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Food and Drug Law Journal FOOD AND DRUG LAW JOURNAL EDITOR IN CHIEF Judy Rein EDITORIAL ADVISORY BOARD CHAIR VICE CHAIR FACULTY ADVISOR Laurie Lenkel Robert Giddings Joseph A. Page FDA – OC Hutchison PLLC Georgetown University Law Center ________________________________ Anthony Anscombe James Flaherty Francis Palumbo Sedgwick LLP Fresenius Medical University of Maryland School of Pharmacy Peter Barton Hutt Abraham Gitterman Covington & Burling Arnold & Porter LLP Sandra Retzky FDA – CTP Barbara Binzak Kimberly Gold Blumenfeld Norton Rose Fulbright Joan Rothenberg Buchanan Ingersoll & LLP FDA - CFSAN Rooney PC John Johnson Jodi Schipper Catherine Clements FDA Imports FDA – CDER Express Scripts Alan Katz Christopher van Gundy Kellie Combs toXcel, LLC Keller and Heckman Ropes & Gray LLP Sara Koblitz James Woodlee Nathan Cortez Fish & Richardson Kleinfeld Kaplan & Becker LLP Southern Methodist University Valerie Madamba Emily Wright Blue Apron Pfizer Brian Dahl Dahl Compliance Alan Minsk Kimberly Yocum Consulting LLC Arnall Golden Gregory TC Heartland LLC LLP Sandra dePaulis Lowell Zeta FDA – CVM Nicole Negowetti Hogan Lovells The Good Food Ian Fearon Institute Patricia Zettler British American Tobacco Georgia State James O’Reilly University Law School University of Cincinnati OFFICERS OF THE FOOD AND DRUG LAW INSTITUTE CHAIR: Allison M. Zieve, Public Citizen Litigation Group VICE CHAIR: Jeffrey N. Gibbs, Hyman, Phelps & McNamara, P.C. TREASURER: Frederick R. Ball, Duane Morris LLP GENERAL COUNSEL/SECRETARY: Joy J. Liu, Vertex Pharmaceuticals IMMEDIATE PAST CHAIR: Sheila Hemeon-Heyer, Heyer Regulatory Solutions LLC PRESIDENT & CEO: Amy Comstock Rick GEORGETOWN UNIVERSITY LAW CENTER STUDENT EDITOR IN CHIEF Dana Shaker STUDENT MANAGING EDITORS Jacob Klapholz Christine Rea STUDENT NOTES EDITOR SYMPOSIUM EDITOR Lauren Beegle Alexander P. Kramarczuk STUDENT EXECUTIVE EDITORS Courtney L. Blandford Lindsay Laddaran Christopher R. Lombardi Thomas Crimer Jackson Lavelle Emily Salomon STUDENT SENIOR STAFF EDITORS Colleen Hespeler Arvind S. Miriyala Bonnie Fletcher Price Yang Li Sheaniva H. Murray Mariah Trisch Laya Varanasi STUDENT STAFF EDITORS Seth Appiah-Opoku Laura Higbee Nicholas Prust Natalie Camastra Nicholas Hill Erik Rynko Emma Chapman Meaghan Jerrett Thomas Sanford Daniel Elkus Daniel Krisch Shaun Weiss Adam Harris Yinan Lin Tiffany Weston Lacey Henry Allison Parr LLM EDITORS Holly Hedley Hayley Scheer Dena Kirpalani Andrew Hennessy-Strahs Julia Kuelzow Cheng Zeng Laura Malavé FACULTY ADVISOR Joseph A. Page FACULTY ADVISORY BOARD Oscar Cabrera Lisa Heinzerling David C. Vladeck Vicki W. Girard John R. Thomas Timothy M. Westmoreland Lawrence O. Gostin Rebecca Tushnet O’NEILL INSTITUTE ADVISOR Eric N. Lindblom FOOD AND DRUG LAW JOURNAL VOLUME 71 NUMBER 4 2016 _______________________________________ 544 Early Developments in the Regulation of Biologics Terry S. Coleman 608 FDA Regulation of Clinical Applications of CRISPR-CAS Gene Editing Technology Evita V. Grant 634 E-cigarette Regulation and Harm Reduction: The Case of Hong Kong Shue Sing Churk 658 The Extent of Harm to the Victim as an Alternative Aggravating Factor for the Conviction of Felony Fraud in the Context of Food-Safety Violations Yi-Chen Su 673 Knowledge Sharing as a Social Dilemma in Pharmaceutical Innovation Daria Kim FDLI FDA Regulation of Clinical Applications of CRISPR-CAS Gene-Editing Technology EVITA V. GRANT* I. ABSTRACT Scientists have repurposed an adaptive immune system of single cell organisms to create a new type of gene-editing tool: CRISPR (clustered regularly interspaced short palindromic repeats)-Cas technology. Scientists in China have reported its use in the genome modification of non-viable human embryos. This has ignited a spirited debate about the moral, ethical, scientific, and social implications of human germline genome engineering. There have also been calls for regulations; however, FDA has yet to formally announce its oversight of clinical applications of CRISPR-Cas systems. This paper reviews FDA regulation of previously controversial biotechnology breakthroughs, recombinant DNA and human cloning. It then shows that FDA is well positioned to regulate CRISPR-Cas clinical applications, due to its legislative mandates, its existing regulatory frameworks for gene therapies and assisted reproductive technologies, and other considerations. II. INTRODUCTION About a decade ago, scientists confirmed that some bacteria have an adaptive immune system that responds specifically to viral DNA that it had previously been infected with.1 In such bacteria, their genome comprises of a series of about 20-50 base pair repeats known as CRISPR (the acronym for clustered regularly interspaced short palindromic repeats), that are separated by non-bacterial DNA “spacer” sequences of about 20-70 base pairs.2 These “spacer” sequences are remnants of previous exposure to DNA of invading pathogens, and are part of an immunological memory that is utilized to defend against subsequent attacks by pathogens containing that particular DNA sequence. Scientists quickly recognized the gene-editing potential of CRISPR-Cas systems. The ability of the CRISPR-Cas system to recognize and cleave a specific sequence of DNA allowed it to be developed into artificial restriction enzymes that can be used to * Evita Grant is an associate in the patents and innovations practice at Wilson Sonsini Goodrich & Rosati in Palo Alto, CA. She has a JD from Harvard Law School and a PhD in Medical Engineering and Medical Physics from Harvard University. Her scientific background includes research in HIV vaccine development. 1 Rodolphe Barrangou et al., CRISPR Provides Acquired Resistance Against Viruses in Prokaryotes, 315 SCIENCE 1709, 1709–12 (2007). 2 Addison V. Wright et al., Biology and Applications of CRISPR Systems: Harnessing Nature’s Toolbox for Genome Engineering, 164 CELL 29, 29–44 (2016). 608 2016 FDA REGULATION OF CRISPR 609 alter specific sites of DNA in any organism. Such modifications can be used to add, activate, delete, or suppress genes. The applications of CRISPR-Cas systems are innumerable. In February 2014, Chinese researchers reported the successful application of CRISPR-Cas gene-editing technology to precisely target genes of one-cell-stage embryos of monkeys.3 A year later, on April 22, 2015, a different group of Chinese scientists became the first to report the successful use of CRISPR-Cas system to edit the genome of a human zygote, an early embryo. Alarmed by the use of CRISPR-Cas system for gene-editing of human embryos, scientists have discussed privately in meetings4 and publicly in scientific journals5 and congressional hearings,6 the moral and ethical propriety of human germline genome modifications. Congress has prohibited the use of federal funding on any activities related to human embryo modification.7 The National Institute of Health (NIH), at this time, will not fund any research involving human germline genome modification.8 The Food and Drug Administration (FDA) has been silent on the regulation of CRISPR-Cas clinical applications as of March 2016. This paper shows that precedent supports the regulation of CRISPR-Cas clinical applications by FDA. Even though the paper focuses on clinical applications, the use of CRISPR-Cas systems is not limited to human applications alone. It can be used for genome modification of plants and animals as well.9 Part II explains the CRISPR-Cas system and its application as a gene-editing tool. Part III reviews FDA oversight of two prior controversial biotechnologies—recombinant DNA (rDNA) and gene therapies, and human cloning. In particular, this paper examines how FDA extended its oversight and the regulations it applied. Part IV discusses why FDA should regulate clinical applications of CRISPR-Cas systems. 3 Yuyu Niu et al., Generation of Gene-Modified Cynomolgus Monkey via Cas9/RNA-Mediated Gene Targeting in One-Cell Embryos, 156 CELL 836, 836–43 (2014). 4 David Baltimore et. al., A Prudent Path Forward for Genomic Engineering and Germline Gene Modification, 348 SCIENCE 36, 36–37 (2015). 5 Katrine S. Bosley et al., CRISPR Germline Engineering—the Community Speaks, 33 NATURE BIOTECH., 478, 478–86 (2015). 6 The Science and Ethics of Genetically Engineered Human DNA: Hearing Before the Subcomm. on Research and Tech. of the H. Comm. on Science, Space, and Tech., 114th Cong. (2015), https://science. house.gov/legislation/hearings/subcommittee-research-and-technology-hearing-science-and-ethics- genetically [https://perma.cc/7QXP-Q7W3]. 7 Consolidated Appropriations Bill, 2016, Pub. L. 114-13, § 749, 129 Stat. 2242, 2283 (2015), https://www.congress.gov/bill/114th-congress/house-bill/2029/text. 8 Statement on NIH funding of research using gene-editing techs. in human embryos, (Apr. 29, 2015), http://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using- gene-editing-technologies-human-embryos (statement of Francis S. Collins, Director, National Institutes of Health). 9 Wright, supra note 2, at 39. See also Eric S. Lander, The Heroes of CRISPR, 164 CELL 18, 18 (2016); Devavish Rath et al., The CRISPR-Cas Immune System: Biology, Mechanisms, and Applications, 117 BIOCHIMIE 119–28 (2015); Letter from Michael Firko, APHIS Deputy Administrator, Dep’t of Agric. to Yinong Yang, College of Agric. Sciences, The Pennsylvania State University (Apr. 13, 2016), https://www.aphis.usda.gov/biotechnology/downloads/reg_loi/15-321-01_air_response_signed.pdf (stating that CRISPR-edited white button mushroom will not be regulated
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