12/3/2018. Prof. Steven S. Saliterman Department of Biomedical Engineering, University of Minnesota

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1 Department of Biomedical Engineering, University of Minnesota Prof. Angela Panoskaltsis-Mortari s BMEn 5361, 3D Bioprinting The ensemble of science, bioethics, law, regulation, and intellectual property. FDA 3D Printing, bioprinting and biologicals. Combination products. Investigational device exemption. Humanitarian device exemption. Intellectual Property (IP) 1. What does public opinion drive? 2. Who promotes morality. 3. Where do regulations come from? 4. What about IP? Science e.g. Bioprinting Bioethics Laws & Regulations Adopted from Buechner, B. "Embryonic Stem Cell Research in Law, Ethics and Science: When Law and Ethics Rule, Research Has to Pay?". Cytotherapy 15, no. 4 (Apr 2013): S27-S27. 1

2 Biopharmaceutical Research and Development Disease modeling generally Solid organs and other tissue replacement. Prosthetics and other implants. Models for pre-surgical training. Purpose Replacing diseased tissues and organisms how about for enhancement? Source of Cells Embryonic stem cells how about combined with animal cells? The use of an instrument to manipulate human nature. Eugenics & cloning? New species? Information and consent. Public need to know, privacy and human subjects in experimentation. Safety Unknown risk/benefit ratio vs established therapy. Justice and access. Affordability; availability, commodification (parts as commodity). Patuzzo S, Goracci G, Gasperini L, Ciliberti R. 3D Bioprinting Technology: Scientific Aspects and Ethical Issues. Science and Engineering Ethics. 2018;24(2): Laid the foundation for current guidelines on informed consent and human experimentation. Aswar, U.M. Ethical Principles: Nuremberg code, declaration of Helsinki and Belmonte Report, Sinhgad Institutes, 9/17/2013 2

3 In a letter to the editor of Lancet in 1990, Arthur Caplan a University of Minnesota Ethicist stated: Ethicists have offered opinions about the morality of research proposals and generally support bodies such as institutional review boards to oversee clinical research. The primary hindrance to controlled clinical trials in the USA today is not the regulations that emerged in the 1970s. Nor is it the rantings of ethicists about the immorality of such trials. The morality of randomized trials is being questioned by patient advocacy groups and by many pharmaceutical and device companies. Otto, I. A., C. C. Breugem, J. Malda, and A. L. Bredenoord. "Ethical Considerations in the Translation of Regenerative Biofabrication Technologies into Clinic and Society." [In English]. Biofabrication 8, no. 4 (Dec 2016): 7. In translational medicine, dynamic interactions between scientists, clinicians, ethicists, patients, and other members of society are instrumental in enabling effective scientific progress. 1 Ethics is sometimes regarded as a brake on science, yet in our perspective, ethics provides moral guidance and the incentive to continuously refocus on the scientific direction and its impact van Delden J JMand Bredenoord AL 2015 Future challenges for bioethics: regenerative medicine Global Bioethics: What for? edgsolinis (Paris: UNESCO Publishing) pp Otto, I. A., C. C. Breugem, J. Malda, and A. L. Bredenoord. "Ethical Considerations in the Translation of Regenerative Biofabrication Technologies into Clinic and Society." [In English]. Biofabrication 8, no. 4 (Dec 2016): 7. 3

4 Positive ethical consequences, for example, creating alternatives to animal testing (e.g. drug testing), filling a therapeutic need for minors and avoiding species boundary crossing. There is a need for disease and drug testing models. 3D bioprinting remains an untested clinical paradigm and is based on the use of living cells placed into a human body; there are risks including teratoma and cancer, dislodgement and migrations of implant. Vermeulen, Niki et al. "3d Bioprint Me: A Socioethical View of Bioprinting Human Organs and Tissues." J med Ethics 43 (2017): 7. In 2006, Shinya Yamanaka described successful reprogramming of human somatic cells into a pluripotent state that was similar to ESCs in both its phenotype and transcriptome. Researchers may now pursue the more recently developed Induced Pluripotent Stem Cells (ipsc) technologies, or collect multipotent stem cells (adult/somatic stem cells) for producing pluripotent stem cells for 3D tissue engineering in order to bypass the destruction of human embryos. Li, P., and A. Faulkner. "3d Bioprinting Regulations: A UK/EU Perspective." European Journal of Risk Regulation 8, no. 2 (Jun 2017): Anderson, C. W., et al. "Stem Cells in Cardiovascular Medicine: The Road to Regenerative Therapies." Current Cardiology Reports 19, no. 4 (Apr 2017). Star Tribune, Minneapolis, MN, October 30,

5 Star Tribune, Minneapolis, MN, November 28 & 30, Protecting personal data. Inappropriately extending the human lifespan. Inappropriate cosmetic use. Managing public expectations. Avoiding scientific research exploitation. Conflict of interest of the experts. Transparency of the entire process. Making it affordable. Meeting supply and demand of human or non-human animal transplants. All 116,533 Kidney 95,291 Pancreas 873 Kidney/Pancreas 1,616 Liver 13,698 Intestine 253 Heart 3,861 Lung 1,470 Heat/Lung 46 U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. 5

6 FDA Authority Medical Device Act of 1976 FDA Modernization Act of 1997 Federal Food, Drug and Cosmetic Act (FFDCA) 1997 Medical Device User Fee Act (MDUFA) Generally speaking, under the Federal Food, Drug and Cosmetic Act (FFDCA), manufacturers: Are prohibited from selling an adulterated product; Are prohibited from misbranding a product; Must register their facility with FDA and list all of the medical devices that they produce or process; Must file the appropriate premarket submission with the agency at least 90 days before introducing a nonexempt device onto the market; and Must report to FDA any incident that they are aware of that suggests that their device may have caused or contributed to a death or serious injury. Johnson, J. A., FDA Regulation of Medical Devices, 2016 Mehta, Shreefal S. Commercializing Successful Biomedical Technologies : Basic Principles for the Development of Drugs, Diagnostics, and Devices. Cambridge ; New York: Cambridge ; New York : Cambridge University Press,

7 Device Classification Medical Device Marketing Applications Premarket Approval (PMA) PMA Supplements Evaluations of the PMA and PMA Supplement Process Humanitarian Device Exemption (HDE) 510(k) Notification Substantially Equivalent Device Traditional 510k Abbreviated 510k Special 510k De Novo 510k Postmarketing Surveillance and the National Evaluation System for Health Technology (NEST) Postmarket Surveillance Studies ( 522 Studies ) Adverse Event Reporting Medical Device Tracking The Sentinel Initiative Unique Device Identification (UDI) System Johnson, J. A., FDA Regulation of Medical Devices, 2016 Device Classification Example Safety/Effectiveness Controls Class I Elastic bandages General Controls Examination Glove Hand-held surgical tools Class II Class III Powered wheelchairs Infusion pump Surgical drapes Hear Valve Silicon implants Implanted cerebral stimulators Metal-on-m hip joint Dental implants General & Special Controls General Controls & Premarket Approval General Controls Required Submission Registration only unless 510(k) specifically required 510(k) unless exempt IDE possible PMA application -IDE probable 510(k) notification Johnson, J. A., FDA Regulation of Medical Devices,

8 To Market or 510(k) Notification Substantially equivalent to a device already in the market (predicate device). Must have the same intended use and technological characteristics as the predicate). Premarket Approval (PMA) FDA Clearance Risk Assessment FDA Approval In May 2016, the US Food and Drug Administration (FDA) released draft guidance for medical device manufacturers working with additive manufacturing. Technical considerations. Characterizing and validating devices. Type of information to be submitted premarket submissions. Does not address the use or incorporation of biological, cellular, or tissue-based products. FDA, Technical Considerations for Additive Manufactured Devices, Draft Guidance for Industry and FDA Staff May 10, 2016 Bauer, H. K., M. et al. "Social and Legal Frame Conditions for 3d (and) Bioprinting in Medicine." [In English]. International Journal of Computerized Dentistry 19, no. 4 (2016): Involved FDA Centers: Center for Devices and Radiological Health (CDRH). Cleared additively manufactured devices for over a decade within the existing medical device regulations Center for Drug Evaluation and Research (CDER). Approved the first 3D printed drug within the existing chemistry, manufacturing and control standards that all other drug products are regulated by. Center for Biologics Evaluation and Research (CBER). Following the literature and interacting with stakeholders. Di Prima, Matthew at al. "Additively Manufactured Medical Products - the FDA Perspective." 3D Printing in Medicine 2:1 (2016). 8

9 3D bioprinting is regulated by existing laws, mainly those concerning medicinal products and medical devices. (Title 21 Food & Drugs ) Part 1271: Human Cells, Tissues and Cellular and Tissue-Based Products. An electronic registration and listing system for establishments that manufacture human cells, tissues, and cellular and tissue-based products. To establish donor-eligibility, current good tissue practice, and other procedures to prevent the introduction, transmission, and spread of communicable diseases. (Safety and quality control.) Bauer, H. K., M. et al. "Social and Legal Frame Conditions for 3d (and) Bioprinting in Medicine." [In English]. International Journal of Computerized Dentistry 19, no. 4 (2016): Currently, products that use stem cells or are derived from stem cells are treated by the FDA as somatic cellular therapies and are regulated as biologics under Section 351 of the Public Health Act. Office of Cellular, Tissue and Gene Therapies works with the Office of Combination Products to: Regulate, review and develop policy on: Tissues, Cellular and tissue based products, Gene therapies, Xenotransplantation, Combination products containing living cells or tissues, Unique assisted reproduction (ooplasm transfer). Bioprinted tissues typically used in research do not require FDA approval during animal and in vitro testing because they are not intended for use on humans. Title 21 of the Federal Code of Regulations defines certain restrictions with regard to shipping and disposal of these products. Varkey, Mathew, and Anthony Atala. "Organ Bioprinting: A Closer Look at Ethics and Policies." Wake Forest Journal of Law & Policy 5, no. 2 (2015):

10 Cell, tissue and gene therapy do not need PMA if: There is minimal manipulation. There is homologous use. They are not combined with a drug or device. They exert no system effect They exert a systemic effect, but they are not: Autologous Allogenic in a first or second-degree relative For reproduction use. Biological products are defined as combination products under 21 CFR 3.2(e) if they are produced as a single entity but are physically or chemically combined with at least one integral constituent, independently regulated part. The FDA classifies these combination products according to the claimed primary mode of action (MoA), the characteristics of the active substance, and the way in which it is combined in the finished product. This includes medical devices that consist of biological materials, medical technologies, and drugs of different compositions. Bauer, H. K., M. et al. "Social and Legal Frame Conditions for 3d (and) Bioprinting in Medicine." [In English]. International Journal of Computerized Dentistry 19, no. 4 (2016): ) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; 2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; FDA 10

11 3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose. FDA 4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. FDA A combination product will command a high level of regulatory scrutiny, particularly for the manufacturer that makes multiple constituent parts. Major regulatory concerns are in the process from design to manufacture, software system chain control and validation, and potential variation in critical quality attributes (CQAs) of the final manufactured product. Hourd, P., et al. 3d Bioprinting Exemplar of the Consequences of the Regulatory Requirements on Customized Processes." [In English]. Regenerative Medicine 10, no. 7 (2015):

12 Allows the device to be used in an a clinical study in order to collect safety and effectiveness data. Usually in support of the PMA. An investigational plan approved by an institutional review board (IRB). If the study involves a significant risk device, the IDE must also be approved by FDA; Informed consent from all patients; Labeling stating that the device is for investigational use only; Monitoring of the study and; Required records and reports Do not require PMA, 510(k), establishment registration or listing. Exempt form Quality System. FDA 12

13 The device will not expose patients to an unreasonable or significant risk of illness or injury, and the probable benefit to health from use of the device outweighs the risk of injury or illness from its use while taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. The device would not be available to a person with the disease or condition in question without the HDE, and no comparable device, other than another device approved under an HDE or Investigational Device Exemption (IDE) is available to treat or diagnose such disease or condition. FDA Prohibits profit from sales of the device. Excepting pediatric products. Institutional Review Board (IRB) must approve such use beforehand. As distinguished from investigational use or clinical investigation. There are exceptions for Emergency Use. FDA The ensemble of science, bioethics, law, regulation, and intellectual property. FDA 3D Printing, bioprinting and biologicals. Combination products. Investigational device exemption. Humanitarian device exemption. 13