DISCUSSION OF FDA’S DRAFT GUIDANCE ON HOMOLOGOUS USE OF HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS NOVEMBER 4, 2015 INTRODUCTION The issuance of the FDA’s Draft Guidance on Homologous Use of Human Cells, Tissues and Cellular and Tissue-Based Products released on October 28, 2015 has created a number of concerns, particularly as it relates to amniotic tissue and MiMedx. MiMedx issued a press release on October 29, 2015 responding to some of the concerns that had developed around this complex subject. However, the Company believes that additional commentary and documentation of this regulatory area is appropriate. Therefore, MiMedx has developed these discussion points related to these particular FDA regulations. In addition, the Company has included the information and facts that support our assertion that we are in compliance with the HCT/P, 21 CFR 1271 Regulations on Homologous Use. We have outlined the information herein, and created links to various FDA, and other independent websites where the reader can easily verify the facts on his or her own. This Draft Guidance has been submitted in accordance with the FDA’s procedures for Guidance Documents. This allows industry and interested parties to prepare for presentations at a public hearing on April 13, 2016. At this hearing, stakeholders will be provided the opportunity to discuss FDA’s policy on regulation of HCT/P’s related to this Draft Guidance as well as three other Draft Guidance documents related to human tissue that were published last year. Relative to Amniotic Tissue, there has been guidance and pronouncements from the FDA over the last 15 years that are relevant in today’s regulatory environment. Those issues will be clearly delineated in this document. Some of the definitions and regulations can be quite confusing, but this document should clarify those matters so that individuals can assess these potential regulatory changes. After the FDA assimilates the written and verbal comments from its April 13th hearing, they are expected to publish final Guidance Documents from which it may make future interpretations around each of these product areas. If those Guidance Documents have, in effect, changed the regulations, then we believe there should be subsequent legislative oversight of the Agency’s justification for changing their existing regulations. As we stated in our October 29, 2015 press release, MiMedx strives to be compliant with all applicable regulations, and based on several facts, including those listed below, believes that we have been, and are still in compliance with the homologous use requirements for amniotic tissue. Furthermore, there is a lengthy process involved in making any guidance document final, but even if the Guidance Document were finalized as is, it is our opinion that MiMedx would remain in compliance and that our position with respect to the homologous use of our products is consistent with those taken by the FDA in the Draft Guidance. This document has the following Sections: 1. Homologous Use of Human Tissue 2. Basic Functions of Amniotic Membrane 3. MiMedx Intended Uses Compared to the Draft Guidance 4. Homologous Use Draft Guidance Document 5. Guidance Document and Congressional Focus 6. Tissue Regulation History 7. Appendix of References 11/4/2015 Page 1 of 10 SECTION 1: HOMOLOGOUS USE OF HUMAN TISSUE The current human tissue regulations were codified in 2001 in 21 CFR 1271. In the final regulation, homologous use was defined in 1271.3(c) as: “the replacement or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions as in the donor.” Additionally, in the preamble to the final regulations, FDA specified that Homologous Use specifically references “objective intent,” meaning the HCT/P’s labeling and advertising material. The FDA further stated that it would “look not at the actual use of an HCT/P, but at the manufacturer’s objective intent for a non-homologous use.”1 This concept is discussed at length in the preamble, highlighting the fact that the FDA’s Homologous Use regulation is focused on the labeling and advertising material, not the clinical use of such HCT/Ps. Further, in instances where companies have labeling outside of the requirements, companies generally have not been required to remove their products from the market if a labeling change could bring them back into compliance. SECTION 2: BASIC FUNCTIONS OF AMNIOTIC MEMBRANE Amniotic membrane has been used in various wound covering and wound healing applications for over 100 years and has been highly publicized throughout this time period. Amniotic membrane and some of its “basic functions” have been repeatedly referenced by the FDA for over 15 years. These references formed the basis for the MiMedx position relative to our marketing materials for many years. The specific FDA statements related to the “basic functions” of amniotic tissue are referenced below, along with hyperlinks to the pertinent websites. Copies of these documents are also included at the end of this document. Below are specific details and references to these FDA materials: 1. FDA letter to Bio-Tissue Regulatory Counsel, November 26, 20012 In the preamble to the final rule, the FDA stated that amniotic tissue use in the eye would not be Homologous Use. Bio-Tissue, a company that marketed amniotic tissue for surgical reconstruction procedures in the eye, challenged this position, and was able to convince the FDA to reverse its position. In doing so, the FDA defined what it meant by “basic function” and acknowledged several basic functions of amniotic tissue in utero. In a letter to Bio-Tissue dated November 26, 2001, the FDA stated “Bio-Tissue presented persuasive information that both in utero and on the ocular surface, the amniotic membrane product described in the Request for Designation (RFD) acts as an anti-scarring agent, an antiinflammatory agent, and a anti-angiogenic agent”. FDA further stated that “Bio-Tissue's amniotic membrane product… meets the criteria contained in 21 CFR 1271.10(a), including homologous use.” While the Bio-Tissue letter limits the opinion to Bio-Tissue’s product, the position of the FDA regarding the function of amniotic tissue in utero is not product specific, as the in utero function does not change based on the tissue’s use in the recipient. 1 Federal Register, Vol 66 No 13, p 5458, January 19, 2001: http://www.gpo.gov/fdsys/pkg/FR-2001-01-19/pdf/01-1126.pdf November 26, 2001 FDA Letter to Bio-Tissue, Inc. http://www.fda.gov/downloads/CombinationProducts/JurisdictionalInformation/RFDJurisdictionalDecisions/RedactedDecisionL etters/UCM113701.pdf 2 11/4/2015 Page 2 of 10 2. Vol 69, No. 226, Federal Register, November 24, 2004, p. 686433 In the preamble to the final rule on Current Good Tissue Practice for HCT/P product establishments, the FDA noted that amniotic membrane for ocular repair (an eye wound) is homologous use. This was confirmed in the Federal Register that the FDA considered ocular repair as homologous use of amniotic membrane. 3. Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Small Entity Compliance Guide; p. 4, item 34 Included “Amniotic membrane when used alone or without added cells” in a list of products that meet the criteria in 21 CFR 1271.10(a), which includes minimal manipulation and homologous use. 4. CBER Cellular, Tissue and Gene Therapies Advisory Committee Meeting, May 14, 2009 At the Cellular, Tissue, and Gene Therapies Advisory Committee’s 47th meeting, on May 14-15, 2009, a representative of an amniotic tissue company, Bio-Tissue, presented to the committee. The Issue Summary stated that amniotic membrane and cells recovered from amniotic membrane have specific uses that qualify as HCT/P including “wound dressing, treatment for leg ulcers, skin loss, reconstruction of pelvic floor, vaginal epithelialization, oral cavity reconstruction, replacement of nasal mucosa, ear surgery, and otolaryngology procedures (ref 2), ocular repair, stem cells (ref. 3)."5 Dr. Sheffer Tseng of Bio-Tissue also shared a presentation showing that amniotic membrane acts as an anti-scarring agent, an antiinflammatory agent, and an anti-angiogenic agent and supports epithelial adhesion and differentiation6. In the records of the meeting, a question was asked about the homologous use of amniotic tissue, and FDA representative, Martha Wells, confirmed the FDA’s finding that amniotic tissue used for ophthalmic reconstruction (eye wound) was indeed a homologous use7. 5. FDA Untitled Letter to OKTOS Surgical Corporation, June 23, 20058 In this letter, the FDA stated “FDA has recognized that amniotic membrane that has not been dehydrated or decellularized may be used for wound repair and wound healing”. This is yet again an acknowledgement by the FDA that amniotic membrane’s basic functions in utero include wound repair and wound healing. 3 Federal Register Vol 69, No 226, P68643, November 24, 2004 http://www.gpo.gov/fdsys/pkg/FR-2004-11-24/pdf/0425798.pdf 4 Small Entity Compliance Guide; Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); CBER, FDA, August 2007, Page 4 http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm06 2592.pdf 5 Issue Summary; Cellular, Tissue and Gene Therapies Advisory Committee, 47th Meeting, May 14-15, 2009, P 5. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/Cellular TissueandGeneTherapiesAdvisoryCommittee/UCM155431.pdf 6 Human Amnion, Current Scope of Utilization, Scheffer C.G. Tseng, MD, PhD., CSO, Bio-Tissue, Inc.; presentation to FDA, Slide #13 http://1.usa.gov/1dWRlt0 7 Minutes, Meeting of the Cellular, Tissue and Gene Therapies Advisory Committee, CBER, FDA, May 14, 2009; p125-126: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/Cellular TissueandGeneTherapiesAdvisoryCommittee/UCM224960.pdf 8 June 23, 2005, FDA Letter to OKTOS Surgical Corp: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/U ntitledLetters/ucm091804.htm 11/4/2015 Page 3 of 10 At the time, OKTOS Surgical Corporation was marketing a product from Celgene that was a dehydrated and decellularized amniotic membrane and was promoting it for wound repair and healing. The FDA sent OKTOS an Untitled Letter because the act of decellularizing the tissue resulted in the “removal of cytokine containing cells from the tissue”, and such removal “would interfere with human amniotic membrane’s ability to actively mediate wound repair and healing.” The FDA explicitly recognized that basic functions of amniotic membrane in utero include wound repair and wound healing. Further, these functions can be marketed as “intended uses” for amniotic membrane provided that the tissue is not decellularized. It should be noted that, in keeping with this FDA holding, the MiMedx allografts are not decellularized. In a presentation to the AATB (American Association of Tissue Banks) on September 8, 2008, then-Director of the Division of Human Tissues of CBER, Ruth Solomon, further explained the cytokine removal as the key issue in this case, and not the dehydration of the product.9 MIMEDX PURION® PROCESSED TISSUES SUCH AS EPIFIX® AND AMNIOFIX® ARE NOT DECELLULARIZED. THEY RETAIN THE CYTOKINE CONTAINING CELLS, AND AT LEVELS SHOWN TO BE ESSENTIALLY EQUIVALENT TO FRESH AMNIOTIC TISSUE. In summary, as all this information demonstrates, the FDA has explicitly indicated that the “basic functions” of amniotic membrane in utero include anti-inflammatory, anti-scarring, and anti-angiogenic functions, and acting as a wound repair and wound healing agent. These functions have been accepted by the FDA as basic functions of amniotic membrane. Notice that these basic functions describe general uses, or ”intended uses”, and do not specify conditions such as dermal ulcers, which represents a more specific indication for use, rather than the more general FDA recognized intended uses. Table 1 below summarizes amniotic tissue homologous use.         Table 1: Amniotic Tissue & Homologous Use FDA Basic Functions & Homologous Non-Homologous Use Use of Amniotic Tissue Per October 2015 Draft Homologous Use Guidance Document 2 Anti-inflammatory  Healing of Dermal Ulcers Anti-angiogenic2  Bone Tissue Replacement 2 Anti-scarring Wound repair8 Wound healing8 Barrier7 Cover (Draft Guidance) Protect (Draft Guidance) 9 Dr. Ruth Solomon, HCT/P Regulatory Pathways and Jurisdiction: 361 HCT/P, Biological Product or Medical Device, Sept 8, 2008: http://www.aatb.org/files/HCTP%20Regulatory%20Pathways%20and%20Jurisdiction%20-%20Ruth%20Solomon.pdf 11/4/2015 Page 4 of 10 SECTION 3: MIMEDX INTENDED USES COMPARED TO THE DRAFT GUIDANCE The stated intended uses for EpiFix have been, and are, that it enhances wound healing, reduces (modulates) inflammation, and reduces scar tissue formation. Further, it serves as a wound covering and a barrier. The stated uses for our other main product, AmnioFix, have been, and are, that it enhances healing, reduces (modulates) inflammation, reduces scar tissue formation, and acts as a barrier. These are all basic functions of amniotic tissue as recognized by the FDA, and were all carefully considered as the MiMedx advertising and labeling were developed. These are consistent with the recognized basic functions and homologous use that can be found in Table 1. Additionally, MiMedx has been audited by the FDA related to our HCT/Ps on three occasions: in 2011, 2012, and 2014. Among the items reviewed in these audits were our intended uses for our amniotic membrane products, which included the wound repair and wound healing intended uses as well as the anti-inflammatory and anti-scarring uses. The auditors reviewed marketing materials and instructions for use, which clearly identified these intended uses. In all three audits, the FDA had zero findings related to our marketing material or homologous use statements. Additionally, on at least two occasions, during our discussions regarding our micronized tissue, the FDA specifically commented that it had no issues with our sheet allografts. SECTION 4: HOMOLOGOUS USE DRAFT GUIDANCE DOCUMENT The central point of concern appears to be specifically related to Section 4-2 in the Homologous Use Draft Guidance document. This section states: “The basic functions of amniotic membrane include serving as a selective barrier for the movement of nutrients between the external and in utero environment and to retain fluid in utero. An amniotic membrane product is used for wound healing of dermal ulcers and defects. This is not homologous use because wound healing of dermal lesions is not a basic function of amniotic membrane.” This statement was not a surprise to MiMedx, nor do we believe it applies to our products as we market them. The reason is that promoting amniotic tissue for use in healing Dermal Ulcers is a much more specific clinical indication than any of the above referenced “intended uses”, which are the homologous uses accepted by the FDA, such as wound healing and wound repair. Fundamentally, it comes down to the “basic functions” of amniotic tissue and its homologous uses. Unfortunately, this Draft Guidance Document does not list all the basic functions of any of the tissues listed. This is understandable, however, because if the FDA provided a complete list, the seven page document could turn into a document of well over 100 pages, making it very unwieldy. Related to amniotic tissue, the Draft Guidance Document only listed a few of the “basic functions,” as the document specifically said that the basic functions “include” the list of functions provided, but in no way indicated these were the only functions. As indicated in this paper, there are numerous basic functions and their related homologous uses of amniotic tissue that have been recognized by the FDA over the past 15 years. 11/4/2015 Page 5 of 10 SECTION 5: GUIDANCE DOCUMENT AND CONGRESSIONAL FOCUS On October 28, 2015, the FDA published, for comment purposes only, Draft Guidance on Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products. The deadline for submitting comments on the draft guidance is April 29, 2016, and FDA has scheduled a public hearing to be held on April 13, 2016, to provide stakeholders with the opportunity to discuss FDA’s policy on regulation of HCT/Ps related to the Draft Guidance, as well as three other draft guidance documents related to HCT/Ps that were published in 2014, including the Draft Guidance on Minimal Manipulation of HCT/Ps. The guidance documents are in draft form and a long way from being final. Even if they become final, they would not be binding on the FDA or the public and will not have the force of law. Moreover, we currently believe our position with respect to the homologous use of our current membrane products is consistent with the positions taken by the FDA in the Draft Guidance. Additionally, we note that the comment period for this Draft Guidance is longer than the initial comment period for the other three draft guidance documents related to HCT/Ps that were issued last year. To rectify that, FDA extended the comment period with respect to those guidance documents to coincide with the due date of the comments on the Draft Guidance on Homologous Use. We hope that extension, as well as the scheduled public hearing on all four guidance documents, is evidence of a willingness on behalf of FDA to be more collaborative with industry and other stakeholders in the development of its guidance. We also note, however, that guidance documents cannot amend the existing regulations or dramatically change a well-established regulatory scheme. Such changes may only be accomplished through formal notice and comment rulemaking pursuant to the Administrative Procedure Act. To the extent these guidance documents can be read effectively to amend the current regulations, we believe that a more complete process is required for such rules to be finalized. There have been significant concerns with the way the FDA has been using Guidance Documents to attempt to modify or change regulations. These concerns have developed over an extended period of time, and they relate to biologics, pharmaceuticals and medical devices. By law, the FDA may not make substantive changes to rules without going through what is called the “Notice and Comment Rule Making Process.” This process requires, among other things, that the FDA must take into account the comments of industry and other stakeholders and give a reasoned explanation for rejecting comments. Attached is a letter to FDA Commissioner Margaret Hamburg, dated May 6, 2014 from Senators Lamar Alexander, Richard Burr, Johnny Isakson and Orrin Hatch10. This letter was specifically focused on the concerns that these Senators, some of whom are Committee Chairmen, had about Draft Guidance Documents being used in an attempt to make substantive policy and regulatory changes. The letter highlights four major concerns about the use of Draft Guidance Documents. This letter should be reviewed in the context of the other information that appears in this document. 10 May 6, 2014 Letter to Commissioner Margaret Hamburg from Senators Alexander, Burr, Isakson and Hatch http://www.hpm.com/pdf/blog/AlexanderFDAGuidanceLetter.pdf 11/4/2015 Page 6 of 10 There have been instances in which the FDA has released a Draft Guidance, provided industry 60 days to comment, and then implemented final guidance that included substantive changes to policy and regulations. Such an approach would be violative of the APA to the extent that substantive policy and rule changes were effected. In the MiMedx Press Release of October 29, 2015, the Company took the position that the FDA’s decision to hold a Good Guidance practice “notice and comment” hearing on April 13th was positive since the hearing is designed to allow industry and outside sources to communicate with the FDA relative to the issues highlighted in its Draft Guidance Documents. In the previous related Draft Guidance Document on Minimal Manipulation, which was filed in December of 2014, the Agency’s process was more truncated, initially allowing only a 60 day comment period. FDA received numerous comments from multiple trade associations and manufacturers on the process it was attempting to utilize to implement this Guidance. Subsequently, the agency changed its approach, delaying comments on the Minimal Manipulation Draft Guidance in order to allow for the more fulsome procedure now afforded. It is important to note that before these draft documents become finalized after the April 13th meeting, we expect there will be Congressional oversight if the Guidance Documents represent substantive changes to the regulations. Typically, this process could take a couple of years or longer. However, this certainly ensures that all interested parties have had time to provide scientific input, clinical input, and discuss the unintended consequences of such regulatory changes. Generally speaking, we expect industry would have no issues if a process of this nature is conducted through the issuance of regulations in accordance with the law, including the APA. MiMedx is on record stating that some additional oversight into certain commercialization of human tissue is appropriate so that corporate entities without sufficient expertise do not cause issues for patients, physicians or this industry segment. As additional insight into Congressional overview of the FDA, the House Energy and Commerce Committee’s Subcommittee on Oversight and Investigations has initiated an inquiry into the FDA’s practices related to issuance of Untitled Letters and use of Guidance Documents to change rules and policies. The practices being investigated by the House Subcommittee are similar to those that were experienced by the Company in relation to its 2013 Untitled Letter concerning our micronized product line. Reference the letter from Tim Murphy, Chairman of the Subcommittee on Oversight and Investigation of the House Energy and Commerce Committee.11 In conclusion, it is clear there is significant interest by Senators and Congressmen and their staff on the matter of the FDA’s Guidance Documents. These individuals appear to be well informed on the subject because of the potential dire impact of regulatory changes without proper oversight. SECTION 6: TISSUE REGULATION HISTORY Human tissues have been used as therapeutic products for more than one hundred years, but they were not regulated by FDA until late in the twentieth century. Human tissues were not regulated as drugs when the Federal Food, Drug, and Cosmetic Act (FDCA) was enacted in 1938, or when it was amended in 1962. 11 May 27, 2015 Letter to Acting Commissioner Ostroff, M.D. From Congressman Tim Murphy http://www.fdanews.com/ext/resources/files/05-15/05-29-15-untitledletters.pdf?1432933418 11/4/2015 Page 7 of 10 Human tissues also were not regulated as biological products when the Public Health Service Act (PHSA) was enacted in 1944, or when responsibility for the PHSA was transferred to FDA in 1972. Nor were human tissues regulated as medical devices when the Medical Device Amendments were passed in 1976. Instead, human tissue regulation was left to the states and to voluntary quality assurance programs, particularly those established in 1976 by the American Association of Tissue Banks (AATB). FDA began asserting its authority over human tissue products during the late 1980s. For instance, in 1987, FDA declared imported human dura allografts to be adulterated devices because they were not "process[ed] and handle[d] ... according to guidelines such as those of the [AATB]." In 1991, FDA announced that it would regulate heart valve allografts as devices. Those efforts led to rulings from both the U.S. District Court for the District of Maryland and the Seventh Circuit suggesting that FDA had violated the Administrative Procedure Act (APA) by attempting to regulate tissue products without ”Notice and Comment”. Beginning in 1993, FDA sought to develop a more comprehensive approach to human tissue products. That effort, which lasted more than a decade, began with an interim rule establishing new requirements for donor testing, recordkeeping, inspections, and recalls for human tissues in Part 1270 of Title 21, CFR. The interim rule was intended "to prevent the transmission of communicable disease" and was promulgated pursuant to FDA's authority under section 361 of the PHSA, 42 U.S.C. § 264. In 1997, FDA proposed a "new regulatory framework for cells and tissues that would protect the public health without imposing unnecessary government oversight." This framework would "provide adequate protection of public health… while enabling investigators to develop new therapies and products with as little regulatory burden as possible. “Proposed rules regarding registration and listing were published in 1998. FDA's preamble made clear that covered products would be regulated "solely" under Section 361 of the PHSA and would not be subject to premarket clearance. The registration and listing rules were finalized as Part 21 CFR in January of 2001. Additional rules regarding donor eligibility and good tissue practices were soon added. Together, these rules form a "comprehensive" system intended to encourage "significant innovation." The linchpin of that system is 21 C.F.R. § 1271.10, which lists the requirements that must be met to qualify for regulation "solely" under section 361. Minimal manipulation includes, for structural tissues, "processing that does not alter the original characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement." Homologous uses include, for any type of tissue, "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." These provisions recognize that a given type of human tissue can have more than one homologous use and that the extent of manipulation must be evaluated in terms of the characteristics that are relevant to the specific homologous use or uses for which the tissue product is intended. Additional clarity was provided in the preambles published with the Part 1271 regulations. The final preamble from 2001 stated that FDA would consider the following procedures, among others, to be examples of minimal manipulation: "sterilization," "separation," "lyophilization", (dehydration), and "cutting, grinding, or shaping." The same preamble also stated that FDA "intend[ed] to interpret 'nonhomologous' narrowly." Products derived from amniotic membranes are among the best known and among the most widely used human tissue products in modern medicine. Literature reports regarding the therapeutic use of amniotic 11/4/2015 Page 8 of 10 membranes predate World War 1. By the early 1980s, the use of amniotic membranes as an adjunct in wound healing, particularly open or chronic wounds like burns or ulcers, was a common practice. Unsurprisingly, FDA addressed amniotic membrane products during the development of the Part 1271 regulations. In 1997, FDA suggested that amniotic membrane would not be used in a homologous fashion if used for wound healing-the agency speculated that wound healing involves the growth of new cells, which is not a function that the amniotic membrane "normally perform[s] in utero." A similar statement was contained in the 2001 final preamble. These statements drew strong objections from industry, and they were subsequently repudiated by the agency. Specifically, in November 2001, FDA ruled that amniotic membrane products marketed by Bio-Tissue, Inc. qualified for regulation as HCT/Ps. FDA found that preserving and freezing the amniotic membrane was minimal manipulation, as long as the cells are not viable after processing. FDA also found that the amniotic membrane functions in utero as (1) a physical barrier; (2) an anti-scarring agent; (3) an antiinflammatory agent; and (4) an anti-angiogenic agent. According to FDA, amniotic membrane products provide the same four functions when used on the ocular surface. In 2004, this decision was referenced in the final preamble for FDA's Good Tissue Practices, which stated that the use of amniotic membrane for ocular repair is homologous. In 2005, FDA again addressed the legal status of amniotic membrane tissue when it concluded that a decellularized product marketed by OKTOS Surgical Corporation (OKTOS) and processed by Celgene, did not qualify for regulation as an HCT/P when marketed for certain homologous uses. FDA recognized that "dehydration and decellularization…constitute minimal manipulation when the amniotic membrane is used as a wound covering." OKTOS, however, also marketed its product as an adjunct in wound repair and wound healing. FDA recognized that those uses also were homologous, but concluded that the process used by OKTOS resulted in more than minimal manipulation because it removed cytokinecontaining cells, which reduced the tissue's "ability to actively mediate wound repair and wound healing." Several lessons can be drawn from these FDA decisions. First, the in utero functions of amniotic membrane tissue include not just acting as a physical barrier, but also acting as an anti-scarring, antiinflammatory, and/or anti-angiogenic agent. The potential homologous uses that derive from those functions include, at a minimum, ocular repair, wound covering, wound repair, and wound healing. Second, the permissible forms of minimal manipulation for amniotic membrane include preserving, freezing, and dehydration. Finally, decellularization does not constitute minimal manipulation for the homologous uses of wound repair and wound healing if the process results in the removal of cytokinecontaining cells because such removal would interfere with the tissue's ability to actively mediate wound repair and wound healing. Cytokines and other types of proteins are well-known influencers and mediators of things like cell proliferation, cell migration, angiogenesis, and so forth. In August 2007, FDA issued a guidance for immediate implementation stating that amniotic membrane products meet all of the requirements in 21 C.F.R. § 1271.10(a). Similarly, in May 2009, the Cellular, Tissue and Gene Therapies Advisory Committee met to consider the risk of transmission of certain infectious diseases posed by gestational tissues. The Issue Summary prepared by CBER staff identified amniotic membrane and cells as having the following recognized uses: 11/4/2015 Page 9 of 10 Wound dressing, treatment for leg ulcers, skin loss, reconstruction of the pelvic floor, vaginal epithelialization, oral cavity reconstruction, replacement of nasal mucosa, ear surgery, and in otolaryngology procedures, ocular repair, stem cells During this meeting, the Committee received an update on the "Current Scope of Manufacture and Utilization" of human amniotic membrane products. The speaker identified products manufactured by MiMedx as among the leading amniotic membrane products on the market and noted that the claims allowed by FDA for such products included "Wound coverage," "Wound repair," "Wound healing," "Antiscarring," and "Anti-inflammatory." After his presentation, a Committee member questioned whether these uses could be considered homologous under the Part 1271 regulations. The acting Director of the Division of Human Tissues confirmed that they were. 11/4/2015 Page 10 of 10 APPENDIX Summary of Reference Files Included: 1. 2. 3. 4. Federal Register Vol 66, No. 13, p. 5458, January 19, 2001 November 26, 2001 FDA Letter to Bio-Tissue, Inc. Federal Register Vol 69, No. 226, p 68643, November 24, 2004 Small Entity Compliance Guide; Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); CBER, FDA, August 2007, Page 4 5. Issue Summary; Cellular, Tissue and Gene Therapies Advisory Committee, 47th Meeting, May 14-15, 2009, p 5. 6. Human Amnion, Current Scope of Utilization, Scheffer C. G. Tseng, MD, PhD., CSP BioTissue, Inc.; presentation to FDA; Slide #13 7. Minutes, Meeting of the Cellular, Tissue and Gene Therapies Advisory Committee, CBER, FDA, May 14, 2009; p 126. 8. June 23, 2005 FDA Letter to OKTOS Surgical Corp 9. Dr. Ruth Solomon, HCT/P Regulatory Pathways and Jurisdiction: 361 HCT/P, Biological Product or Medical Device, Sept 8, 2008; Link included as file is too large. http://www.aatb.org/files/HCTP%20Regulatory%20Pathways%20and%20Jurisdiction%2 0-%20Ruth%20Solomon.pdf 10. May 6, 2014 Letter to Commissioner Margaret Hamburg from Senators Alexander, Burr, Isakson and Hatch 11. May 27, 2015 Letter to Acting Commissioner Ostroff, M.D. from Congressman Tim Murphy V. 2015.11.04 1. Federal Register Vol 66, No. 13, p. 5458, January 19, 2001 V. 2015.11.04 5458 Federal Register /Val. 66, No. 13/Friday, January 19, 2001/Rules and Regulations (Comment 28) We received many comments on the term homologous use, which we defined in proposed § 1271.3(d) as follows: Below, in comment 29, we discuss our decision to look not at the actual use of an HCT/P, but at the manufactuer's objective intent for a nonhomologous use. Under this approach, a practitioner Homologous use means the use of a could use an HCT/P, such as cellular or tissue-based product for hematopoietic stem cells or fascia lata, replacement or supplementation and: (1) For structural tissue-based products, for a nonhomologous use in the occurs when the tissue is used for the same treatment of the physician's patients. basic function that it fulfills in its native Thus, we would not look at the surgical state, in a location where such structural use of HCT/P's such as fascia lata or function normally occurs; or pericardium allografts, but instead at (2) For cellular and nonstructural tissuewhether they were advertised, labeled, based products, occurs when the cells or or otherwise objectively intended by the tissue is used to perform the function(s) that manufacturer for a nonhomologous use. they perform in the donor. In the absence of advertising, labeling, One comment praised the definition or other indications of the as reasonable, but urged us to develop manufacturer's intent for such use, we a process for resolving differences of would not require premarket opinion between FDA and tissue Should such review be submissions. manufacturers. Another comment required for a product that has been supported our preamble statement that used safely and effectively for years in the "[b)asic function of a structural nonhomologous ways, and that is tissue is what the tissue does from a intended for a nonhomologous use, we biological/physiological point of view, would expect that data would already or is capable of doing when in its native exist to facilitate the review process. state" (63 FR 26744 at 26749). As an We disagree that the term exampl e, this comment pointed to "homologous use" should be eliminated surgical use of fascia lata or pericardium as a criterion for regulation of human allografts to replace or repair damaged cells or tissues under section 361 of the dura mater or to construct a bladder PHS Act. Regulation solely under support sling from a fascia lata allograft section 361 and part 1271 is not to prevent incontinence. Another warranted unless it is clearly comment questioned whether the demonstrated that the use of an HCT/P homologous/nonhomologous criterion is in the recipient is homologous to the a meaningful indicator of the need for function the HCT/P would carry out in premarket review; this comment cited the donor. We continue to consider fascia lata as an example of a tissue that nonhomologous use to be a meaningful has been used safely and effectively for indicator that regulation solely under years in ways that may be considered section 361 of the PHS Act is not nonhomologous. One comment in sufficient. For example, promotion of an response to our statement (63 FR 26744 HCT/P for an unproven therapeutic use, at 26749) that the use of hematopoietic su ch as curing cancer, would clearly stem cells for treatment of adrenal make it inappropriate to regulate the leukodystrophy is an example of HCT/P solely under section 361 of the nonhomologous use stated that logical PHS Act and the regulations that will be application of hematopoietic stem cells in part 1271. for their known hematologic, We have, however, rewritten the immunologic or metabolic effects as definition of homologous use in treatment of human disease should be response to the comments' concerns. considered within the practice of The new definition (codified at medicine and not subject to regulation § 1271.3(c)) reads: "Homologous use by FDA. means the replacement or Approximately 10 comments argued supplementation of a recipient's cells or that the term " homologous use" should tissues with an HCT/P that performs the be eliminated. Many of these comments same b asic function or functions in the asserted that the term is vague and open recipient as in the donor." The to subjective interpretation. One rewording eliminates the distinction comment stated that the phrase "fulfills between, on the one hand, structural in its native state" implies that tissue tissues and, on the other, nonstructural must be used in the identical place and tissues and cells. The new wording does for identical purposes, which ignores not include the statement that, for the realistic use of most tissue products. structural tissues, homologous use Many comments questioned the occurs "in a l ocation where such application of the term " homologous structural function normally occurs." use" to bone allografts. One asserted This language was understood, contrary to our intention, to limit the use of that it is unusual for allograft tissues to be used in a homologous location, structural tissue to the same location from which is was derived. However, a especially with regard to the spine. use of a stru ctural tissue may be homologous even when it does not occur in the same location as it occurred in the donor. For example, the use of bone for repair, replacement, or reconstruction anywhere in the skeleton of the recipient (including the vertebral column) would be considered homologous use. However, it should be understood that, for the use of a structural tissue to be considered homologous, the HCT/P must perform the same basic function or functions in the recipient as it did in the donor; the use of structural tissue in a location where it does not perform the same basic function as it did in the donor would not be homologous. We intend to interpret "nonhomologous" narrowly. Examples of uses that would be considered nonhomologous include: The use of dermis as a replacement for dura mater, the use of amniotic membrane in the eye, and the use of cartilage in the bladder. As noted above, an HCT/ P that is intended by the manufacturer for one of these uses would not be regulated solely under section 361 of the PHS Act and these regulations, but as a drug, device, and/or biological product. (Comment 29) We received approximately six comments agreeing with our focus in proposed§ 1271.10(b) on the promotion or labeling of HCT/P' s for nonhomologous uses, rather than on their actual use. One of these comments noted that the use of a product should be determined not by the practice of surgeons but by the promotion, labeling, and objective intent of the manufacturer. Another noted that the manner in which we intend to determine homologous use is consistent with the way we determine the intended use of other products under our jurisdiction. Two comments interpreted proposed§ 1271.10(b) as relieving clinicians from restrictions on use of tissue, and one of these comments asserted that the exception should be extended to certain clinical transplant programs. Another supportive comment questioned how we will regulate the labeling of 361 HCT/P's. Among other things, the comment asked whether we will require 361 HCT/ P's to be labeled for their homologous use. The comment also queried whether cutting, shaping, or processing a product in a manner that makes it amenable to nonhomologous use would be considered promotion, in the absence of labeling or advertising. We appreciate the comments on this issue, and we have decided to maintain the regulation's focus on the objective intent of the HCT/P's manufacturer for a nonhomologous use, rather than on V. 2015.11.04 2. November 26, 2001 FDA Letter to Bio-Tissue, Inc. V. 2015.11.04 4 ,4**'"". (., f 0 DEWTM"" H&um&""*" s m w ~ Public Health Service $ * . a . Food and Drug Administration Rockville MD 20857 Office of the Ombudsman 5600 Fishers Lane Room.148-03, HF-7 Rockvil'le, MD 20857 November 26,2001 3 L Regulatory ~ o u n s e i C -3 1301 K Street, N.W. Washington, D.C. 20005 Re: Request for Designation Bio-Tissue, Inc. Amniotic Membrane for Ocular Surface Reconstruction Our file: 2001-016 Dear C We have completed our review of the request for designation (RFD)-for BioTissue's amniotic membrane product for ocular surface reconstruction, fiidd by this office on June 28, 2001. The RFD sought confirmation that Bio-Tissue's amniotic membrane product is a medical device that would be reviewed and regulated by the Center for Devices and Radiological Health. On July 30, 2001, representatives of the Food and Drug Administration and Bio-Tissue held a meeting to discuss the RFD. On September 12, 2001, Bio-Tissue supplemented the RFD with additional information, and agreed to extend the RFD response deadline to give FDA an opportunity to review the new information. Amniotic membrane is the innermost layer of the fetal membrane. It consists of an epithelial layer, a basement membrane, and an avascular stroma. Amniotic membrane encloses the fAtus, and serves as a physical barrier separating the fetus from the surrounding maternal environment. Bio-Tissue submitted information demonstrating that amniotic membrane has four other properties that protect the fetus: an anti-scarring 3 function; and anti-inflammatory function; an anti-angiogenic function; C: C . p :. Bio-Tissue gathers amniotic membrane from women undergoing elective Cesarean section procedures, preserves it with C 2 ,and freezes it at L 3.' No cells, such as corneal limbal cells, are seeded or cultured on the amniotic membrane product described in the RFD. Surgeons use the product to reconstruct the ocular surface when the cornea o i conjunctiva is damaged. Like amrliotic membrane, I According to Bio-Tissue, this method of preservation has been shown to devitalize cells. On July 25, 2001, Bio-Tissue sent FDA a copy of an article concluding that arn~lioticmembrane is no longer viable after processing. Crvopreserved human amniotic membrane for ocular surface reconstruction; Graefe's Arch Clin Exp Ophthalmol(2000),238:68-75. V. 2015.11.04 Bio-Tissue, Inc. November 26,2001 Page 2 the ocular surface consists of an epithelial layer, a basement membrane, and an avascular strorna. The RFD stated that Bio-Tissue's amniotic membrane product P L c include c c, 3 . * A According to the RFD, the effects of amniotic membrane transplantation 3 . -3 Bio-Tissue submitted the RFD seeking confirmation that its amniotic membrane product is a medical device to be reviewed and regulated by CDRH because of its understanding that the product would not be eligible for regulation solely under section 361 of the PHs Act. This understandingwas based on prior FDA statements that the amniotic membrane intended for use in the eye would require premarket approval of a However, when FDA reviewed the information contained in the marketing app~ication.~ RFD, the agency began to reconsider whether the amniotic membrane product described therein is suitable for regulation as a tissue product rather than as a medical device or biologic. As described below, we have now concluded that Bio-Tissue's amniotic membrane product for ocular surface reconstruction meets all the requirements for regulation as a tissue product solely under section 361 of the Public Health Service Act (PHs Act). a tissue may be regulated solely under Under recently adopted reg~lations,~ section 361 of the PHs Act if it meets all the following criteria: the product must be minimally manipulated; the product must be intended for homologous use; the product must not be combiried with a drug or device, except for a sterilizing, preserving or storage agent; and the product must not have a systemic effect and is not dependent on the metabolic activity of living cells for its primary function. 21 CFR 1271.10(a). FDA's prior position that premarket approval of a marketing application would be required was based on the conclusion that use of amniotic membrane in the eye was not a homologous use. Homologous use means the replacement or supplementation of a recipient's cells or tissues with a human cell, tissue, or cellular or tissue based product that performs the same basic function or functions in the recipient as in the donor. 21 CFR 1271.3(c). A tissue's basic function is what it does from a biological/physiological point of view, or is capable of doing when in its native state. The use of a tissue product may be homologous even when it does not occur in the same location as it occurred in the donor. See the Proposed Approach to Regulation of Cellular and Tissue-Based Products, February 28, 1997, page 17. See also the preamble to the final rule "Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing," published in the Federal Register of January 19,2001 (66 FR 5447, 5458). 3 21 CFR 1271; Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing, published in the Federal Register of January 19,2001,66 FR 5447. V. 2015.11.04 Bio-Tissue, Inc. November 26,2001 Page 3 Bio-Tissue's RFD contained new detailed information about the ways in which its amniotic membrane product performs its protective function in utero, and how it performs when transplanted to the ocular surface. We conclude that amniotic membrane acts as a physical barrier against the external 'environment both in utero and on the; ocular surface. In addition, Bio-Tissue presented persuasive information that both in utero and on the ocular surface, the amniotic membrane product described in the RFD acts as anti-scarring agent, an anti-inflammatory agent, and an anti-angiogenic agent, and c.. 3 After considering this new information, and consulting with appropriate officials in the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research, FDA now concludes that Bio-Tissue's amniotic membrane product for ocular surface reconstruction, as described in RFD 2001.016, meets the criteria contained in 21 CFR 1271.10(a), including homologous use. Accordingly, the product is suitable for regulation solely under section 361 of .the Public Health Service Act and the regulations promulgated thereunder at 21 CFR Parts 1270 and 1271. Sincerely yours, Steven H. Unger Ombudsman V. 2015.11.04 3. Federal Register Vol 69, No. 226, 68643, November 24, 2004 V. 2015.11.04 Federal Register / Vol. 69, No. 226/ Wednesday, November 24, 2004/ Rules and Regulations spread of communicable disease. We have removed proposed paragraph (b); § 1271.370 no longer covers claims. (Comment 149) One comment on proposed§ 1271.370{b) asserted that HCT/ Ps with claims for reconstruction or repair should be regulated under section 351 of the PHS Act because it cannot be assumed, in the absence of substantial clinical evidence, that these products perform as intended. The comment provided as an example autologous expanded cartilage. (Response) As previously noted, we have removed the proposed provision on claims from§ 1271.370. However, the comment's scope extends beyond the proposed language, and for that reason we note our disagreement. HCT/ Ps with claims for "reconstruction or repair" can be appropriately regulated solely under section 361 of the PHS Act if such HCTIPs meet all of the criteria in§ 1271.10, including minimal manipulation and homologous use. To further clarify this point. we have added the terms "repair" and " reconstruction" to the definition of "homologous use" under§ 1271.3(c). The example provided by the comment is not appropriate. Autologous expanded cartilage cells are not regulated solely under section 361 because they are more than minimally manipulated when they are cultured and, thus, do not meet the criteria in § 1271.10. (Comment 150) Two comments asserted that proposed§ 1271.370(b)(2) is unnecessary and could create confusion regarding the definition of homologous use. These comments suggested removing the paragraph in question and allowing the existing definition of "homologous use" to stand as the sole definition. (Response) We agree with this comment and have removed the proposed paragraph on claims from § 1271.370. "Homologous use" is defined in§ 1271.3(c)(the registration final rule) as "the 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." As previously noted, we have added reconstruction and repair to the definition of "homologous use" under § 1271.3(c). (Comment 151) One comment asserted that we should clarify this rule to identify examples of homologous use claims. (Response) This rule no longer contains language relating to homologous use claims. However. we take this opportunity to note that the examples of homologous and 68643 nonhomologous claims given in the registration final rule are still valid, with one exception (see 66 FR 544 7 at 5458). After reviewing additional data from one manufacturer, we now consider the use of that manufacturer's minimally manipulated amniotic membrane alone for ocular repair as homologous. However, when amniotic membrane is combined with limbal stem cells, such an HCT/P is regulated under section 351 of the PHS Act. existing FDA practice. To date, both EBAA and AATB have participated in regional training courses for FDA representatives, and we hope to continue this useful practice. The suggestion that special recognition be given to establishments that are accredited by a professional association has already been implemented, in that we give establishments that are not accredited a higher priority for inspection. (Comment 153) One comment E. Part 1271, Subpart F-Inspection and suggested amending§ 1271.400 to Enforcement of Establishments require that FDA representatives be Described in§ 1271.10 appropriately trained to examine establishments that manufacture HCT/ 1. Applicability(§ 1271.390) Ps according to the type of tissue Proposed subpart F of part 1271 manufactured by the facility. contains provisions on inspections; (Response) We decline to modify HCT/Ps offered for import; and orders of § 1271.400 as suggested. FDA retention, recall, destruction, and representatives receive significant cessation of manufacturing. Subpart F training on an ongoing basis, and they would apply only to those will continue to do so. establishments described in§ 1271.10 (Comment 154) One comment (i.e., those establishments that expressed concern that inspections manufacture HCT/Ps regulated solely would disrupt the practice of under the authority of section 361 of the reproductive medicine. (Response) FDA inspections involve PHS Act and the regulations in part document review; interviewing 1271, and not as drugs, devices, and/or employees; and physical inspection of biological products). We received no equipment, products, labeling, facilities, comments on this section. and operations. We conduct these 2. Inspections (§ 1271.400) activities in a manner that is as Proposed§ 1271.400 would require an unobtrusive as possible, and our establishment to permit an authorized expectation is that: an establishment will representative of FDA at any reasonable be able to conduct business as usual time and in a reasonable manner to during the course of an inspection. FDA inspect the establishment. has extensive experience conducting (Comment 152) In the proposed rule, inspections in a variety of clinical we invited comments on possible settings (e.g., hospital bloodbanks alternative inspection and enforcement performing time-critical activities and provisions that would leverage our confidential donor screening). resources, be cost-effective, and achieve We recognize and understand that the public health goals of the proposed responsible personnel at times may be involved in procedures that make them rule (66 FR 1508 at 1523). We received four comments in response to this temporarily unavailable to the FDA request. These comments suggested representative. In this situation, the third-party inspections, training of FDA FDA representative will perform some representatives by professional other aspect of the inspection that does organizations, and special recognition not require the responsible person's for accreditation. presence until that person is again (Response) We appreciate these available to be interviewed. helpful comments. Instituting a thirdInspections will focus on assessing party inspectional process would compliance with applicable require additional resources (for startup) requirements; to make this clear, we and would also require that have added the word "applicable" to the first sentence of§ 1271.400(a). For establishments have an inspectional history. Because many HCT/P example, the inspection of an establishments do not have an establishment that engages solely in inspectional history, and because of processing would address processingrelated requirements, rather than donor resource limitations, we decline to adopt this approach at present. testing and screening. With respect to However, we intend to reconsid er the establishments that manufacture idea in the future. reproductive HCT/Ps regulated solely The suggestion that the agency and under section 361 of the PHS Act and these regulations, an inspection would industry organizations partner to train FDA representatives is also a good idea, be limited to issues of compliance with and would represent the continuation of the donor-eligibility requirements V. 2015.11.04 4. Small Entity Compliance Guide; Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); CBER, FDA, August 2007, Page 4 V. 2015.11.04 Contains Nonbinding Recommendations 1271.20). These HCT/Ps are subject to section 351 of the PHS Act and/or the act, and applicable 4 regulations in Title 21 of the CFR. 2. For establishments that manufacture a drug, device or biological product that is considered an HCT/P, what must the establishment do if a requirement in 21 CFR Part 1271 conflicts with a requirement in 21 CFR Parts 210, 211, or 820? In the event that a regulation in 21 CFR Part 1271 is in conflict with a requirement in 21 CFR Parts 210, 211, or 820, the establishment must follow the requirements that are more specifically applicable to the product, rather than the more general requirements (21 CFR 1271.150(d)). 3. What are examples of some 361 HCT/Ps that meet the criteria in 21 CFR 1271.10(a)? • • • • • • • • • • • • • • • Amniotic membrane when used alone or without added cells Bone Cartilage Cornea Fascia Ligament Pericardium Peripheral or umbilical cord blood stem cells (for autologous use or use in a first or second degree blood relative) Sclera Skin Tendon Vascular graft Heart valves Dura mater Reproductive cells and tissues (e.g., semen, oocytes, embryos) All of the above are minimally manipulated, intended for homologous use only, and not combined with another article, with some exceptions. 4. For HCT/Ps recovered before May 25, 2005, which subparts of 21 CFR Part 1271 apply? All HCT/Ps recovered before May 25, 2005 are subject to certain regulations in 21 CFR Part 1271, Subpart A (General Provisions) and Subpart B (Procedures for Registration and Listing), as appropriate. In addition, such HCT/Ps are subject to the regulations in 21 CFR Part 1270. The regulations in 21 CFR Part 1271, Subparts C through F do not apply to HCT/Ps recovered before May 25, 2005. 4 Applicable regulations include, but are not limited to, 21 CFR 207.20(f), 210.1(c), 210.2, 21l.l(b), 807.20(d), and 820.1(a), which require establishments to follow the procedures in 21 CFR Part 1271 , Subparts B, C, and D. 4 V. 2015.11.04 5. Issue Summary; Cellular, Tissue and Gene Therapies Advisory Committee, 47 th Meeting, May 14-15, 2009, p 5. V. 2015.11.04 The following table summarizes information about the specific HCT/Ps under consideration: Examples of HCT/Ps Recovered From the Reproductive System or Gestational Tissues Tissue Amniotic Membrane & cells recovered from amniotic membrane Placenta & cells recovered from placenta Cells recovered from menstrual blood Foreskin & cells recovered from foreskin Description Innermost layer of the placental membrane; often used decellularized, either as a surgical patch, or as a rich substrate for seeding other cell types (Ref. 1); decellularized amnion contains collagen fibers, glycosaminoglycans and elastin fibers Fetomatemal organ connected to the fetus by a fetal cord; has a role in transfer of gases and nutrients to the fetus and endocrine function Shed menstrual blood collected into a container processed for long-term storage, and banked/stored Usually from infant foreskin but also may use adult foreskin Umbilical cord blood (HPC-C) Blood which remains in the umbilical cord of a newborn, after clamping, is collected, processed for long-term storage, and banked/stored (Ref. 13) Placental blood derived stem cells Extracted from placenta after placental/umbilical cord blood is recovered (Ref. 16) Examples ofProducts/Uses Wound dressing, treatment for leg ulcers, skin loss, reconstruction of the pelvic floor, vaginal epithelialization, oral cavity reconstruction, replacement of nasal mucosa, ear surgery, and in otolaryngology procedures (Ref. 2), ocular repair, stem cells (Ref. 3) Used to replace or supplement damaged or inadequate integumental tissue; Stem cells (Refs. 4-5) Stem cells (Refs. 6-8) Fibroblast cells used as component of a cell/scaffold product (Refs. 9-10); Research ongoing re: potential for stem cells (Refs. 11-12) Hematopoietic stem cells derived from cord blood used for reconstitution of the hematopoietic system during the treatment of malignant and nonmalignant diseases, most commonly in pediatric patients (Refs. 14- 15) Used in conjunction with cord blood for hematopoietic reconstitution (Refs. 17-19) V. 2015.11.04 6. Human Amnion, Current Scope of Utilization, Scheffer C. G. Tseng, MD, PhD., CSP BioTissue, Inc.; presentation to FDA; Slide #13 V. 2015.11.04 • Corneal Diseases - Persistent Epithelial Defects - Corneal Ulcers (central or peripheral) - Descemetocele or Pertormation - Neurotrophic Keratitis - Bullos Keratopathy - Band Keratopathy - Following Removal of Corneal Scar • Devastating Diseases - Chemical Burns, StevensJohnson Syndrome - High-Risk PKP • Conjunctival Diseases - Primary &Recurrent Pterygia Pingueculae Tumors Conjunctivochalasis Superior Limbic Keratoconjunctivitis Scars and Symblepharon V. 2015.11.04 7. Minutes, Meeting of the Cellular, Tissue and Gene Therapies Advisory Committee, CBER, FDA, May 14, 2009; p 126. V. 2015.11.04 125 portion of the and impression just for definition , my I need but some I had the clarification that understanding that included an application which was homologous . This 1s not a homologous application , as I understand it . DR. TSENG: as a it ' s homologous not surface , Structurally, functionally . because they It was designated by FDA are the amnion two and different the eye types of tissues . MEMBER GERSON: Yes , I got that par t . (Laughter.) My understanding of just DR . But TSENG: maybe Martha can clarify t his. MS . WELLS: Actually , there was some controversy on this in the beginning that we did say initial l y that homologous use. call the this would be a non- Then we went through what we request for designation Your biotissue provided a process . lot of information NEAL R. GROSS COURT REPORTERS ANDTRANSCRIBERS (202) 234-4433 1323 RHODE ISLAND AVE., N.W. WASHINGTON, D.C. 20005-3701 V. 2015.11.04 IWIW.nealrgross.com 126 that convinced homologous use barrier the in FDA that because eye , this it ' s similar would be a acting as a to the barrier So we did that it is i n its original site . determine that this would be a homologous use for utilization for corrections of issues in the ocular reconstruction . That ' s very helpful. MEMBER GERSON : Thank you. ACTING CHAIRMAN URBA : MEMBER ALLEN: questions . One processing . I this amniotic relates Dr . Allen? I have to procurement at quick and guess it seems like you take layer and split the histology , it from the I guess , from chorion when you ' re processing. looking two it they ' re intimately in contact , looks obviously. like So you have this membrane and then you have this cellular element. Is there any quality control in terms of making sure that there aren ' t inherent cells on that tissue? NEAL R. GROSS V. 2015.11.04 COURT REPORTERS ANDTRANSCRIBERS 1323 RHODE ISLANDAVE., N.W. (202) 2344433 WASHINGTON, D.C. 20005-3701 www.nealrgross.com 8. June 23, 2005 FDA Letter to OKTOS Surgical Corp V. 2015.11.04 11/2/2015 Untitled Letters (Biologics) > AmbioDry Amniotic Membrane Tissue Grafts U.S. Food and Drug Administration Protecting and Promoting Your Health Archived Content The content on this page is provided for reference purposes only. This content has not been altered or updated since it was archived. AmbioDry Amniotic Membrane Tissue Grafts OKTOS Surgical Corp June 23, 2005 Mr. Erich Zieler OKTOS Surgical Corporation 3151 Airway Avenue Suite I- 1 Costa Mesa, CA 92626 Re: AmbioDry Amniotic Membrane Tissue Grafts Dear Mr. Zieler: The Office of Compliance and Biologics Quality (OCBQ) in the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has reviewed your internet website http://www.oktoophtho.com for the AmbioDry Amniotic Membrane Tissue Grafts (AmbioDry). Copies of the pertinent Internet website pages are enclosed for your reference. Dehydrated, decellularized amniotic membrane, such as AmbioDry, is a human cell, tissue, or cellular or tissue-based product (HCT/P) regulated under section 361 of the Public Health Service Act (PHSA) and 21 CFR Parts 1270 and 1271, as long as it complies with the criteria in 21 CFR 1270.10(a). One of these criteria is that the HCT/P be minimally manipulated (21 CFR 1271 .1O(a)(1 )), which is defined for cells and nonstructural tissues as "processing that does not alter the original relevant biological characteristics of cells or tissues" (21 CFR 1271.3(f)(2)). A characteristic is "original" if it is present in the tissue in the donor. A characteristic is "relevant" if it could have a meaningful bearing on how the original tissue performs. We have concluded that dehydration and decellularization of amniotic membrane constitute minimal manipulation when the amniotic membrane is used as a wound covering . Such manipulations do not alter the original characteristics of the HCT/P in a way that could have a meaningful bearing on how the HCT/P performs as a wound covering. However, your website describes AmbioDry's use for wound repair and wound healing , uses that are based on complex interactions between the wound and the product, which actively mediates the healing process through the action of biologically active proteins produced by the cells that reside in this tissue. Examples from your website of wound repair and wound healing claims for your product include: • "The proprietary AmbioDry tissue process removes the cellular components within the tissue to allow for healthy host revascularization and normal healing integration within the patient's body." • "The recent availability of AmbioDry Deyhdrated (sic) Amniotic Membrane Allografts for pterygium surgery has provided surgeons with better results that (sic) traditional therapies." Pterygium surgery involves reepithelialization, a process that is V. 2015.11.04 http://www .fda.gov/Bi ologicsBI Q(J(jl/acci nes/Gui danceCom pi ianceRegulatorylnformation!Com pi ianceActivi ties/Enforcem ent/U ntitledletters/ucm091804.htm 1/2 11/2/2015 Untitled Letters (Biologics)> AmbioDry Amniotic Membrane Tissue Grafts actively mediated by cellular factors. • "Our main goal with the AmbioDry technology has been, and continues to be, to replace the time consuming techniques traditionally employed by ophthalmologists for the treatment of pterygium," stated Erich Ziegler, President of OKTO Ophtho." FDA has recognized that amniotic membrane that has not been dehydrated or decellularized may be used for wound repair and wound healing . However, the dehydration and decellularization of AmbioDry alters the characteristics of the original amniotic tissue in a way that could have a meaningful bearing on how the HCT/P performs when used for wound repair or wound healing. More specifically, based on a review of the published literature and other data available to the agency, FDA has concluded that removal of cytokine containing cells from this tissue would interfere with human amniotic membrane's ability to actively mediate wound repair and wound healing. Therefore, when intended for these uses, AmbioDry is more than minimally manipulated and does not meet the criteria in 21 CFR 1271 .1O(a)(1) for regulation solely under section 361 of the PHSA and 21 CFR Parts 1270 and 1271. The wound repair and wound healing claims described in your website require a pre-market application or notification before the product may be legally marketed. We also note that the articles listed on the "References" page of your website raise concerns which we would like to discuss with you. To the extent that these articles describe wound healing and wound repair uses of amniotic membrane that is minimally manipulated, the articles have very limited relevance to AmbioDry, which is more than minimally manipulated . AmbioDry may continue to be regulated under Section 361 of the Public Health Service Act and 21 CFR Part 1270 and 1271 as a 361 HCT/P only if all materials are revised to indicate that this product is only intended for wound covering. Please submit a written response to this letter within 10 business days of the date of this letter, describing your intent to comply with this request, listing all materials for AmbioDry that contain claims the same as or similar to those described above, and explaining your plan for discontinuing use of such materials . Please direct your response to Mr. Glenn N. Byrd, Chief, APLB, at the Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448, facsimile 301-827-3528. We remind you that only written communications are considered official responses . If you choose to revise your materials, APLB is willing to assist you in assuring that your revised materials comply with applicable statutes and regulations by reviewing your revisions before you use them. Sincerely, ----- signature ----Robert A. Sausville Director, Division of Case Management Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research Enclosure: More in Untitled Letters (Biologics) 1/BioloaicsBioodVaccines/GuidanceComolianceReaulatorvlnformation/ComolianceActivities/Enforcement/Untitledletters/default.htfn) V. 2015.11.04 http://www .fda.gov/BiologicsBioodVaccines/Gui danceCom pi ianceRegulatorylnformation/Com pi ianceActivities/Enforcement/Untitledletters/ucm091804.htm 2/2 9. Dr. Ruth Solomon, HCT/P Regulatory Pathways and Jurisdiction: 361 HCT/P, Biological Product or Medical Device, Sept 8, 2008; Link included as file is too large. http://www.aatb.org/files/HCTP%20Regulatory%20Pathways%20and%20Jurisdiction%2 0-%20Ruth%20Solomon.pdf V. 2015.11.04 10. May 6, 2014 Letter to Commissioner Margaret Hamburg from Senators Alexander, Burr, Isakson and Hatch V. 2015.11.04 T036. I MR KIN, IOWA, HMRMAN HAHBAHAA. MIKULSKI, was" manner-n. rates we rm.- MICHAEL a. run. m. marom' Inca-man URH. noun cam-nuns nearer P. user, at. max-son. croscm raw n. "me. sane rant. an AL ramsrn, MINNESOTA onnrn i-mcn. umn "l tf ta a tl: MICHAEL F. smart. coumaoo FAT nosrm's, Kansas sartrion WHIIEHUUSE, ISLAND USA MuaKowssl. IMAMY sALowm, than: KIRK, - cnnisroPI-ira s.swarm,constencut COMMIT-1 EE ON LABOR, AND PENSIONS WASHINGTON, DC 205100300 PAMLLA J. DIRECTOR DAWD P. CHEARY. DIRECTOR May 6, 2014 The Honorable Margaret Hamburg Commissioner US. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20093 Dear Commissioner Hamburg: We write today to express signi?cant concern about the US. Food and Drug Administration?s (FDA) use of draft guidances to make substantive policy changes. According to the FDA website, ?Level 1 guidances set forth the agency?s initial hiterpretations of new significant regulatory requirements; describe substantial changes in earlier interpretation or policy; and deal with complex scienti?c or highly controversial issues.? Stakeholders tell us that draft guidances are increasingly becoming default FDA policy and position. Draft guidances state that the ?guidance document is being distributed for Comment purposes only.? However, in the absence of finalized guidance, drafts are the only information that FDA review staff, patients, clinicians, and FDA-regulated entities have on the agency?s most current thinking on important issues. One major Concern is that the agency?s website does not differentiate between draft and ?nal guidances, making it seem that the documents have equal weight, and undercutting the important purpose of soliciting public comment on draft guidances. A second concern is that these draft guidances are not being revised, ?nalized, or withdrawn in a timely manner. We believe that public comment from FDA-regulated entities, health care providers, consumers, and patients not only will help shed light on any unintended consequences of the agency?s draft guidance, but better inform and, ultimateiy, improve that guidance. It is integral that those improvements are re?ected in updated guidance documents and the guidance is being appropriately and consistently applied by product reviewers. Third, we are concerned that, although the agency?s draft guidances state that the ?guidance document is being distributed for comment purposes only,? in the absence of ?nalized guidance these drafts are the only information that FDA review staff, patients, clinicians, and FDA- regulated entities have on the agency?s most current thinking on important issues and feel compelled to follow draft guidances as if they were ?nal. V. 2015.11.04 For example, at the Health, Education, Labor and Pensions Committee Hearing on Thursday, March there was a discussion on the guidance on abuse-deterrent formulations and you said that ?the guidance is very important and lays out how we?re thinking about it?, yet that guidance is still in draft form and states ?Not for implementation.? Another example: draft guidance, published in June 2013 on cyclosporine emulsion bioequivalence, is still available in draft form even after doctors and patients, including the American Academy of Ophthalmology and American Glaucoma Society, submitted comments expressing concerns regarding the safety and reasoning behind the guidance. Because that draft is still available, and is only public statement, FDA application reviewers, drug manufacturers, doctors, and patients may believe that it is the Agency?s current thinking. If that draft guidance is not current thinking, or current thinking has changed due to the concerns raised in the comments, it would be best to withdraw, revise, or ?nalize the draft guidance. In addition, according the President?s Council of Advisors on Science and Technology in the Report to the President on Innovation in Drug Discovery, Development. and Eva/nation, drug manufacturers require greater clarity about how innovative products are regulated. The report states that ?the development of rapid, clear, and thorough guidance documents that re?ect the consensus of the scienti?c community on new and emerging areas of scienti?c innovation could help address this need.? Our fourth concern is that, despite those ?ndings, FDA issues guidance that seemingly does not take into account, or may even con?ict with, the scienti?c community. For example, FDA recently issued a draft guidance on the use of blood glucose monitoring systems in patient care settings, and chose not to follow the international scienti?c community?s recommendation on regulatory standards. To help us better understand the use of guidances to effectively communicate with FDA- regulated entities seeking advice on how to bring life?saving medical products to patients, we respectfully request that you provide information and answers to following questions: 1. A list of all Level 1 Draft Guidances, including the date issued, and the timeline with which you plan to withdraw, revise, or ?nalize each guidance. 2. An update on Agency-wide activities to implement the ?best practices? to make the ?nalization of guidance more ef?cient and expeditious, as discussed in the 201 I report Food and Drug Administration Report on Good Guidance Practices: Improving Ef?ciency and Transparency. 3. Have you implemented the President?s Council of Advisors on Science and Technology recommendation to rely more on the biomedical community in help developing and revising guidances, and if so, could you provide examples of speci?c guidances? V. 2015.11.04 4. For the guidances still in draft form, how do you ensure your staff does not follow the guidance in the absence of any other policy or ?nal guidance? 5. What is the average amount of time in calendar days that the FDA has taken to ?nalize draft guidances in the last ?ve years? What is the range? Thank you for your consideration of this request. If you have any questions, please have your staff reach out to Ranking Member Alexander?s staff Grace Stuntz at (202)224-6770. Sincerely, Lamar Alexander Richard Burr Ranking Member US. Senator I ohnny Isaksoh Orrin G. Hatch US. Senator US. Senator V. 2015.11.04 11. May 27, 2015 Letter to Acting Commissioner Ostroff, M.D. from Congressman Tim Murphy V. 2015.11.04 4,1171? :i llri'r i-u of incurs iiH?JlSt? oi i i i 111:: ill i Hi} 1' t'lr'_ Ii May 27, 2015 The Honorable Stephen Ostroff, MD. Acting Commissioner Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20903 Dear Dr. Ostroff: Pursuant to Rules and XI of the US. House of Representatives, the Committee on Energy and Commerce is examining the Food and Drug Administration?s (FDA) policies and practices regarding the use and publication of untitled letters, including whether such policies and practices are consistently fair, effective, and ef?cient in gaining compliance. In the event ofa violation of the Federal Food, Drug, and Cosmetic Act, FDA may give individuals and ?rms an opportunity to take voluntary and prompt action to correct the violation before the FDA initiates an enforcement action.I FDA will issue either a warning letter or an untitled letter to individuals or ?rms notifying them of such violations to allow them to voluntarily comply with the law. Warning letters are used for violations that may lead to enforcement action ,if not and adequately corrected. Untitled letters request correction of violations that do not meet the threshold of regulatory signi?cance for a warning letter.2 Further. unlike warning letters, untitled letters do not include a statement that FDA will advise other federal agencies of the issuance of the letter so that they may take this information into account when considering the awarding of contracts. While every FDA center that issues untitled letters has posted some of these letters, each center has its own policy on which letters get posted. For example, the Center for Drug Evaluation and Research (CDER) only posts untitled letters related to advertising and promotional labeling, the Center for Food Safety and Nutrition CF SAN) posts untitled letters related to violations from manufacturing controls or labeling that do not meet the threshold of regulatory signi?cance for a Warning Letter, or that are issued to lntemet websites (cyber letters), while the Center for Veterinary Medicine (CVM) posts all untitled letters 1 FDA Regulatory Procedures Manual (RPM), Chapter 4: Advisory Actions (March 2009) FDA RPM 4-2- V. 2015.11.04 Letter to The l-lonorable Stephen Ostroff, MD. Page 2 issued by the Center, but not those issued by the ?eld of?ces. Other centers have still different policies. recent handling of an untitled letter illustrates questions raised about the issuance and posting of such letters. In this instance, an FDA inspection ofa ?rm resulted in a No Action Indicated classi?cation; an FDA Form 483, which lists inspection observations that may indicate an DA-regulated product is in violation of FDA requirements, was not issued. More than a year later, the ?rm received an untitled letter from FDA asserting a violation based on information collected during the insPection. FDA also sent the untitled letters to the ?rm?s related distributors. The violation alleged by FDA was based on the agency?s conclusion that the ?rm?s product should also be regulated as a drug, not just as a biologic, because the ?rm?s manufacturing process did not meet a certain criterion. The letters did not mention how the information collected during the inspection supported the basis for conclusion. Three business days after sending the untitled letters, FDA publicly released the letters on its website, a rapid posting in comparison to other similar instances.3 By 12:55 pm. on the day of the letters? release, the business press had published an article about the untitled letters. At one point on the same day, the stock price for the ?rm?s shares declined 70 percent before recovering some of its losses for a net loss of 36 percent in share price in one day. A shareholder lawsuit was ?led against the ?rm related to the untitled letter and is still in litigation. The FDA Regulatory Procedures Manual explicitly aims to limit the economic impact of an untitled letter by noting that unlike a warning letter an untitled letter does not include a statement that about notifying other federal agencies, yet FDA posted the untitled letters during the trading session that were likely to affect the markets and before the ?rm was able to engage with FDA about its concerns and take corrective action. Policies and practices surrounding untitled letters would address not just the timing of their release, but whether suf?cient details are included about the basis for conclusion of a violation and the adequacy of notice of a violation. Again, in this instance it is not clear that practices are consistently fair, effective, or ef?cient. For several weeks, the ?rm sought details from FDA about the basis for the violation. After about 90 days, FDA issued a second letter to the ?rm including reasons for its conclusion. More than a year after the issuance of the second letter, FDA published a draft guidance governing the ?rm?s product and the basis for conclusion. The draft guidance used similar language and reasoning as the second letter to the ?rm and provided a case-study example that matched the firm?s situation, and seemed to be based on the ?rm?s case. This raises questions about whether the FDA center was using an untitled letter to advance new policies or interpretations without providing adequate prior notice to the ?rm and other manufacturers in this product category. This case study represents some of the broader concerns about the untitled letter practices. Committee staff has heard generalized concerns from individuals involved with different FDA-regulated industries about decentralized, inconsistent practices with 3 For example, a few weeks later the same FDA center sent another ?rm an untitled letter. and did not post the letter until almost a month after its issuance to this ?rm. By that time, this other ?rm was able to announce that it had reached agreement with the FDA on a regulatory pathway for its product. V. 2015.11.04 Letter to The Honorable Stephen Ostroff, MD. Page 3 untitled letters. Some of the inconsistencies involve the publicizing of untitled letters. In some cases, FDA will quickly post the letter on its website. In other cases, committee staff has heard of complaints about Freedom-of-lnfonnation-Act requesters making multiple attempts to get copies of untitled letters that FDA has decided not to make public. Other concerns have been raised about the need for FDA to be more thoughtful about the consequences from the impact of both disclosure and timing of untitled letters on DA-regulated companies, in which FDA purports to seek compliance as opposed to punishment of the ?rm. To assist the committee?s examination, we request that FDA provide a brie?ng to committee staff. In preparation for this brie?ng, please respond in writing to the following by June ID, 2015: l. Do FDA centers use different criteria for issuing untitled letters? If yes, please identify and explain the criteria used by each center, and the rationale for FDA centers using different criteria. If no, please identify and explain the criteria used by all the FDA centers. Please identify and explain the criteria used by each FDA center for posting or not posting an untitled letter, and how many days after the untitled letter is sent to the ?rm until the letter posted on the FDA website. Please also explain why FDA does not have consistent policies and practices among its centers for publishing untitled letters. Do any of the FDA centers use the number of Freedom of Information Act (FOIA) requests to FDA for untitled letters sent to a named ?rm as a basis for posting an untitled letter? If yes, what is the numerical threshold of FOIA requests used, and why does the FDA center have this practice? Regarding the posting on its website of untitled letters that are sent to publicly traded ?rms, could practice be modi?ed to schedule the posting at times after the trading session has closed, after 4:00 pm? If not, why not? What is objective in sending untitled letters alleging violations found by a center (not the inspector) of which the ?rm was not noti?ed during an inspection classi?ed as No-Action-Indicated with no FDA Form 483 and not given an opportunity to correct and/or respond? How is this approach more ef?cient in gaining a ?rm?s compliance than providing prior notice before issuing (or at least some reasonable period of time before posting) and giving the ?rm an opportunity to take corrective action? What evidence does FDA have that supports the superior ef?ciency of this approach? Do any of the FDA centers use untitled letters as a way to announce new regulatory approaches or policies? What due process or other legal considerations apply, if any, to untitled letters that state a ?rm is in violation based on a new application by FDA of regulatory standards without prior notice to regulated industry? How is approach more ef?cient than providing prior notice to the ?rm of the violation and the factual basis in support of conclusion of violation? V. 2015.11.04 Letter to The Honorable Stephen Ostroff, MD. Page 4 8. Does FDA have any awareness of the economic and legal sensitivities associated with posting untitled letters sent to publicly traded companies? How does FDA account for these sensitivities in its policies and practices in posting untitled letters? 9. For each FDA center, what are examples of the ?relatively minor violations? (per an FDA task force) that are the basis for untitled letters issued as a result of inspection? If you have any questions regarding this request, please contact Alan Slobodin with the committee staff at (202) 225-2927. Sincerely, Tim Murphy Chairman Subcommittee on Oversight and Investigations Cc: The Honorable Fred Upton, Chairman The Honorable Frank Pallone, Jr., Ranking Member TheHonorable Diana DeGette, Ranking Member Subcommittee on Oversight and Investigations V. 2015.11.04