many promising new therapies encompassing an increasingly diverse range of substances, notably cell‐based therapies. These substantial recent developments and the progress in the health care and therapeutics fields necessitate a new regulatory framework agile enough to accommodate these unique therapies and acknowledge their differences with traditional pharmaceuticals. In the United States, recent proposed changes in the regulatory framework for autologous human cells, tissues, and cellular and tissue‐based products (HCT/Ps) and their perceived risk–benefit analysis for patients remain controversial in the scientific field. To provide perspective on of the current status of the most recent attempts to redefine and conceptualize these changes in the United States, we will examine 4 draft guidance documents implemented by the Food and Drug Administration in interpreting relevant concepts and terminology pertaining to HCT/Ps: the Bipartisan Policy Center think tank report, “Advancing Regenerative Cellular Therapy: Medical Innovation for Healthier Americans,” the proposed REGROW Act for HCT/Ps, and the current 24 Food and Drug Administration‐approved HCT/Ps and related products in the United States.

In the United States, original attempts by the Food and Drug Administration (FDA) to address cell therapy regulations were based on modification of existing policies for chemical drugs, biologics, and vaccines. The relevant regulatory framework is included in Sections 351 and 361 of the Public Health Service (PHS) Act of 1944, which define biological products and provide the FDA with the authority to prevent the spread of communicable diseases, respectively (FDA, 2017k), and in Title 21 of the Federal Code of Federal Regulations of 2001, Part 1271 (referred to as 21 CFR Part 1271), which outlines regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps;FDA, 2017d). The FDA defines HCT/Ps as any product "containing or consisting of human cells or tissues intended for implantation, transplantation, infusion, or transfer into a human recipient" (FDA, 2017d). In 2001, HCT/P therapies were broken down into the following three-tier regulation classification system (FDA, 2001c): -First tier (low risk): Considered current medical practice and not subject to FDA preapproval, that is, organ transplant, blood transfusion as defined 21 CFR Part 1270 (FDA, 2017c) or 21 CFR Part 1271.15 (FDA, 2017d).
-Second tier (middle risk): Also referred to as "361 HCT/P products" after Section 361 of the PHS Act, which governs their use.
Eligible products (a) must be minimally manipulated for (b) homologous use (as determined by advertising and labelling of product), (c) cannot be combined with "another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent" (these exemptions must not present clinical safety concerns), and (d) do "not have a systemic effect" and are "not dependent upon the metabolic activity of living cells for their primary function" (unless they are for autologous use, for allogeneic use in the first-degree or second-degree blood relative, or for reproductive use; FDA, 2017d). Such 361 HCT/Ps are not subject to premarket FDA approval or clearance (21 CFR Part 1271.10; FDA, 2017d).
-Third tier (high risk): Also referred to as "351 products" after Section 351 of the PHS Act that governs their regulation. These include any cell-based therapies that do not fulfil all four second-tier criteria and therefore require a full premarket biologics license application (BLA) and must follow the same premarket and postmarket regulation as medical devices, drugs, or biologics (21 CFR Part 1271.20;FDA, 2017d). Thus, not all 351 products are HCT/Ps, but some HCT/Ps are regulated as 351 products.
Most would consider this patchwork system to be inefficient in accommodating the inherent differences between traditional pharmaceuticals and cell-based products. However, between 2001 and the enactment of the 21st Century Cures Act, the FDA made minimal changes to these regulations, with most changes even further limiting the cell types eligible for the pathways available within the existing lower risk tiers.
As a result of the slow-to-change FDA, patients turned both to stem cell tourism, pursuing cell therapy treatments in countries with less regulation, and to the, as of 2016, 570 domestic clinics selling unapproved stem cell therapies that have sprouted up across the United States (Turner & Knoepfler, 2016). Recently, there has been much media attention given to the deregulation of stem cell therapies in Texas through a recent law that allows for patients to access unapproved stem cell products if a physician approves and oversees the treatment (Servick, 2017). In early August 2017, the U.S. Senate unanimously voted to pass a "Right to Try" bill, which gives terminally ill patients access to experimental therapies that have not yet been approved by the FDA (Pear & Kaplanug, 2017). This bill that has been part of a lager movement that has resulted in the rapid adoption of similar "Right to Try" legislation by 38 of the 50 U.S. states as of October 2017 (Goldwater Institute, 2017). Although this bill still requires ratification by Congress, the current political climate in the United States appears to be ripe for a bill supporting further deregulation of the federal government to pass. If passed, this bill could be the first to restrict the FDA's current control over the regulation of cell therapies (FDA, 2017d).
Given this political context, this article will focus on providing an overview of the regulatory momentum that has been gathering over the past 5 years in the United States to specifically reframe the translation policies for HCT/Ps. This review will outline the four draft guidance documents released by the FDA before the enactment of the

| FOUR DRAFT GUIDANCE DOCUMENTS FRAMING FDA PERSPECTIVES ON HCT/Ps
Draft guidance documents outline the FDA's current definition and recommendations on certain topics within their jurisdiction. They are not official regulations unless they are officially adopted, but they provide useful insight into the FDA's perspective on certain controversial topics and can serve as a litmus test for organizations applying for certain FDA-warranted approvals. The FDA usually disseminates such documents in part to provide advice and recommendations to the relevant establishments and organizations that may need to apply for product approval, but also to collect feedback and commentary from the pertinent stakeholders on the topics before finalizing the document. The four criteria necessary for products to qualify for the second tier within the FDA's HCT/P regulatory hierarchy have been the focus of much of the regulatory debate related to cell therapies. In particular, most of the recent debate has been centred around clarifying the FDA's definitions of "homologous use" and "minimal manipulation," two requirements relevant to "the 361 HCT/Ps" that fall under this second tier and are exempt from FDA premarketing regulation. In this draft guidance, the FDA narrowly defines the "same surgical procedure exception" for HCT/P uses that would fall outside of FDA regulation. In order for the surgical exception to apply, three criteria must be met: (a) HCT/Ps must be removed from and implanted into the same patient, (b) the surgical removal and implantation must occur within the same procedure, and (c) HCT/Ps must remain "in their original form," so that the "communicable disease risks" would remain the same as those usually associated with surgery (FDA, 2014c). Eligible procedures were narrowly defined to involve HCT/P removal and implantation back into the same patient within a single operation performed at the same establishment. Rinsing or cleaning, labelling, and temporary storage of HCT/P were the only cell processing steps allowed within what could be considered the same surgical procedure exception.
"Autologous use" is the term given to describe the first criteria for surgical exception and is further defined in this draft guidance to include "the implantation, transplantation, infusion, or transfer of human cells or tissue back into the individual from whom these cells or tissue were originally removed" (FDA, 2014c). Although this guidance presents additional criteria for exemption from FDA preapproval in addition to those outlined in the first and second tiers, interestingly, this guidance limits eligible procedures to include only those that occur within the same patient, whereas the earlier 361 product criteria viewed autologous use to be the same level of risk as allogeneic use in a close relative. This guidance was finalized with the same title in November 2017 (FDA, 2017n). Cells, Tissues, and Cellular and Tissue-Based Products (FDA, 2014b) In this draft guidance, the FDA provide further definition of minimal manipulation expanding on the original description given in 21 CFR Part 1271 and providing numerous examples of procedures that qualify as minimal manipulation or would otherwise be considered more than minimal manipulation (FDA, 2014b). As in the original regulation, the definition for minimal manipulation is divided into two sections within this guidance depending on whether the relevant cells/tissues are classified as structural tissues or are considered cells/nonstructural tissues. Structural tissues are defined as those that serve as a barrier or provide support within the body, such as bone, skin, blood vessels, or adipose tissue. Nonstructural tissues are defined to "serve predominantly metabolic or other biochemical roles in the body, such as hematopoietic, immune, and endocrine functions" and include tissues such as cord blood, bone marrow aspirate, lymph nodes, and pancreatic tissue (FDA, 2014b).

| Minimal Manipulation of Human
Minimal manipulation for structural tissues was originally defined as processing that does not alter the "original relevant characteristics of the tissue, relating to the tissue's utility for reconstruction, repair,   Processes that qualify as minimal manipulation of adipose tissue include "aliquoting, rinsing, removal of macroscopic debris, and freezing" (FDA, 2014a). Processing that decellularizes, isolates certain essential cellular components, or otherwise decomposes adipose tissue in a manner that it cannot perform its relevant functions of "cushioning and support" are considered more than minimal manipulation (FDA, 2014a).
Interpretation of the second criteria, homologous use of adipose tissue-derived HCT/Ps, requires that the product perform a relevant adipose tissue function in the recipient. HCT/Ps from adipose tissue replacing an adipose tissue defect, such as in cosmetically filling spaces in a patient's face or hands, would be considered homologous use.
However, use of HCT/Ps from adipose tissue to treat bone and joint disease would generally be considered nonhomologous uses, as adipose tissue does not have bone-, or joint-specific functionality. In a recent profile on unapproved cell therapy clinics, some businesses were found to advertise their stem cell therapies as treatments for over 30 diseases, most of which could not possibly qualify as homologous use under the definitions outlined in this draft guidance (Turner & Knoepfler, 2016). Concerningly, the sixth most common cell type marketed by these clinics was categorized "undefined" in this analysis (Turner & Knoepfler, 2016), which would pose complications given that the FDA specifies homologous use of products is determined by product "labeling, advertising, or other indications of manufacturer's objective intent" (Munos, 2009). Further, some clinics would interchange terms such as "placental stem cells" and "amniotic stem cells," making the true source of such clinics' cells unclear (Turner & Knoepfler, 2016).
The content of this draft guidance was finalized in the recent guidance document on minimal manipulation and homologous use (FDA, 2017n). The recent final guidance explicitly highlights that any HCT/P used "for a myriad of diseases or conditions" is unlikely to be implemented homogenously (FDA, 2017n). Given this context and the recent legislation in Texas legalizing patient access to unapproved cell therapies as long as they are physician-overseen (Servick, 2017), there is an apparent discrepancy between the federal regulatory policy and some states' policies in enforcing how cell therapies progress and are regulated within this rapidly growing, unregulated industry. The evolution and potential future judicial resolution of this seeming discrepancy in jurisdiction will be interesting to observe.    Table 2 shows detailed information on the contents of the proposed REGROW Act (Coffman et al., 2016;Kirk et al., 2016). The most substantial changes proposed within the bill were motivated by the changes recommended in the BPC Report and were related to the approval process for cellular therapies and the classification of cellular therapeutics (BPC, 2015). The Act proposed the creation of a 5-year conditional use period for cellular or tissue therapeutics demonstrating sufficient safety and efficacy, without Phase III investigation (Coffman et al., 2016;Kirk et al., 2016). To be approved under this proposed conditional approval system, the eligible products are adult human cells and tissues that have been either minimally manipulated for nonhomologous use or more than minimally manipulated products for homologous or nonhomologous use but "do not provoke a significant unintended immune response in the recipient" (Coffman et al., 2016;Kirk et al., 2016). The adult cells and tissue must be used for "a specific indication" and should "achieve or restore, the same, or similar, function in the recipient as the donor" (Coffman et al., 2016;Kirk et al., 2016). Within 5 years of conditional approval, an annual report and adverse event reports would need to be submitted to the FDA before and in addition to "an application for approval of a biological product" under the new legislation (Coffman et al., 2016;Kirk et al., 2016). During the conditional approval period, doctors must inform each patient of the products' conditional approval status.
The expedited approval pathway presented in the REGROW Act would have not only accelerated approval for a broader group of eligible regenerative medicine therapeutics, rather than just for those addressing serious or life-threatening illnesses, as under the existing guidelines, it also would have enabled these products to enter the market before traditional Phase III testing. Critics of this proposed legislation urged that the appropriate existing expedited pathways already existed and warned that circumventing Phase III trials would expose patients to ineffective and potentially harmful products (Turner & Knoepfler, 2016). The attrition rate for prospective drugs and therapeutics can be as high as 40% in Phase III testing due to concerns over safety or inefficacy (Servick, 2017 (Editorial, 2016).
Supporters of the REGROW Act insisted that the traditional clinical trial process was too arduous, time-consuming, costly, and likely prevented perfectly safe and effective treatments from reaching patients in critical need (BPC, 2015). The amount of time it takes to get potential drugs and therapies from patenting to commercialization has increased over the years with average estimates now well over a decade (Pammolli, Magazzini, & Riccaboni, 2011). The costs of taking a product through the entire development process has also exponentially increased over the past decades, and now total costs are approximately $2 billion to take a product to the market (Munos, 2009).
Supporters of the REGROW Act also pointed to the recent changes in British and Japanese legislation that may enable these countries to break ahead or attract previously U.S.-based companies abroad to drive the progress of regenerative medicine products (RMPs) and therapies under more amenable legislative conditions (BPC, 2015). Further, supporters viewed the changes proposed by this Act as an essential pathway to treatment access for patients suffering from rare diseases that could be treated with RMPs and that currently slip through the existing expedited regulations or may not yield the required patient numbers for conducting timely Phase III clinical trials (Cetrulo, 2016).  Section 2. Cellular therapeutics (a) Current pathways-No part of the proposed bill is intended to modify the current pathway to market is overseen by the Food and Drug Administration (FDA), governed through Sections 351 and 361 of the Public Health Service (PHS) Act.
(b) Approval for therapies-Section 351 of the PHS Act is amended by adding the following: • Sec. 351B. Approval for cellular therapies (a) Conditional approval of cellular or tissue therapeutics: Calls for creation of a program for the conditional approval of safe cellular therapeutic products without Phase III clinical trials.
(b) Additional requirements for conditional approval: Qualified conditionally approved products can enter a 5-year conditional use period if the following requirements are met: (1) Are "adult human cells or tissues" (2) Examination of immunogenicity reveals no "significant unintended immune response" (3) Are (A) "minimally manipulated for a non-homologous use" or (B) "more-than-minimally manipulated for a homologous or non-homologous use, but are not genetically modified" (4) Are "produced for a specific indication" (5) Perform "the same, or similar, function in the recipient as in the donor" (6) A biological product approval application (described under PHS Act Section 351(a)) is submitted within 5 years (7) "Annual reports and adverse event reports" should be submitted throughout the conditional approval period until the biological product (8) Approval application is approved (9) Submitted a sponsor application to treat patients within the 5-year conditional use period (10) The product has not been previously conditionally approved for the same use (11) Informed use: Patients must be notified of the conditional approval status of the product and that it has not been proven efficacious.
(12) Stem cell banking: "Public and private cord blood banks, tissue banks, and bone marrow repositories shall be in full compliance with good tissue practice requirements" under 21 CFR 1271.
Section 3. Devices used in recovery, processing, and delivery of cellular therapeutics (a) Clearance-Outlines editing changes to be made to Section 510(k) of the Federal Food, Drug, and Cosmetic Act (FFDC Act).
(b) Clearance or approval of cellular therapeutics.
• Sec. 515B. Classification of cellular therapeutics • Cellular therapeutic device clearance or approval will depend on in vitro testing performance.
• Classifications of devices "used for cell therapy," should be determined by their general uses: "harvesting, delivery, or processing cells and sustaining the viability and function of the cells in vivo." • No additional clearance required for approved devices to be used with cells unless they impact the intended use of the device.
• Reclassification of low risk class III products and those lacking previous approval without cells are governed by the FFDC Act.
(c) Combination products-Outlines editing changes to be made to Section 503 of the FFDC Act.
Section 4. Guidance: Amended regulations (a) Guidance-A draft guidance may be released to clarify any of the presented changes within 1 year of enactment, and a final guidance will be issued within 180 days from the end of the comment period.
1 In general-Any amendments to 21 CFR to clarify the presented changes should be completed within 1 year of the enactment.
2 Procedure-Outline of amendment process.
After 2005, the products now target a broader range of applications, including some of the most life-threatening diseases, such as heart disease or cancer. The low number of these approved 351 products is reflective of the lengthy and costly regulation that these HCT/Ps were forced to follow in order to obtain FDA approval. These changes attempted to counteract FDA action by reducing the number of products that would fall under the FDA jurisdiction through redefinition of the product regulatory categorizations and reduction of necessary clinical trial evidence before product release onto the market.
Many of these modifications resembled the conditional and time-limited authorization for RMPs in Japan. The concept of creating an expedited approval pathway for certain therapies was not new. "Accelerated approval" pathways for drugs and biologics for serious or life-threatening illnesses already exist in the United States (Yano, Watanabe, & Yamato, 2016). "Conditional market authorization" of drugs for serious and life-threatening diseases, emergency situations, and orphan diseases as well as "market authorization under exceptional circumstance" of drugs also exist in the European Union (Yano et al., 2016). In 2014, Japan became the first country to introduce an expedited approval system that would create a conditional approval pathway for RMPs in the "Pharmaceuticals, Medical Devices and Other Therapeutic Products (PMDA) Act" (Hara, Sato, & Sahara, 2014 This Japanese legislation was the initial spark for much of this controversial discussion about regulation of cell therapies amongst the international scientific community (Hara et al., 2014;Konomi, Tobita, Kimura, & Sato, 2015). Critics of the newly implemented conditional and time-limited authorization system for RMPs in Japan raised concerns that these changes may be too lax and may "flood" the Japanese market with ineffective therapies (Editorial, 2015). Although it will take years before the impact of the recent changes in the Japanese system are fully understood, the first RMP, HeartSheet®, was already approved implemented "for a myriad of diseases or conditions" are unlikely compatible with the criteria of homologous use required for HCT/Ps to qualify as 361 products. This guidance also lays out a warning that products presenting a higher risk based on their "site of administration" and those implemented for "non-homologous use, particularly those intended to be used for the prevention or treatment of serious and/or life-threatening diseases and conditions" will be the first to be targeted by FDA compliance enforcement. With exception of the most nefarious clinics, which are currently FDA scrutiny, manufactures have been given 3 years to come into compliance, but this premeditated description of products that will be subject to regulation make the FDA's intentions clear, and only time will tell if the Agency has the necessary infrastructure to broadly enforce compliance.
The recent action by the FDA warning several cell therapy clinics that they need to acquire FDA approval in order to sell some of their products shows that the Agency certainly has an interest in attempting to enforce its authority.
The original draft guidance on adipose tissue-derived products highlighted that implementation of adipose tissue-derived HCT/Ps for breast augmentation would not be considered a homologous use. However, in the final guidance, this implementation is listed as a homologous use, as cushioning and support are considered some of the original functions of the harvested adipose tissue. Although a seemingly subtle difference, the original draft guidance could, arguably, have been seen as FDA encroachment on medical practice. The regulation of medical practice is outside of the jurisdiction of the FDA as it can only control the dissemination and regulation of medical products. Under U.S. law, the authority to regulate the practice of medicine lies with the individual states. The FDA, however, has been extending its authority and in some instances, arguably, has encroached on the practice of medicine related to HCT/P therapies. The revision of the categorization of some adipose tissue-derived products for breast augmentation in the final guidance may reflect the FDA's cognizance of this boundary to its authority. However, considered in the context of the "Right to Try" movement and the deregulation of stem cell therapies in Texas, this overlap of authority may foreshadow future clashes over jurisdiction.
The power balance between the U.S. federal and state governments is complex, and ultimate changes to this distribution of power can only the settled through the slow justice of the judicial branch.
Although the REGROW Act died in the previous Congress (GovTrack US, 2017), some believe that a bill with similar more detailed regulation of the HCT/P therapeutic approval process can be anticipated to reappear in the future, as there is still much room for optimization in the translation of bench-top discoveries to bedside therapies within the existing U.S. system. Through the recent release of several draft guidance documents (FDA, 2017b and warnings to stem cell clinics (FDA, 2017h, 2017i), the FDA has been taking steps to exert its authority. At the same time, in the wake of the REGROW Act (Coffman et al., 2016), the gathering momentum of the "Right to Try" movement (Goldwater Institute, 2017;Pear & Kaplanug, 2017;Servick, 2017), and the current deregulatory political environment in the United States, there appears to be legislative momentum that could begin to create legal avenues by which the FDA could be side-stepped and the diplomatic provisions of the 21st Century Cures Act could become a thing of the past.

CONFLICT OF INTEREST
K. Yano is also an employee of Medtronic Japan Co., Ltd. M. Yamato is a shareholder of CellSeed Inc.