FDA Regulation of Stem Cell Therapies. Regulation of adipose derived stromal preps

Transcription

1 2018 FDA Regulation of Stem Cell Therapies Regulation of adipose derived stromal preps

2 EMERGING NEW FIELD BUT STILL A TODDLER Regenerative medicine technologies for orthopedic medicine application has produced basic science and clinical research in investigating the use of stem cells in several areas including, but not limited to: Osteoarthritis 1,2 Articular cartilage repair 3,4 Anterior cruciate ligament (ACL) reconstruction 5 8 Tendon healing 9 12 Meniscus regeneration 13 15

3 References Koh YG, Choi YJ, Kwon OR, Kim YS. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med 2014;42(7): Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 2014;32(5): Anderson JA, Little D, Toth AP, et al. Stem cell therapies for knee cartilage repair: the current status

4 NEW UPDATES ON FDA GUIDELINES Recent FDA documents released over 2 years: CURES Act: Act passed to give FDA guidance. Important part of reg process. FDA has guidance documents. But as we all know, guidance documents are not binding, therefore, are often left to interpretation. This is as a draft form but there are no requirements to issue final document. FDA is supposed to promote: SAFETY INNOVATION Mary Ann Chirba, JD, DSc, MPH

5 Current Good Tissue Practice CGTP Facilities CGTP: CGMPs provide for systems that assure proper design, monitoring and control of manufacturing processes and facilities. Supplies Environment Labeling CGMP Flexible to implement best controls and to allow companies to use current up-to-date technologies. Equipment Storage Donors Distribution

6 FDA REGULATION Love / Hate Relationships Everything that the FDA does should be consistent with these goals. We should NOT be anti-regulation. FDA needs to be faithful to regulations and so do we. We are going to have to learn to steer through this land mine of reg requirements and we CANNOT do this alone. Many of us are silo ed in our private practices and many are trying to come into compliance. What has brought this on. BAD ACTORS

7 FDA Power to Regulate FDA REGULATES CELL & TISSUE PRODUCTS AS PART OF ITS IMPLEMENTATION OF 2 FEDERAL LAWS: FDCA Food, Drug & Cosmetics Act (FDCA, drugs & devices) Public Health & Service Act (PHSA biologics) REGULATION: Can issue draft guidance documents but not required to issue final document. Not required to reply to comments and recommendations. CURES Act requires the FDA to issue guidance documents. They can do this with no obligation to finalize the document and thus can leave it in limbo.

8 Tiered Risk: FDA took a tiered risk approach, to improve health and safety concerns: Communicable disease transmission Unsafe practices Ineffective products, etc. The tiered, risk-based approach is contained in a set of regulations commonly referred to as the tissue rules.

9 Use OF HTCP TISSUES AND CELLS 21 CFR Arose from organ transplants. Sets out the legal framework for manufacturers of Human Cells, Tissue, and Cellular and Tissue based products (HCT/P). An adult stem cell also falls within the FDCA s definition of a drug because it is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease and intended to affect the structure or function of the body.

10 21 CFR Definitions MAY BE GOOD AT END ADDED Indicates that bone marrow and whole blood are not HCT/Ps Except for vascularized organs, some reproductive materials, etc. Adipose tissue at this point is an HCT/P.

11 21 CFR (d) HCT/Ps: Human cells, tissues, cellular or tissue-based products = HCT/Ps. Articles containing bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, semen and other reproductive tissue.

12 Role of 21 CFR (d) cont. The following articles are not considered HCT/Ps: Whole blood or blood components or blood derivative products subject to listing under part 607 and 207 respectively. Minimally manipulated bone marrow for homologous use and not combined with other articles (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow.

13 Blood & Bone Marrow dodged the bullet How did bone marrow and blood get by the FDA? Something cannot be regulated by 2 federal agencies at the same time. Bone marrow and blood are regulated by different federal agencies than the FDA. They had to carve this out is a law and they would have to change the law. Therefore bone marrow and blood, can be exempt so long as you remain compliant with homologous use and other FDA regulations such as culture and expansion, etc. In Europe, it is possible that bone marrow and blood will be considered a drug in the near future.

14 Do s & Don ts DO S AND DON Ts for minimal manipulation: Cutting, sizing, shaping, cleansing are okay for the most part. Physically altering the characteristics of the structural tissue/cell away from or how it is found in the body is not OK. Destroying the structure of the fat tissue to acquire MSCs NO WE WILL LOOSE THIS UNLESS Culture and expansion of cells NO

15 Homologous use origin BMAC: Many cells that serve no function in the tissues where are injecting. However, MSCs mobilize from marrow and can be found in soft tissues, etc. We are placing specific cells contained within bone marrow into tissues that also have the same cells. Homologous use? Probably. Injection of same cells into the IV for systemic use or systemic effect. NOT hom. use!!!

16 Homologous use continued You need to have one or more functions of bone marrow (1271) not all the same functions as bone marrow. Since the MSCs can be found in the periphery serving a regenerative function, secretion of regulatory proteins, etc. we will continue to stick with this argument. So far, so good.

17 Do s & Don ts for homologous use: Saphenous vein graft to transplant to another location in the body. Yes Extract, fat, wash it and use it as a graft for subcutaneous injection in the face or hand. Yes Place that same fat in breast NO You cannot digest fat or process it to release cells (SVF) for use as a treatment. AFG intra-articular: We will loose this tool because of homologous use definition. STRUCTURAL TISSUE

18 Mixing You can mix certain things ie; saline, etc. You cannot mix other articles that would have a biologic effect on the cells. At point of service, some believe you can mix such as PRP and BMAC. Others do not believe you can and state the injections, if you are going to use other products, need to be done separately.

19 21 CFR (b) A little somethings extra part (b) If you are a domestic or foreign establishment that manufactures an HCT/P described in paragraph (a) of this section: 1. You must register with the FDA. 2. You must submit to FDA list of each HCT/P, manufactured. 3. You must comply with other requirements contained in this part. Some believe if you are using these products you are an extension of the manufacture, and you need to register?

20 21 CFR (b) (b) You are not required to comply with the requirements of this part if you are an establishment that removes HCT/Ps from individual implants such HCT/Ps into the same individual during the same surgical procedure. This has been subject to interpretation, used and abused. You have to have a quality system, you can be audited, records, etc. 15(b) allows you not to have to register.

21 The odd thing You are the manufacturer when you acquire and process cells. When you are in the OR or procedure suite with the syringe and needle in your hand you are the physician in the practice of medicine. The land mines

22 What we have been living with FDA draft guidance doc 2014 Oct same surgical procedure. FDA draft guidance doc 2014 dec adipose tissue. FDA draft guidance doc 2015 minimal manip. FDA draft guidance doc 2015 homogous use. Draft guidance: do not have legal authority. There is no precedent established and these drafts are purely advisory. This has been the problem. We have DC d SVF and mourn it s loss.

23 Now we have the guidance doc It does not change a word in The regulatory framework will not be altered BUT You will now have a better understanding We understand better homologous use. We understand better use of adipose tissue and AFGs and SVF. It is not that this does not work

24 3 Catagories of HCTP s No special HCTP Oversight under FDCA Essentially not regarded as GCTP Whole blood, blood derived products Minimal Oversight under PHSA 361 Greater Oversight under PHSA 351 HTCP s are a hybrid and thus can fall into one category, 2 or all 3 catagories. This is where we can get into trouble. What I am frustrated with is how do I REASONABLY come under compliance and pray that they do not destroy this

25 42 U.S.C. 262 (i)(1) An adult stem cell is a biological product under the PHSA because like a therapeutic serum, blood, blood component or derivative, protein or analogous product, it is applicable to prevention, treatment or cure of a disease or condition in human beings. Ok SO FAR : )

26 4 Key Terms: MANURACTURER: A physician becomes a manufacturer of HCT/Ps by engaging in any or all steps in HCT/P recovery, processing, storage, labeling, packaging, or distribution. ESTABLISHMENT: AN establishment is a physician s office, clinic, or any place of business under one management that manufactures HCT/Ps. COMBINING: Combining HCT/Ps with other articles can increase safety concerns and thereby increase the degree of regulatory oversight. REGULATIONS THUS EXEMPT COMBINATION OF HCT/P with water, crystalloids, or a sterilizing, preserving, or storage agent, provided that their addition poses no additional concerns regarding clinical safety.

27 MINIMAL MINIPULATION. THE NEMESIS Minimal Manipulation. The regulation defines it separately for structural tissue and cells nonstructural tissues both are relevant TO ORTHOPEDIC MEDICINE PRACTICE medicine although manipulation of cells and nonstructural tissues is the focus of this discussion. Structural tissue: adipose tissue, bone, cartilage, etc. Non structural tissue: blood, bone marrow blood, fluids 21 CFR

28 Minimal Manipulation Minimal Manipulation. The regulation defines it separately for structural tissue and cells nonstructural tissues both are relevant TO ORTHOPEDIC MEDICINE PRACTICE medicine although manipulation of cells and nonstructural tissues is the focus of this discussion. Structural tissue: adipose tissue, bone, cartilage, etc. Non structural tissue: blood, bone marrow blood, fluids

29 Minimal manipulation cont. For structural tissue minimal manipulation involves processing of the HCT/P that does not alter the original relevant characteristics of the tissue relating to the tissue s utility for reconstruction, repair, or replacement. For cells or nonstructural tissues, minimal manipulation is processing of the HCT/P that does not alter the relevant biological characteristics of cells or tissues. The degree of cell manipulation is critical in determining where an HCT/P will fall in the following three-tiered framework. ü ü ü Category 1: No HCT/P Oversight Category 2: Section 361 Products with Minimal Oversight Category 3: Section 351 s Extensive Regulation of HCT/Ps as Biologics and Drugs

30 Lets look at these 3 important categories. Category 1: No HCT/P Oversight 21 CFR Products in this category are not regulated as HCT/Ps because they are deemed to be of low risk. Category 1 includes vascularized human organs for transplantation, whole blood and blood-derived products, and extracted human products such as collagen and bone marrow that are minimally manipulated, for homologous use and not combined with another article (except for the purpose of sterilizing, preserving, or storing). By default, Category 1 also includes cells that are expressly exempted from Categories 2 and 3, described later.

31 Category 1: No HCT/P Oversight CFR. For us: exemption covers an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure 21 CFR (b) NOTE: This is only if minimally manipulated & complies to homologous use Regs. Not combined with other articles. We must comply with cgtps

32 Category 2: Section 361 Products with Minimal Oversight The FDA views Section 361 products as posing a greater risk with regard to safety and regulates them more extensively to prevent contamination, infection, and disease transmission. Section 361 products that are commonly used in sports medicine include bone, cartilage, ligament, tendon, and skin. 21 CFR To fall within Section 361, these products must be: No more than minimally manipulated which, again, for structural tissue, means preserving the original relevant characteristics of the tissue relating to the tissue s utility for reconstruction, repair, or replacement and for cells or nonstructural tissues, prevents a change in the relevant biological characteristics of cells or tissues during processing, storage, etc. 21 CFR

33 Category 2: Section 361 Products with Minimal Oversight Combined with no other cells, tissues, or articles except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that their addition poses no additional concerns regarding clinical safety. 4. These products must also have either a. No systemic effect or otherwise depend on the metabolic activity of living cells for their primary function or BIO D example b. A systemic effect or depend on the metabolic and for activity of living cells for their primary function, i. Autologous use

34 Bio-D: sold sheets of amnionic membrane for wound cover. Approved Then they said it HELPS the wound heal faster. NO, non homologous use and they Got a letter from the FDA!!!

35 Category 2: Section 361 For cells and nonstructural tissues, certain methods have been expressly characterized as minimal manipulation; that is, as involving no change in cell function or characteristics during processing, storage, and the like. They include the following: Centrifugation Cutting, grinding, or shaping Soaking in antibiotic solution Sterilization by ethylene oxide treatment or irradiation Cell separation Lyophilization Cryopreservation or freezing

36 Category 2: Section 361 Physicians who use or manufacture Section 361 HCT/Ps must employ cgtps, register their office or clinic as an establishment, and submit an annually updated list of each HCT/P manufactured to CBER.30,31 They need not obtain premarketing approval before using the product or follow current Good Manufacturing Practices (cgmps) in preparing them.

37 Category 3: Section 351 s Extensive Regulation of HCT/Ps as Biologics and Drugs Products are most likely to shift from the comparatively relaxed oversight of Section 361 to the more stringent requirements of Section 351 if at least in the FDA s view they present greater risks. While Section 361 focuses on safety and preventing infection and disease transmission, Section 351 concentrates on both safety and effectiveness. For the clinician, this imposes more onerous requirements (such as cgmps and premarketing approval) with little distinction between individuals and small physician practices versus larger pharmaceutical industries. Thus, cells or processing methods that fail to satisfy any of Section 361 s requirements will cast a product into the heavily regulated

38 Category 3: Section 351 s Extensive Regulation Section 351 track A product will fall within Section 351 if more of the following: it is one or More than minimally manipulated, which for cells and nonstructural tissue means to present a risk of change in cell morphology, function, expression, or other relevant biological characteristics during processing, storage, etc. Used for a nonhomologous purpose. 3. Combined with other articles that may pose additional concerns regarding clinical safety. 3. Have a systemic effect or otherwise rely on the metabolic activity of living cells for its primary function, and be used in a context other than autologous use, allogeneic use in a first or second degree

39 Compliance with 351 Section 351: Must register and file list of hct/p requires to list and file each HCT/Ps with CBER each year. Must obtainin formal premarket approval from the FDA. This can involve submitting a IND!!! an Investigational New Drug Application, Biologics License Application, or, when dealing with a Section 501k medical device, a premarket approval application or premarket notification. Costly and time-consuming controlled trials to establish product safety, purity, potency, efficacy, and stability. Also must follow GMP standards which includes Rx prescription drug labeling requirements similar to major pharma. Without this product will be considered adulterated and /or misbranded. as per fdca and phsa. This is true even using autologous cell preps!!!

40 Office based gmp? It may be possible It will be expensive

41 351 vs 361 It must be emphasized that Section 351 applies equally to autologous and allogeneic use in contrast to Section 361, which treats autologous and allogeneic use differently. Consequently, treating a patient with a Section 351 HCT/P means that the physician as manufacturer and the office, clinic, or hospital as establishment are marketing the cell product. Treatment of this kind requires premarket approval even if those cells are to be injected into the same patient from which they were harvested.

42 Navigating the mine field of regulations Determining which regulatory track applies is also difficult because as therapies evolve and technologies improve, definitional ambiguities remain unresolved. In this respect, one of the most difficult challenges is defining what qualifies as minimal versus more than minimal manipulation. This is a key factor in 351 or 361. determining

43 CASE EXAMPLES

44 Intraoperative Isolation of Autologous Bone Marrow Derived Stem Cells by Centrifugation and Injection This is likely to qualify as a Category 1 non-hct/p because the cell product involves a specifically exempted product (bone marrow Is autologous, used for a homologous purpose, and not combined with other articles. Moreover, the FDA has long viewed centrifugation as minimal manipulation. Recent draft guidances,35 37 however, Still some questions exist and ambiguous wording in draft guidelines will be clarified to characterize centrifugation and other means of isolation as it pertains to MM.

45 INTRA OPERATIVE BMAC cont. In this case probably exempt under cat 1. Will probably not have to comply with 351 and file HCT/Ps w/ CBE and provide annual reports, etc. Will not need to file under 361.

46 INTRAOPERATIVE SVF BY CENTRIFUCATION 1. Current regulations treat stem cells derived from bone marrow and fat differently. Bone marrow derived stem cells explicitly qualify as Category 1/nonHCT/Ps but only if they are for autologous and homologous use, minimally manipulated, not combined with articles that raise safety concerns, and have no systemic effect. Adipose tissue derived stem cells are not expressly exempted and, therefore, are typically regulated as Category 2/Section 361 or Category 3/Section 351 products depending on the level of manipulation, intended use, etc. A recent draft guidance would subject adipose stem cells, which are obviously cellular, to the structural as opposed to cellular definition of minimal manipulation. 1-3 FDA. Minimal Manipulation of Human Cells, Tissues and Cellular and

47 Intra-op SVF by centrifugation Adipose tissue derived stem cells are not expressly exempted and, therefore, are typically regulated as Category 2 / Section 361 or Category 3 / Section 351 products depending on the level of manipulation, intended use, etc. This immediately incited a broad array of concerns among clinicians that may sway the FDA to alter its position.

48 Intra-op SVF by centrifugation The scenario described here, however, should involve the kind of same surgical procedure that is exempt from Sections 361 and 351 because we feel so long as it is : Same day Autologous, homologous, qualified for minimal manipulation Harvested, processed and reinjected without interruption of the overall process BUT, based on new draft fda will need to clarify or dismiss its recent draft guidance. a question could be raised as to whether using an adipocyte technically qualifies as homologous use as the cell source fat arguably has little to do with the object of repair. To date, this has not been a regulatory focus but the FDA has signaled that it will examine this more closely.

49 Intra-op SVF by centrifugation For now, this procedure would most likely fall within Category 1 s same surgical procedure exemption as the cells are withdrawn, centrifuged, separated, and reinjected into the same patient, and completed within the same room during a time frame of several hours. Under Category 1, the treatment could go forward with no need to register the establishment, submit lists of HCT/Ps, obtain premarket approval or follow manufacturing or labeling requirements.

50 Examples 1. Isolation by centrifugation

51 Worst case scenario At most, it is likely to fall within Category 2 s relatively minimal Section 361 oversight as cell separation is accomplished through centrifugation, a form of minimal manipulation, and the resulting product will be used autologously. Should Section 361 control, the physician as manufacturer would need to register the office, clinic, or hospital as an establishment with CBER, and also provide CBER with an annually updated list of all HCT/Ps used at that establishment.

52 Intraoperative Selective Isolation of Adipose- Derived Stem Cells through Treatment of the Stromal-Vascular Fraction with Collagenase and Albumin and Injection Collagenase produces a higher yield of MSC We were previously stating that FDA has not formally defined whether or not this constitutes more than minimal manipulation. Several agency warnings and nonbinding guidance documents issued by the FDA indicate that introducing an enzyme to increase yield may qualify as more than minimal manipulation as it may pose a risk of changing cell behavior or characteristics. Now we know this is not disallowed

53 I am going to continue until they stop me

54 Enzymatic SVF..IF IF if We hope!!!!!! if not cat 1 that it will fall under cat 2 section 361: More than minimal manipulation Requires registration and Hct/p listing with cber. If you decide that introduction of collagenase presents little risk to cell morphology and behavior, the fda has broad discretion to disagree. fda informal statements to date suggest that it will characterize SVF with collagenase as more than minimal manipulation, thereby triggering Category 3 s Section 351 requirements.

55 SVF. Slipping out of our control What do we do?? Persuade the FDA to classify this or any specific procedure as minimal manipulation under Category 2/Section 361. The only remaining option is to abide by Section 351 and complete all of the following: Register with CBER Submit lists of HCT/Ps used to CBER Follow cgmps for pharmaceutical drugs Follow prescription drug labeling requirements 3. Undertake the time and obtaining premarket controlled expense involved in approval (including clinical trials)

56 If you do not comply 32 CFR Failing to satisfy any of these requirements will expose the physician and clinic: ü ü ü ü stiff sanctions site inspections permanent injunction shutdown of operations

57 Category 3: Section 351 s Extensive Regulation of HCT/Ps as Biologics and Drugs Section 361 focuses on safety and preventing infection and disease transmission. Section 351 concentrates on both safety and effectiveness. cgmps and premarketing approval

58 Reminder: 351 More than minimally manipulated, which for cells and nonstructural tissue means to present a risk of change in cell morphology, function, expression, or other relevant biological characteristics during processing, storage, etc. Used for a nonhomologous purpose. Combined with other articles that may pose additional concerns regarding clinical safety. Have a systemic effect or otherwise rely on the metabolic activity of living cells for its primary function, and be used in a context other than autologous use, allogeneic use in a first or second degree relative, or reproductive use.

59 2 more points on 351 Harvest of Cells in the United States with Culture, Expansion, and Delayed Injection Overseas Harvest here go over there. Will end up being a 351 under purview of fda Harvest of Cells there and inject there, will be out of jurisdiction of fda To be blunt, it makes no sense for the FDA to insist that a practicing physician

60 Thoughts: What ever the future holds for in office procedures to we will have losses and few gains. It will start to become more expensive and increase operational cost. We may have to have GMP labs WITHIN OUR OWN OFFICES!

61 Historical points in medicine 2000 BCE: Here, eat this root AD: That root is heathen. Here, say this prayer AD: That prayer is superstition. Here, drink this potion AD: That potion is snake oil. Here, swallow this pill AD: That pill is ineffective. Here, take this antibiotic AD: That antibiotic is artificial. Here, eat this root.

62 Historical points in orthopedic medicine 1950 Here lets inject with dextrose 1960 It hurts? Lets cut that out. 1970: Here take this opiod 1980: It hurts? I told you we should have cut that out. 1990: Surgery wont work go exercise 2000: Lets inject PRP 2010: Lets try stem cell injection 2015: Stem cell seems to be working lets mix all this together.

63 Not what but how

64 Thank you Michael N. Brown, MD