Food and Drug Law Journal

FOOD AND DRUG LAW JOURNAL

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Dana Shaker

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FOOD AND DRUG LAW JOURNAL

VOLUME 71 NUMBER 4 2016

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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 since they did not contain any introduced genetic material).

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III. UNDERSTANDING CRISPR-CAS GENE EDITING TECHNOLOGY

Until recently, scientists believed that single cell organisms such as bacteria did not have an adaptive immune system. An adaptive immune system is distinct from an innate immune system because of its specificity,10 the ability to mount an immune response to a particular antigen; and its memory,11 the ability to mount subsequent immune responses more rapidly and vigorously against an antigen it has been previously exposed to. CRISPR, along with DNA-cleaving Cas proteins, were recently determined to be an adaptive immune system for some bacteria against invading DNA- containing pathogens such as viruses. The intriguing story of the discovery of the CRISPR-Cas adaptive immune system and its repurposing for gene-editing has been elegantly described elsewhere.12 Scientists have been able to repurpose the CRISPR- Cas system to alter genes in non-bacterial cells, including human cells. The potential application of CRISPR-Cas gene-editing technology to the modification of human reproductive cells and embryos has generated spirited conversations within the scientific and bioethics communities. This section explains the CRISPR-Cas technology, and reviews both sides of the controversial debate about the application of CRISPR-Cas to human germline genome modification. A. CRISPR-Cas System: An Adaptive Immune System Repurposed for Gene-Editing Single cells such as bacteria use different forms of innate immune systems that lack specificity or memory to defend themselves against infection by pathogens.13 For example, bacteria use restriction enzymes to cut up and destroy foreign DNA but not their own DNA. 14 However, these enzymes lack the attributes of an adaptive immune system, specificity and memory, because they do not target the DNA of a specific pathogen, and they mount the same response to each subsequent exposure to foreign DNA. Adaptive immune systems that have specificity and retain memory for subsequent responses were known to exist only within multicellular organisms, until recently. Discovery of CRISPR-Cas Adaptive Immune System of Single Cell Organisms 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

10 ABUL K. ABBAS & ANDREW H. LICHTMAN,, CELLULAR AND MOLECULAR IMMUNOLOGY 1–22 (8th ed. 2014). 11 Id. 12 Lander, supra note 9, at 18–28. In the comments section of PubMed Commons, Emmanuelle Charpentier and Jennifer Doudna, two researchers involved in a patent battle over CRISPR-Cas technology, commented that the author of the article did not fact check with them on their contributions to the development of CRISPR-Cas gene-editing technology. 13 ABBAS & LICHTMAN, supra note 10, at 65–86. 14 Id.

2016 FDA REGULATION OF CRISPR 611 infected with.15 In such bacteria, the genome comprises of a series of ~20-50 base pair repeats known as CRISPR, that are separated by non-bacterial DNA “spacer” sequences of about 20-70 base pairs.16 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. For example, Escherishia coli (E. coli), a bacterium commonly found in the human gut, has CRISPR encoded in its genome. When a virus infects E. coli for the first time and releases its DNA within it, E. coli bacterial enzymes cut (and in so doing destroy) the viral DNA into smaller pieces of about 20-50 base pairs. These smaller pieces of viral DNA are inserted between pairs of CRISPR repeats at one end of the CRISPR loci as “spacers.” Insertion into the bacterial genome allows this information to be passed on to subsequent generations of E. coli. So as E. coli cells encounter different pathogens, short snippets of the pathogen’s DNA are inserted into the CRISPR loci as spacers, expanding a chronological collection of previous exposure to pathogens which will be used to fight future exposure to a pathogen containing that exact DNA sequence. Transcription of E. coli DNA CRISPR loci produces long precursor CRISPR RNA molecules.17 These precursor CRISPR RNA molecules are cut by E. coli enzymes just upstream of each spacer segment to produce many smaller CRISPR RNA (crRNA) molecules.18 If E. coli becomes infected by another virus, or pathogen, containing a DNA sequence that complementarily matches the sequence of one of the crRNA molecules, that particular crRNA molecule binds to the viral DNA.19 The complex of viral DNA and bacterial crRNA signals bacterial enzymes that specifically cut DNA, Cas DNA-cleaving endonucleases, to cut the viral DNA into smaller, ineffective pieces, and thus disrupting the infection cycle of the invading virus.20 Repurposing CRISPR-Cas for Genome Editing 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 alter specific sites of DNA in any organism. Such modifications can be used to add, activate, delete, or suppress genes. For example, to deactivate the expression of a specific gene, the CRISPR-Cas genes can be introduced into the cell by transfection using a plasmid. The crRNA complementary to the target gene and the Cas proteins are expressed within the transfected cell. The crRNA binds to the target gene sequence and the Cas protein cut both strands of the target DNA. If the transfected cell repairs the double-stranded break in its DNA using non-homologous end-joining, this error-prone DNA repair system often inserts base pairs into or deletes base pairs from the DNA sequence. In so doing, the insertion or deletion of base pairs changes the DNA sequence and inactivates the

15 Barrangou, supra note 1. 16 Wright, supra note 2. See also Rath, supra note 9. 17 Wright, supra note 2. See also Rath, supra note 9. 18 Wright, supra note 2. See also Rath, supra note 9. 19 Wright, supra note 2. See also Rath, supra note 9. 20 Wright, supra note 2. See also Rath, supra note 9.

612 FOOD AND DRUG LAW JOURNAL VOL. 71 gene. Similarly, to introduce a gene into the genome of a cell at a specific site, the cell can be transfected with a plasmid containing the CRISPR-Cas genes and the gene to be incorporated. As previously explained, the CRISPR-Cas genes are expressed and the target DNA sequence in which the gene is to be inserted is cleaved. If the double- stranded break is repaired by homologous recombination, this repair system is likely to insert the gene of interest into the cleaved site. The applications of CRISPR-Cas systems are innumerable. It is currently being used as a research tool for the creation of animal models for human diseases.21 Several researchers are exploring both in vivo and ex vivo preventive, diagnostic, and therapeutic applications for humans.22 The application of CRISPR-Cas systems is not limited to human applications alone; it can be used for genome modification of plants and animals as well.23 B. Application of CRISPR-Cas Technology to Human Germline Modification 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.24 A year later, the MIT Technology Review published an article “Engineering the Perfect Baby,” in which it was revealed that three American research centers as well as scientists in China and the United Kingdom were working on genome modification of human germline cells (reproductive eggs and sperms) and human embryos.25 Alarmed by the possibility that CRISPR-Cas systems can be successfully used to modify the genome of human germline cells and embryos, a group of scientists and other interested stakeholders convened in Napa, California in January 2015 to discuss the scientific, medical, legal, and ethical implications of this revolutionary breakthrough in genome biology.26 Following the meeting, the participants published the following recommendations on April 3, 2015: (1) any attempts of germline modifications for clinical applications in humans should be strongly discouraged, even in countries with lax jurisdictions, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations; (2) forums in which experts from the scientific and bioethics communities can provide information and education about this new era of human biology should be created; and (3) globally representative group of researchers, experts, government agencies, public and interest groups should convene to consider important issues and recommend policies.27 On April 22, 2015, Chinese scientists became the first to report the successful use of CRISPR-Cas system to edit the genome

21 Rath, supra note 9, at 125–6. 22 Id. 23 Id.; See also Kelly Servick, U.S. to Review Agricultural Biotech Regulations, 349 SCI. 131 (July 10, 2015). 24 Niu, supra note 3, at 836–43. 25 Antonio Regalado, Engineering the Perfect Baby, MASS. INST. OF TECH. REV., 26-33 (Mar. 5, 2015). 26 Baltimore, supra note 4, at 36. 27 Id. at 37–8.

2016 FDA REGULATION OF CRISPR 613 of a human zygote, an early embryo, thus confirming the rumors in the MIT Technology Review article.28

Opponents of Human Germline Genome Modification Edward Lanphier, Chairman of the Alliance for Regenerative Medicine in Washington D.C., has been one of the vocal leaders of scientists who oppose all applications of CRISPR-Cas technology to human germline genome modification.29 Lanphier argues that genome editing of human germline cells and embryos may have unpredictable effects on future generations, making such activity dangerous and ethically unacceptable.30 Lanphier and his colleagues are also concerned that CRISPR- Cas technology may be exploited for non-therapeutic uses (e.g., eugenics), and that the resulting public outcry could hinder the application of a promising area of therapeutic development.31 Lanphier is not convinced that CRISPR-Cas systems have any therapeutic applications in human embryos. He asserts that existing established technologies such as standard prenatal genetic diagnostics and in vitro fertilization (IVF) with genetic profiling before implantation, can be used to genetically screen and select healthy embryos.32 He also believes that there may be a legal case to be made against human germline genome modification due to the fact that many countries, including 15 of 22 Western European countries, prohibit the modification of the human germline genome.33 Lastly, Lanphier believes that there is a “fundamentally ethical issue” with human germline genome modification as “[w]e are humans, not transgenic rats.”34 Proponents of Human Germline Genome Modification Some scientists disagree with Lanphier’s stance. George Church of Harvard Medical School does not see a fundamental problem with editing the human germline, which he believes is comparable to in vitro fertilization.35 He, however, agrees with his fellow scientists that there should be a moratorium on embryo editing until the safety issues have been solved and there is a general affirmative consensus.36 Nobel Prize Laureate Craig Mello of the University of Massachusetts, Worcester concurs.37

28 Puping Liang et al., CRISPR/Cas9-Mediated Gene Editing in Human Tripronuclear Zygotes, 6 PROTEIN CELL 362, 362–72 (2015). 29 Edward Lanphier et al., Don’t Edit the Human Germ Line, 519 NATURE 410, 410–11 (2015). 30 Id. at 410. 31 Id. Lanphier is also the former President and Chief Executive Officer of Sangamo BioSciences in Richmond, California, a company that is using gene-editing tools to develop therapies that correct genetic defects in people. SANGAMO BIOSCIENCES, INC., Sangamo BioSciences Announces Retirement Of Edward Lanphier As President And CEO; Sandy Macrae Named As Successor, PRNEWSWIRE.COM (June 1, 2016, 7:00AM), http://investor.sangamo.com/releasedetail.cfm?ReleaseID=973633. 32 Lanphier, supra note 29, at 411. 33 Id. 34 David Cryanoski, Embryo Editing Divides Scientists, 519 NATURE 272, 272 (2015). 35 Id. 36 Id. 37 Id.

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He believes that gene-editing of germlines can be used to protect against cancer, diabetes and other age-related diseases in the distant future;38 for the near term, however, gene-editing can be used as a research tool in discarded embryos and embryonic stem cells for research purposes.39 The scientific community may appear divided on the ethics of human germline genome editing, but there is a consensus that germline engineering is inevitable, despite the major outstanding technical and biological barriers to achieving germline modification for clinical applications.40 Scientists are also aware that the potential individual benefits of germline engineering must be weighed against the associated individual health risks;41 similarly, the potential societal benefits must be considered in view of the societal risks.42 there is no consensus on which clinical applications of germline engineering will be ethically acceptable.43 As such, many believe some form of oversight is needed.44 Response of Legislative and Executive Branches Many scientists and bioethicists have called for the development of a regulatory framework to guide human genome modification using CRISPR-Cas technology, especially due to the safety issues.45 At least one researcher has reported that modifying one gene in stems cells resulted in unwarranted mutations elsewhere in the genome–“off-target” mutations.46 As such, there remain technical challenges to be solved in order for the CRISPR-Cas technology to be a highly precise and specific gene-editing tool. While germline gene editing is banned in many countries,47 there are countries like the United States in which germline editing is not banned, and as such, regulations may be needed. In June 2015, the Subcommittee on Research and Technology of the U.S. House of Representatives Committee on Science, Space, and Technology convened a hearing, The Science and Ethics of Genetically Engineered Human DNA, to achieve several objectives: (1) review the science behind the new gene editing technologies; (2) examine the ethical implications and risks; (3) discuss the promise or potential applications; (4) explore how to build a responsible framework for utilizing gene editing technologies; and (5) determine how the U.S. can provide scientific and ethical

38 Id. 39 Id. 40 Bosley, supra note 5, at 478–79. 41 Id. at 480–81. 42 Id. at 481–82. 43 Id. at 482. 44 Id. at 484. 45 Niklaus H. Evitt et al., Human Germline CRISPR-Cas Modification: Toward a Regulatory Framework, 15 AM. J. BIOETHICS 25, 25–29 (2015). 46 Keiichiro Suzuki et al., Targeted Gene Correction Minimally Impacts Whole-Genome Mutational Load in Human-Disease-Specific Induced Pluripotent Stem Cell Clones, 15 CELL STEM CELL 31, 31–36 (2014). 47 Tetsuya Ishii, Potential Impacts of Human Mitochondrial Replacement on Global Policy Regarding Germline modification, Gene Modification, 29 REPROD. BIOMEDICINE ONLINE 150, 150–55 (2014).

2016 FDA REGULATION OF CRISPR 615 leadership in this area.48 Victor Dzau of the Institute of Medicine, Jennifer Doudna of the University of California, Berkeley, Elizabeth McNally of Northwestern University, and Jeffrey Kahn of John Hopkins testified before the Subcommittee.49 Members of the Subcommittee asked a wide range of questions including the ethical issues that scientists and bioethicists had identified, the details of the recommended moratorium, the potential applications to therapeutic development and eugenics, the importance of federal funding to support basic research, the anticipated timescale for the advent of clinical applications, the sufficiency of current regulatory frameworks, and the means to ensure that the United States remains a leader in this field.50 It was evident that the members of the Subcommittee were interested in understanding the entire big picture to guide any future Congressional decisions. A few months later, Congress passed the $1.1 trillion Omnibus Spending Bill in December 2015. Possibly recognizing the importance of federal funding in biotechnology breakthroughs such as CRISPR-Cas technology, Congress increased the National Institute of Health (NIH) FY2016 budget by $2 billion: “the most encouraging budget outcome in 12 years.”51 Congress, however, placed new restrictions on the use of federal funding for gene editing. In particular, Congress instructed the following: (a) None of the funds made available in this Act may be used for—(1) the creation of a human embryo or embryos for research purposes; or (2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under 45 CFR 46.204(b) and section 498(b) of the Public 5 Health Service Act (42 U.S.C. 289g(b)); and [n]one of the funds made available by this Act may be used to notify a sponsor or otherwise acknowledge receipt of a submission for an exemption for investigational use of a drug or biological product under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 355(i)) or section 351(a)(3) of the Public Health Service Act (42 U.S.C. § 262(a)(3)) in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.52 At the Executive branch level, NIH issued a statement in April 2015 regarding its funding of research involving gene-editing technologies in human embryos.53 NIH has

48 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) (hearing charter), https://science.house.gov/sites/republicans.science.house.gov/files/documents/HHRG-114-SY15- 20150616-SD001.pdf. 49 Id. 50 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., supra note 6. 51 Francis H. Collins, Statement on the FY2016 Omnibus Bill, NAT’L INSTS. OF HEALTH (Dec. 18, 2015), http://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-fy2016-omnibus-bill. 52 H.R. 2029, supra note 7, at §§ 508, 749. 53 Statement on NIH funding of research using gene-editing techs. in human embryos, supra note 8.

616 FOOD AND DRUG LAW JOURNAL VOL. 71 decided not to fund any use of gene-editing technologies in human embryos because there are multiple existing legislative and regulatory prohibitions against this kind of work. FDA has yet to issue an official statement regarding CRISPR-Cas and other gene-editing tools as of March 2016.

IV. FDA REGULATION OF THEN-CONTROVERSIAL BIOTECHNOLOGIES—RECOMBINANT DNA AND CLONING

Tasked with protecting the health of the public,54 FDA has been regulating technologies relating to drugs, biological products, medical devices, and cosmetics, in accordance with the Federal Food, Drug, and Cosmetic Act of 1938 (FDCA),55 the Public Health Service Act of 1944 (PHSA),56 and their subsequent amendments. Not surprisingly, FDA has experience regulating controversial biotechnologies, in particular, technologies relating to rDNA and human cloning. An understanding of FDA’s role in the regulation of such technologies may provide some useful insight as to whether FDA has authority to regulate CRISPR-Cas clinical applications. Part A of this section reviews how FDA established its authority and corresponding regulatory control over rDNA, and Part B reviews the same for human cloning. A. FDA Regulation of Recombinant DNA (rDNA) and Gene Therapy The story of FDA’s regulation of rDNA and gene therapy is one of an agency’s uncertainty in the midst of great controversy and unfamiliarity. Initially, the Recombinant DNA Advisory Commission (RAC), under NIH, was largely responsible for the regulation of a technology that had sparked great debate over its safety. Over time, the regulatory responsibility shifted from RAC to FDA, as FDA slowly defined its regulatory role and approach. Recombinant DNA Regulation by RAC/NIH A detailed and elegant historical review on the regulation of rDNA and gene therapy by RAC and FDA has already been written.57 In 1972-3, scientists reported the ability to remove DNA from one organism and place it in another organism.58 Two years later, Paul Berg of Stanford University proposed an experiment in which DNA from a virus that causes cancer in monkeys will be transferred into a bacterium commonly found in the human gut.59 The proposed experiment alarmed the scientific community. In response, the National Academy of Science convened a panel, headed by Berg, to review his proposal and evaluate its safety. The panel recommended the deferment of

54 PETER HUTT ET AL., FOOD AND DRUG LAW: CASES AND MATERIALS, 14–15 (4th ed. 2014). 55 21 U.S.C. §§ 301 et seq. (2012). 56 42 U.S.C. §§ 201 et seq. (2012). 57 Joseph M. Rainsbury, Biotechnology on RAC-FDA/NIH Regulation of Gene Therapy, 55 FOOD & DRUG L.J. 575, 575–600 (2000); see also SUSAN WRIGHT, MOLECULAR POLITICS: DEVELOPING AMERICAN AND BRITISH REGULATORY POLICY FOR GENETIC ENGINEERING, 1972–1982 (1994). 58 NAT’L INSTS. OF HEALTH, The Paul Berg Papers: Recombinant DNA Technologies and Researchers’ Responsibilities, 1973-1980, https://profiles.nlm.nih.gov/ps/retrieve/Narrative/CD/p-nid/259. 59 Id. See also JEFF LYON & PETER GORNER, ALTERED FATES, 60–61 (1995).

2016 FDA REGULATION OF CRISPR 617 experiments and the establishment of a committee by NIH to evaluate risks of and provide safety guidelines for rDNA research.60 RAC, positioned within NIH, was created for this purpose.61 In 1980, Martin Cline, a physician at the University of California, Los Angeles, conducted the first gene therapy clinical trials in Italy and Israel.62 Despite his lack of success and the absence of any adverse events, Cline’s conduct deeply concerned scientific communities and regulatory agencies.63 It was widely believed that Cline had attempted to circumvent U.S. regulatory rules, and had deceived patients and the relevant Italian and Israeli regulatory authorities regarding the specifics of his clinical trials.64 The Martin Cline incident intensified concerns regarding regulation of rDNA technologies. At the request of then-President Carter, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research studied gene splicing and published its findings in the book, Splicing Life.65 In the book, the Commission recommended either the creation of a new inter-agency body to oversee human gene therapy trials, or the expansion of the oversight role of RAC to oversee both safety and the ethical issues.66 Congressional hearings followed the release of Splicing Life.67 The hearings resulted in a report from the Office of Technology Assessment on human genetic engineering, Human Gene Therapy.68 The report concluded that for “early experiments on human somatic cell gene therapy, present oversight methods that involve local IRBs, RAC, NIH, and FDA appear adequate”; however, “greater government oversight may prove necessary” for other applications.69 The congressional hearings also spurred the creation of the Gene Therapy Working group (later became the Human Gene Therapy Subcommittee) to review human gene therapy protocols for federally-funded experiments.70 Shared rDNA Regulation by RAC/NIH and FDA FDA was slow to answer the call for regulation of rDNA and gene therapy. In 1978, FDA announced that it intended to propose regulations.71 The proposed regulations would require compliance with the requirements of NIH guidelines, and provide

60 41 Fed. Reg. 27,902, 27,902–3 (Jul. 7, 1976). 61 Id. 62 Larry Thompson, CORRECTING THE CODE: INVENTING THE GENETIC CURE FOR THE HUMAN BODY, 189–263 (1994). 63 Id. 64 Id. 65 PRESIDENT’S COMMISS’N FOR THE STUDY OF ETHICAL PROBLEMS IN MEDIC. AND BIOMEDICAL AND BEHAVIORAL RESEARCH, SPLICING LIFE: A REPORT ON THE SOCIAL AND ETHICAL ISSUES OF GENETIC ENGINEERING WITH HUMAN BEINGS (1982). 66 Id. at 81–88. 67 Hearing on Human Genetic Engineering Before the Subcomm. on Investigations and Oversight of the H. Comm. on Science and Technology, 97th Cong., 2d Sess. 441–54 (1982). 68 Human Gene Therapy, OFF. OF TECH. ASSESSMENT, (1984), http://ota.fas.org/reports/8415.pdf. 69 Id. at 39. 70 57 Fed. Reg. 316 (Jan. 3, 1992); 57 Fed. Reg. 14,774 (Apr. 22, 1992). 71 43 Fed. Reg. 60,134, 60,134 (Dec. 22, 1978).

618 FOOD AND DRUG LAW JOURNAL VOL. 71 protections against public disclosure of information.72 These regulations never materialized.73 Six years later, FDA determined that it would finally regulate rDNA- derived products.74 In 1986, FDA claimed jurisdictional authority over gene therapy: “Nucleic acids or viruses used for human gene therapy will be subject to the same requirements as other biological drugs.”75 Despite its jurisdictional claim, FDA noted the possibility that it shared regulatory responsibilities with NIH.76 For a period of time, both RAC and FDA had regulatory oversight over rDNA and gene therapy applications. In 1987, French Anderson of the University of Southern California submitted a protocol to treat Severe Combined Immunodeficiency (SCID) using a retroviral vector.77 RAC refused to approve Anderson’s protocol because the proposed therapy had caused fatalities in primates.78 The first clinical experiment approved by RAC was a gene transfer experiment to be performed by a team of doctors that included Anderson.79 Yet, the team had to obtain approval from six other institutional agencies, including FDA.80 Having received clearances from other gatekeepers, including FDA approval of its Investigational New Drug (IND) application, the team was all set to commence the trial until Jeremy Rifkin, a major critic of gene therapy, filed a federal suit to block the experiment.81 Rifkin claimed that RAC approval procedures did not allow for public input and thus violated the Administrative Procedure Act (APA) and the Federal Advisory Committee Act. Rifkin and NIH settled out of court, after NIH agreed that every future RAC hearing will allow for public input. Finally, with FDA approval, the first gene transfer experiment occurred on May 22, 1989.82 Soon afterwards, the number of RAC-approved gene therapy protocols increased.83 The Human Gene Therapy Subcommittee was merged into the full RAC to decrease regulatory hurdles.84 Yet the requirement for approval by both RAC and FDA remained. In 1994, the National Task Force on AIDS Drug Development met to identify barriers to HIV/AIDS treatment.85 The Task Force recommendations included improvements to interactions between RAC and FDA, and the elimination of any unnecessary overlap; ideally, RAC would become an advisory body and FDA would

72 Id. 73 Rainsbury, supra note 57, at 581. 74 49 Fed. Reg. 50,856, 50,856 (Dec. 31, 1984); see also Rainsbury, supra note 57, at 581. 75 51 Fed. Reg. 23,310, 23,311 (Jun. 26, 1986). 76 Id. 77 William F. Anderson, Human Gene Therapy, 256 SCIENCE 808, 808–13 (1992); see also William F. Anderson, Musings on the Struggle-Part I: The Phonebook, 3 HUM. GENE THERAPY, 251, 251–2 (1992). 78 Lyon, supra note 59, at 129. 79 Leslie Roberts, Human Gene Therapy Test, 241 SCIENCE 419, 419 (1998); see also Anderson, supra note 77 at 808. 80 Rainsbury, supra note 57, at 583. 81 Leslie Roberts, Rifkin Battles Gene Transfer Experiment, 243 SCIENCE 734, 734 (1989). 82 Lyon, supra note 59, at 161. 83 Rainsbury, supra note 57, at 585. 84 57 Fed. Reg. 316 (Jan. 3, 1992). 85 59 Fed. Reg. 43,426, 43,427 (Aug. 23, 1994).

2016 FDA REGULATION OF CRISPR 619 retain sole responsibility for human gene transfer protocols.86 In response, in September 1995, RAC’s ad hoc committee recommended the long-term consolidation of RAC within FDA.87 In its new role, RAC would cease to review gene therapy protocols, except for exceptional cases, and would formally advise FDA on regulatory issues. Then-NIH Director, Harold Varmus, in fact doubted the need for RAC.88 Eventually, RAC became an advisory body as FDA rose to be the primary approval authority.89 Legislative Authority of FDA To regulate rDNA technologies and products, FDA relied on existing legal authorities, the PHSA and the FDCA, that mandated it to regulate products “intended to prevent, treat, or diagnose diseases or injuries.”90 FDA intended to regulate rDNA under its authority to regulate biological products, drugs, and medical devices.91 The PHSA defines biological products as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product . . .or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”92 The FDCA defines a “drug” in part as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals,” and a “device” in part as: “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article . . . intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, . . . which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.”93 FDA also pointed out that the definition for “drug” and “device” include articles “intended to affect the structure or any function of the body.”94 FDA then provided its definitions for somatic cell therapy products and gene therapy products to implicitly justify their regulation as biological products, drugs and devices. Somatic cell therapy products were defined as “autologous (i.e., self), allogeneic (i.e., intra-species), or xenogeneic (i.e., inter-species) cells that have been

86 Id. 87 VERMA AD HOC COMMITTEE, Executive Summary of Findings and Recommendations (Sep. 8, 1995), http://osp.od.nih.gov/sites/default/files/resources/Verma_Report.pdf. 88 61 Fed. Reg. 35,774, 35,775 (Jul. 8, 1996). 89 Rainsbury, supra note 57, at 591–92. 90 58 Fed. Reg. 53,248, 53,248 (Oct. 14, 1993). 91 Id. 92 42 U.S.C. § 262(i) (2012). 93 21 U.S.C. § 321(g)()()–)((h) (2012). 94 21 U.S.C. § 321(h)(3) (2012).

620 FOOD AND DRUG LAW JOURNAL VOL. 71 propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics ex vivo to be administered to humans and applicable to the prevention, treatment, cure, diagnosis, or mitigation of disease or injuries,”95 and gene therapy products were defined as “products containing genetic material administered to modify or manipulate the expression of genetic material or to alter the biological properties of living cells.”96 Without providing an explanation, FDA characterized somatic cell gene therapy products and gene therapy products as biological products and drugs. Moreover, FDA explained how it intended to regulate such products. FDA planned on subjecting somatic cell gene therapy products and gene therapy products to premarket approval for biological products in accordance with the PHSA.97 FDA approval required proof of safety and efficacy, and license applications.98 FDA also applied its mandate under the PHSA to prevent false labeling of biologics and to prevent the introduction, transmission, or spread of communicable diseases through biological products.99 To expand the scope of its regulations, FDA applied its mandate under the FDCA as applicable to drugs and devices to prevent interstate shipment of misbranded drugs and devices.100 FDA did point out that interstate nexus was not required for it to have regulatory authority over somatic cell therapies and gene therapies.101 In addition to the announcement in the Federal Register, FDA also informed the research and medical communities about its regulation of somatic cell and gene therapies.102 However, these FDA notices lacked specific technical standards. The later guidance of 1991, Points to Consider in Human Somatic Cell Therapy and Gene Therapy, circulated by the Center for Biologics Evaluation and Research (CBER), provided specific technical standards as they relate to “preclinical safety data, molecular sequence of the gene/vector, characterization of cell lines used in the manufacture of vectors, and long-term monitoring of the health of experimental subjects.”103 The CBER revised the guidance in 1996 to account for increased use of in vivo techniques.104 The final guidance was published in March 1998.105 Today, it remains a primary source of information for the scientific community and private sector.

95 58 Fed. Reg. 53,248, 53,249 (Oct. 14, 1993). 96 Id. 97 Id. at 53,249–50. 98 Id. at 53,249. 99 Id. 100 Id. at 53,248–49. 101 Id. at 53,249. 102 David A. Kessler et al., Regulation of Somatic-Cell Therapy and Gene Therapy by the Food and Drug Administration, 329 NEW ENG. J. MED. 1169, 1171 (1993). 103 Rainsbury, supra note 57, at 590; see also CTR. FOR BIOLOGICS EVALUATION & RESEARCH, GUIDANCE FOR INDUSTRY (1998), http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Gui dances/CellularandGeneTherapy/ucm081670.pdf. 104 Rainsbury, supra note 57, at 590. 105 CTR. FOR BIOLOGICS EVALUATION & RESEARCH, supra note 103.

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FDA expanded its regulatory requirements laid out in the guidance of 1998 following the death of Jesse Gelsinger, a teenager participating in a Phase I clinical trial for ornithine transcarbamylase (OTC) deficiency therapy. Subsequent investigations following the tragedy revealed several shortcomings in oversight of gene therapy clinical trials.106 One headline-grabbing revelation was that many researchers did not comply with the requirements regarding the disclosure of adverse events.107 To close this gap in regulatory oversight, FDA created the Gene Therapy Clinical Trials Monitoring Plan to strengthen oversight over gene therapy clinical trials and improve the reporting of adverse events.108 It is important to note that the regulation of rDNA technologies and products by FDA is not based on explicit legislative grant of jurisdiction. In its claim of jurisdiction, FDA never explained why the existing legal mandates were applicable. Interestingly, FDA’s authority has yet to be challenged. Attempts at legislative reform to regulate gene therapy waxed and waned as rDNA technology evolved. Following the Gelsinger tragedy, calls for reform by members of the Senate, and the House of Representatives resurfaced.109 Yet, no reform materialized. As noted by Rainsbury: “Congress appears willing to let administrative agencies sort out the difficult issues involved in the regulation of recombinant DNA technology.”110 B. FDA Regulation of Cloning Despite the presence of important moral, ethical, and legal issues, FDA did not regulate reproductive cells, tissues and reproductive therapies until recently.111 There were no indications that FDA was mandated to. In fact, in 1992, Congress passed the Fertility Clinic Success Rate and Certification Act, and did not specify a role for FDA.112 Then in 2001, FDA expanded the definition of “human cells, tissues, or cellular or tissue-based product” (hCTP) to include “semen or other reproductive tissue.”113 It also expanded its regulatory reach to include fertility clinics through its Registration Rule; the requirement that establishments engaged in the recovery, screening, testing, processing, storage and/or distribution of hCTPs must register with FDA.114 FDA explained the recent regulatory changes as necessary to “address the

106 Rainsbury, supra note 57, at 592–94. 107 Id. 108 INSTITUTE OF MEDICINE, OVERSIGHT AND REVIEW OF CLINICAL GENE TRANSFER PROTOCOLS 103-06 (Rebecca N. Lenzi et al. eds., 2014), http://www.ncbi.nlm.nih.gov/books/SeeNBK174837/pdf/ Bookshelf_NBK174837.pdf; see also CTR. FOR BIOLOGICS EVALUATION & RESEARCH, supra note 103. 109 Rick Weiss & Deborah Nelson, Calls Grow for More Oversight of Gene Therapy, WASH. POST, Nov. 24, 1999, at A2. 110 Rainsbury, supra note 57, at 595. 111 Lars Noah, Assisted Reproductive Technologies and the Pitfalls of Unregulated Biomedical Innovation, 55 FLA. L. REV. 603, 605 (2003). 112 Fertility Clinic Success Rate and Certification Act of 1992, Pub. L. No. 102-493, 106 Stat. 3146 (1992). 113 Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing, 66 Fed. Reg. 5447, 5448 (Jan. 19, 2001). 114 Id.

622 FOOD AND DRUG LAW JOURNAL VOL. 71 infectious disease risk” associated with reproductive cells and tissues.115 These regulatory announcements followed on the heels of the controversy surrounding human cloning technologies. Need for Regulation of Human Cloning In February 1997, Ian Wilmut of the Roslin Institute in Scotland reported that his research team had successfully “cloned” a sheep, which they had named Dolly.116 This sparked an intense debate by different members of society on the moral and ethical propriety of human cloning, comparable to the current debate about the application of CRISPR-Cas technology to human germline genome modification. Opponents of human cloning pointed to potential harms to society, potential harms to individuals, potential health risks, and potential for eugenics as reasons to ban human cloning and related therapies entirely.117 Proponents, on the other hand, emphasized the immense potential of cloning, including as a research tool, as a form of assisted reproductive technologies, and as a means of eliminating many genetic disorders.118 Beyond the debate, legislative and executive agencies were trying to assuage public concerns through legislative and executive action. In March 1997, then-President Clinton prohibited the use of federal funding to support human cloning.119 Lawmakers proposed a variety of bills to restrict the use of cloning technologies.120 Concerned that any enacted legislation may stymie medical research, the Pharmaceutical Research and Manufacturers of America and the Biotechnology Industry Organization argued that FDA already had authority to regulate cloning techniques, and as such, further legislation was unwarranted.121 This time, FDA was quick to claim its jurisdiction. Swift Jurisdictional Claim by FDA During an interview on National Public Radio (NPR), Michael Friedman, the then- Acting FDA Commissioner, allegedly confirmed FDA’s authority to regulate human cloning and its intent to do so due to health and safety concerns.122 In response to a question, Friedman allegedly explained that FDA viewed human cloning as another form of gene therapy, which FDA already regulated.123 This revelation hinted to FDA’s reasoning underlying its asserted authority over human cloning.

115 Id. at 5452. 116 I. Wilmut et al., Viable Offspring Derived from Fetal and Adult Mammalian Cells, 385 NATURE 810, 810 (1997). 117 Christine Willgoos, FDA Regulation: An Answer to the Questions of Human Cloning and Germline Gene Therapy, 27 AM. J.L. MED. 101, 106–11 (2001). 118 Id. at 111–13. 119 William J. Clinton, PRESIDENTIAL DIRECTIVE: PROHIBITION ON FEDERAL FUNDING FOR CLONING OF HUMAN BEINGS, (Mar. 4, 1997), http://grants.nih.gov/grants/policy/cloning_directive.htm. 120 Willgoos, supra note 117, at 113–17, 122 n.241 (2001); see also Richard A. Merrill & Bryan J. Rose, FDA Regulation of Human Cloning: Usurpation or Statesmanship?, 1555 HARV. J.L. TECH. 85, 87– 88 (2001). 121 Merrill & Rose, supra note 120, at 98. 122 Id. at 98–99. 123 Id.

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FDA reaffirmed its authority over human cloning a few times afterward. In February 1998, Senator Kennedy was sponsoring legislature to prohibit attempted human cloning.124 The day before the Senate was set to vote on this legislation, FDA Deputy Commissioner for External Affairs, Sharon Holston, wrote a letter to Senator Kennedy to assert FDA’s authority over human cloning technologies, and its intent to exercise its regulatory powers.125 A few months after the letter to Senator Kennedy, FDA sent a letter with the salutation “Dear Colleague” to hundreds of institutional review boards across the country;126 this became known as the “Dear Colleague” letter. The letter publicly confirmed FDA’s statutory authority over “clinical research using cloning technology to create a human being,” as mandated by the PHSA and the FDCA.127 A few years later in March 2001, Kathryn Zoon, Director of FDA’s Center for Biologics Evaluation and Research, testified as witness before the Oversight and Investigations Subcommittee of the U.S. House of Representatives Committee on Energy and Commerce.128 In a statement to the Subcommittee before her scheduled testimony, Zoon reasserted FDA’s authority to regulate human cloning, subject to the biologics provisions of the PHSA, and the drug and device provisions of the FDCA.129 In sharp contrast to the slow morphing of the role of FDA in the regulation of rDNA technologies, FDA was swift and explicit about its regulatory powers in relation to human cloning. This time around, FDA was undeterred by the controversy surrounding human cloning, choosing to focus its actions on “scientific concerns regarding safety” and basing its regulations on “scientific” reasons.130 A document prepared by an unidentified FDA employee provides a detailed analysis of the reasoning underlying FDA’s asserted jurisdiction over human cloning technologies.131 FDA pointed to the PHSA and the FDCA as the sources of its authority.132 Perhaps foreseeing criticism that oppose such a far-reaching interpretation of these statues, FDA emphasized that the statutory purpose of these statutes was “public health protection”.133 By recognizing the statutory purpose of its mandates, FDA set up a potential defense against any textual interpretation of the statutes. FDA then supported its assertion by citing Supreme Court precedent: “[c]ourts have recognized that remedial statutes, such as the FD&C Act and the PHS Act, are to be liberally construed consistent with their public health purpose. See

124 Id. at 99. 125 144 CONG. REC. 1100-01 (1998). 126 Merrill & Rose, supra note 120, at 87, 100–01. 127 U.S. FOOD & DRUG ADMIN., LETTER ABOUT HUMAN CLONING (Oct. 26, 1998), http://www.fda. gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm150508.htm. 128 Merrill & Rose, supra note 120, at 103. 129 FDA CTR. FOR BIOLOGICS EVALUATION & RESEARCH, FDA’S ROLE IN THE USE OF CLONING TECHNOLOGY AS A CAUSE FOR PUBLIC HEALTH CONCERN (Mar. 28, 2001), http://www.fda.gov /NewsEvents/Testimony/ucm115228.htm. 130 Id. 131 U.S. FOOD & DRUG ADMIN., FDA’S JURISDICTION OVER HUMAN CLONING ACTIVITIES (1998), in HUTT, supra note 54, at 1187–89 [hereinafter FDA’S JURISDICTION]. 132 Id. 133 Id.

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United States v. An Article of Drug . . . Bacto–Unidisk, 394 U.S. 784 (1969).”134 The stage had been set; FDA was going to regulate human cloning in accordance with the spirit of its legislative mandate, protecting public health, as supported by the highest U.S. court. Next, FDA explained the scope of its statutory authority to include the regulation of drugs and biological products. The FDCA defined the term “drug” as “articles (other than food) intended to affect the structure or any function of the body.”135 To regulate biological products, FDA relied on section 351 of the PHSA which applies to “any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound), applicable to the prevention, treatment or cure of diseases or injuries of man.”136 The section was amended to include “within the definition of biological products ‘conditions’ as well as diseases” by the Food and Drug Administration Modernization Act of 1997.137 FDA then applied its statutory mandate to regulate drugs and biological products to the regulation of human cloning. FDA characterized human cell clones as both drugs and biological products. In support of its regulatory oversight of human cloning as a drug, FDA explained that: a somatic cell clone is a product intended to affect the structure or function (including the diseases or conditions) of the cloned human being. The continued growth and development of the cloned human being are the result of the maturation of the somatic cell clone. In addition, the somatic cell clone could be viewed as a product intended to affect the structure or function of the woman into whose uterus the somatic cell is to be implanted.138 FDA further stated that: [a] somatic cell clone used to create a cloned human being in order to avoid transmission of a genetic disease from a prospective parent with the disease would be an article intended to prevent the transmission of disease to the cloned human being and thus would fall within this definition. A somatic cell clone used with the intent to create a cloned human being for an infertile couple also could fall within this drug definition in that the product would be used to treat infertility.139 For regulation of human cloning as a biological product, FDA explained that: [a] somatic cell clone used to create a cloned human being for an infertile individual is a product applicable to the treatment of infertility. Likewise, a somatic cell clone used to create a cloned human being to avoid transmission of a genetic disease from a prospective parent is a product

134 Id; see also United States v. An Article of Drug . . . Bacto–Unidisk, 394 U.S. 784, 798 (1969). 135 FDA’S JURISDICTION, supra note 131; see also 21 U.S.C. § 321(g)(1) (2012). 136 FDA’S JURISDICTION, supra note 131; see also 42 U.S.C. § 262 (2012). 137 FDA’S JURISDICTION, supra note 131. 138 Id. 139 Id.

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applicable to the prevention of that genetic disease in the cloned human being.140 Aware that the PHSA does not explicitly reference human clone cells, FDA justified its interpretation by explaining that a human clone cell is “analogous product” under the PHSA. It further explained that [a] somatic cell clone has similarities in composition and function with blood and blood components. A somatic cell clone is analogous to white blood cells, a component of blood, in that both cells are similarly composed because they are somatic cells that contain a nucleus. A somatic cell clone is also like blood and blood components in that they contain cellular elements derived from a living human being and are applicable to diseases or conditions of human beings.141 FDA also distinguished its regulatory approach of human clone cells from that for reproductive tissues that it had proposed in 1997: “Such tissues [i.e. reproductive tissues] raised a number of less substantial issues than those raised by other tissues that have a systemic effect on the body [i.e. human clone cells].”142 Accordingly, reproductive tissues are subject to less regulation. Somatic clone cell, similar to cellular and tissue-based products that have undergone more than minimal manipulation, are subject to FDA premarket review and approval.143 Skepticism over FDA’s Authority There were many critics of FDA’s oversight of human cloning, with regards to authority, capability, and process. 144 Critics questioned whether the provisions of FDCA or PHSA could be expanded to include human cloning.145 In particular, some questioned whether a human clone cell can be considered to be an “analogous product” to a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative.”146 Other critics believed that FDA regulation alone would not suffice and called for more regulation of human cloning.147 Moreover, some queried whether FDA had violated the APA’s requirement for notice-and-comment rulemaking. Despite these criticisms, there has yet to be any judicial challenge to FDA’s assertion of jurisdiction over human cloning. This may partly be due to the “Chevron deference” set forth by the Supreme Court: “if the statute is silent or ambiguous with respect to the specific issue, the questions for the court is whether the agency’s answer is based on a permissible construction of the statute.”148 However, the Court refused

140 Id. 141 Id. 142 Id. 143 FDA’S JURISDICTION, supra note 131. 144 Willgoos, supra note 120, at 119–22; see also Merrill & Rose, supra note 120, at 125–33. 145 Elizabeth C. Price, Does FDA Have Authority to Regulate Human Cloning?, 11 HARV. J.L. & TECH. 619, 641 (1998). 146 Gregory J. Rokosz, Human Cloning: Is the Reach of FDA Authority too far a Stretch?, 30 SETON HALL L. REV. 464, 495–501 (2000). 147 Willgoos, supra note 120, at 119–21. 148 See Chevron, U.S.A., Inc. v. Nat. Res. Def. Council, Inc., 467 U.S. 837, 842–43 (1984).

626 FOOD AND DRUG LAW JOURNAL VOL. 71 to defer to FDA in its regulation of tobacco products.149 As such, these criticisms may prove to be foretelling.

V. PRECEDENT SUPPORTS FDA REGULATION OF CRISPR GENE EDITING TECHNOLOGY

The development of the CRISPR-Cas gene-editing technology has ignited the moral and ethical concerns of scientific breakthroughs, similar to those associated with human cloning. In the backdrop of the ethical and legal concerns, it is important to note that the CRISPR-Cas technology is not the first gene-editing technique. Other gene-editing technologies precede it, and are currently being utilized for the development of therapeutics.150 CRISPR-Cas is distinguishable from existing gene- editing technologies because it is relatively simple to employ by anyone with basic skills in molecular biology, and it is widely available.151 As such, regulations on research may be challenging. However, regulatory frameworks can be used to ensure that any applications to humans are safe, and FDA is well positioned to take on this responsibility. This section will explain the unique attributes of CRISPR-Cas technology and its potential applications; identify existing FDA regulatory frameworks that are currently applicable to the use of CRISPR-Cas products in humans; and provide guidance on how FDA should proceed. A. Distinguishing CRISPR-Cas from Other Gene-Editing Technologies Some have doubted whether the CRISPR-Cas technology is worthy of this ongoing attention and debate.152 Several gene-editing technologies, including meganucleases,153 zinc finger nucleases (ZFNs),154 and transcription activator-like effector nucleases (TALENs)155 precede it, and are actively being used for the development of therapeutics.156 For example, Sangamo Biosciences is conducting clinical trials in HIV patients of a therapy that utilizes ZFN technology.157 CRISPR- Cas technology is distinguishable from the other gene-editing technologies because of

149 See FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120, 125–26 (2000). 150 Cormac Sheridan, CRISPR Germline Editing Reverberates Through Biotech Industry, 33 NATURE BIOTECHNOLOGY 431, 431 (2015). 151 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., supra note 6 (Testimony of Doudna). 152 Sheridan, supra note 150, at 431. 153 Maria Jasin & Rodney Rothstein, Repair of Strand Breaks by Homologous Recombination, 5 COLD SPRING HARBOR PERSP. BIOLOGY 1, 5 (2013). 154 Mattew H. Porteus & David Baltimore, Chimeric Nucleases Stimulate Gene Targeting in Human Cells, 300 SCI. 763, 763 (2003). 155 Matthew J. Moscou & Adam J. Bogdanove, A Simple Cipher Governs DNA Recognition by TAL Effectors, 326 SCIENCE 1501 (2009); see also Jens Boch et al., Breaking the Code of DNA Binding Specificity of TAL-type III Effectors, 326 SCIENCE 1509 (2009). 156 Sheridan, supra note 150. 157 Id.;. see also Clinical Trials, SANGAMO BIOSCIENCES, http://www.sangamo.com/pipeline/clinical- trials.html (last visited Sept. 2, 2016).

2016 FDA REGULATION OF CRISPR 627 its accessibility, its ease of use and its low cost.158 Another scientist, who is skeptical that CRISPR-Cas technology creates any new problems, theorized that meganucleases, ZFNs, and TALENs can be used for human germline modification; he noted that “CRISPR is essentially a revolution because it makes gene-editing accessible to any researchers—that’s all.”159 Separating the signal from the noise, many have pointed out that these conversations may be premature. There still remain major outstanding technical and biological barriers to implementing germline genome modification with clinical applications.160 Specificity of the technology is still a technological concern as there have been reports of off-target genome modifications with CRISPR-Cas.161 Biologically, scientists are still limited by the actual knowledge of the human genome.162 Since many traits are determined by multiple genes, it is challenging to predict the biological consequence of any specific gene modification.163 Moreover, six decades after rDNA biotechnology breakthrough, there are no FDA-approved gene therapies as of March 2016. Similarly, FDA has not received any IND applications for clinical application of modified human embryos. B. Existing FDA Regulatory Frameworks are Applicable to CRISPR-Cas Technology CRISPR-Cas technology is fundamentally a form of rDNA technology. Target cells are transfected with genes encoding CRISPR and Cas proteins; the expression of these genes initiates a series of events that result in the modification of the target gene. Its clinical applications can be divided into three categories: (1) human somatic (non- reproductive cell) genome modification; (2) human germline (reproductive cells and embryos) genome modification; and (3) non-human genome modification. There exist applicable FDA regulatory frameworks for these three categories. Regulation of Human Somatic Genome Modification CRISPR-Cas technology may be used to modify human somatic cells ex vivo. It may also be used to modify human somatic cells in vivo, for example to treat cystic fibrosis. As such, most human somatic genome modification using CRISPR-Cas system fall within the regulatory framework for somatic cell therapy and gene therapy that FDA created in response to the development of rDNA technology. In the 1998 Guidance for somatic cell gene therapy and gene therapy, FDA defined somatic cell therapy as: “the administration to humans autologous allogeneic or xenogeneic living cells which have been manipulated or processed ex vivo”;164 and gene therapy as:

158 Sheridan, supra note 150, at 431. 159 Id. 160 Bosley, supra note 5, at 478–86. 161 Id. 162 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., supra note 6 (testimony of Doudna). 163 Bosley, supra note 5, at 478–86. 164 CTR. FOR BIOLOGICS EVALUATION & RESEARCH, supra note 103, at 3.

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a medical intervention based on modification of the genetic material of living cell. Cells may be modified ex vivo for subsequent administration to humans, or may be altered in vivo by gene therapy given directly to the subject. When the genetic manipulation is performed ex vivo on cells which are then administered to the patient, this is also a form of somatic cell therapy.165 The Guidance emphasized that its scope excluded germline cells by stating that: [f]or the purpose of this Guidance, the term somatic cell therapy refers to the administration to humans of autologous, allogeneic, or xenogeneic living non-germline cells, . . . for therapeutic, diagnostic, or preventive purposes [;] . . . this document “does not discuss genetic manipulation aimed at the modification of germ cells.166 As such, the application of CRISPR-Cas technology to the genome modification of human somatic cells ex vivo or in vivo will be subject to FDA regulations for somatic cell therapy and gene therapy. Regulation of Human Germline Genome Modification By restricting the 1998 Guidance for somatic cell therapy and gene therapy to somatic cells only, FDA signaled that it intended to regulate manipulated germline cells differently but did not provide further information. It is unclear whether FDA considered specific regulations for germline modifications at that time. CRISPR-Cas technology is unlikely to be subject to FDA regulations for human cloning. The human cloning technology used to create Dolly, somatic cell nuclear transfer (SCNT), is fundamentally different from the CRISPR-Cas technology. On FDA’s webpage on cloning, FDA explains SCNT to “involve transferring the nucleus of an adult . . . somatic cell, into a[n] . . . egg from which the nucleus has been removed.”167 As such, SCNT is a form of modification of germline cells, specific to reproductive eggs. However, SCNT is not germline engineering, which refers to targeted, specific modification of genetic information in cells.168 Conversely, CRISPR-Cas technology may not be used to create a cloned cell, whose genetic information is identical to the parent cell; it can, however, be used to modify a cloned cell. Accordingly, FDA regulations for human cloning are not applicable to CRISPR- Cas technology. Since CRISPR-Cas technology is easy to use and widely available, assisted reproduction centers, who likely do not depend on federal funding, may attempt to use CRISPR-Cas systems to modify the genomes of oocytes, sperm, and/or embryos so as to prevent a genetically-linked disease in the offspring. Hence, FDA may be able to regulate the application of CRISPR-Cas technology to human germline cells and embryos as a form of assisted reproductive technologies (ARTs). ATRs are medical

165 Id. 166 Id. (emphasis added). 167 Cloning, U.S. FOOD & DRUG ADMIN., http://www.fda.gov/BiologicsBloodVaccines/CellularGene TherapyProducts/Cloning/default.htm (last visited Sept 2, 2016). 168 Mario R. Cappechi, Gene Targeting in Mice: Functional Analysis of the Mammalian Genome for the Twenty-First Century, 6 NATURE REV. GENETICS 507, 507 (2005).

2016 FDA REGULATION OF CRISPR 629 procedures involving the manipulation of gametes and embryos.169 FDA defines ART as: “[a]ll treatments or procedures that include the in vitro handling of human oocytes and sperm or embryos for the purpose of establishing a pregnancy.”170 There are different types of ARTs. In vitro fertilization is the most commonly performed.171 Other ARTs include intracytoplamisc sperm injection, preimplantation genetic diagnosis/screening and assisted hatching.172 Artificial insemination by itself not considered a form of ART.173 FDA started regulating ARTs, practiced primarily in assisted reproduction centers and fertility clinics, about two decades ago. Before then, regulation was done largely at the state level.174 Then in 1997-98, FDA announced in the Federal Register proposed regulations for ARTs and asked for comments.175 The final regulations were announced in 2001, with the national roll-out expected by 2003.176 Letters were also sent out to centers using ARTs to inform them of the new regulations.177 FDA’s regulation of ARTs and assisted reproduction centers standardized assisted reproduction procedures relating to the handling of gametes and pre-embryos178 and gamete screening.179 All facilities that handle gametes and pre-embryos are required to register with FDA, and are to be audited to ascertain compliance.180 Proponents asserted that FDA’s regulation addressed safety concerns.181 Opponents argued that FDA was reaching beyond its authority to regulate pharmaceutical products and devices and into the realm of medical practice.182 Moreover, opponents argued that regulation could become cumbersome and expensive; this could result in an increase in the cost of treatment, which is often not covered by insurance.183

169 David Adamson, Regulation of Assisted Reproductive Technology in the United States, 39 FAM. L.Q. 727, 727(2005). 170 Briefing Information, Food & Drug Admin. Advisory Committee for Reproductive Health Drugs (Sept. 29, 2003), http://www.fda.gov/ohrms/dockets/ac/03/briefing/3985B1_03_Definitions.pdf. 171 Adamson, supra note 169, at 171. 172 Id. 173 Id. 174 David Balser, FDA Regulation of Assisted Reproductive Technology in the USA, 5 REPROD. BIOMED.ONLINE 90, 90 (2002). 175 Establishment Registration and Listing for Manufacturers of Human Cellular and Tissue-Based Products, 63 Fed. Reg. 26,744 (May 14, 1998) (to be codified at 21 C.F.R. pts. 207, 807, and 1271). 176 Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing, 66 Fed. Reg. 5447 (Jan. 19, 2001) (to be codified at 21 C.F.R. pts. 207, 807, and 1271); see also Adamson, supra note 169, at 736. 177 Adamson, supra note 169, at 735–36. 178 Balser, supra note 174, at 90. 179 Human Cells, Tissues, and Cellular and Tissue-Based Products, supra note 176; see also Adamson, supra note 169, at 735–36. 180 Human Cells, Tissues, and Cellular and Tissue-Based Products, supra note 176; see also Balser, supra note 174. 181 Balser, supra note 174, at 90. 182 Id. 183 Id at 91.

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Assisted reproduction centers are required to attain FDA approval by way of a new drug application to perform various ARTs that manipulate gametes and embryos in different ways, including cytoplasmic transfer, co-culturing, paternal leukocyte immunizations, and SCNT.184 As such, application of CRISPR-Cas technology to manipulate the genome of gametes and embryos may be subject to FDA regulation of ARTs. However, the existing regulations may not be sufficient as the current regulations were designed primarily to reduce the risk of transmission of infection or disease that can be associated with such tissues.185 CRISPR-Cas technology raises different safety concerns. Therefore, the existing ART regulatory framework needs to be revised and expanded to effectively address the safety issues associated with CRISPR-Cas technology. A recent development in molecular biology technology may also be relevant to the regulation of CRISPR-Cas technology. Scientists recently reported technologies for the manipulation of mitochondria of oocytes in order to prevent mitochondria-linked diseases and infertility in women.186 Mitochondria are cellular organelles that play a role in energy production to support cellular processes.187 They also have their own DNA and associated transcriptional and protein synthesizing machinery.188 So far, the medical and scientific communities have identified more than 300 mitochondrial DNA mutations that cause disease.189 Moreover, studies have shown a link between mitochondria and female infertility.190 Reported mitochondria manipulation techniques such as pronuclear transfer, spindle transfer, cytoplasmic transfer/mitochondrial transfer may have therapeutic applications. FDA is currently considering whether to create regulations for oocyte modification for the prevention of transmission of mitochondrial disease or treatment of infertility.191 Since these technologies involve augmenting or replacing mitochondrial DNA in oocytes and early embryos, any regulations developed by FDA may be applicable to CRISPR-Cas technology as well.

184 Adamson, supra note 169, at 735–36. 185 Balser, supra note 174, at 90; see also Lucy Frith and Eric Blyth, Assisted Reproductive Technology in the USA: Is More Regulation Needed? 29 REPROD. BIOMED. ONLINE 516, 517 (2014). 186 Marcos Roberto Chiaratti et al., Therapeutic Treatments of mtDNA Diseases at the Earliest Stages of Human Development, 11 MITOCHONDRION 820, 820–28 (2011); see also Joanna Poulton et al., Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them, 6 PLOS GENETICS 1, 1–6 (2010); Akiko Yabuuchi et al., Prevention of Mitochondrial Disease Inheritance by Assisted Reproductive Technologies: Prospects and Challenges, 1820 BIOCHIMICA ET BIOPHYSICA ACTA 637, 637–42 (2012). 187 FDA Briefing Document, Cellular, Tissue, and Gene Therapies Advisory Committee, Oocyte Modification in Assisted Reproduction of the Prevention of Transmission of Mitochondrial Disease or Treatment of Infertility, at 5 (Feb. 25–26, 2014), http://www.fda.gov/downloads/advisorycommittees/ committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycom mittee/ucm385461.pdf. 188 Id. 189 Id at 8. 190 Id at 11. 191 Id. at 19–22.

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Regulation of Non-Human Genome Modification Researchers are currently using CRISPR-Cas technology in animals to create disease models.192 Hence, application of the technology to non-human cells for clinical application is possible. Accordingly, some applications of CRISPR-Cas technology may be subject to FDA regulation of xenotransplantation:

any procedure that involves the transplantation, implantation or infusion into into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman cells, tissues or organs.193

Xenotransplantation was first attempted in 1905 when a French surgeon inserted slices of a rabbit kidney into a child suffering from renal failure.194 However, FDA did not assert its jurisdiction over xenotransplants until 1980, when it announced that a porcine replacement heart valve, “a medical device,” would require premarket approval or a notice of completion of a product development protocol.195 Since then, FDA has published a few guidances and guidelines, including a guidance in 1999 on health issues due to non-human primate xenografts,196 a 2001 guideline on infectious disease concerns,197 and a 2003 guidance on preclinical and clinical investigations.198 There has been little challenge to FDA’s oversight of xenotransplantation and xenotransplants, probably because such activities require human subjects. As noted by experts in FDA regulations: “whether categorized as drugs, biologics, or medical devices, materials derived from animal implanted in human subjects fall under FDA’s authority to regulate the clinical investigation of medical products.”199 The application

192 Randall J. Platt et al., CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling¸ 159 CELL 440, 440 (2014); see also Lawrence B. Schook et al.,, Emerging Technologies to Create Inducible and Genetically Defined Cancer Models, 7 FRONTIERS GENETICS 1, 1–2 (2016). 193 U.S. FOOD & DRUG ADMIN., Xenotransplantation, http://www.fda.gov/biologicsbloodvaccines/ xenotransplantation/default.htm (last visited Sept. 2, 2016). 194 Luis H. Toledo-Pereyra & F. Lopez-Neblina, Xenotransplantation: A View to the Past and an Unrealized Promise to the Future, 1 EXPERIMENTAL & CLINICAL TRANSPLANTATION 1, 1 (2003). 195 Cardiovascular Devices; Effective Date of Requirement for Premarket Approval; Replacement Heart Valve, 52 Fed. Reg. 18162 (May 13, 1987) (to be codified at 21 C.F.R. pt. 870); see also Cardiovascular Devices; General Provisions, 45 Fed. Reg. 7904 (Feb. 5, 1980) (to be codified at 21 C.F.R. pt. 870); Cardiovascular Devices; Premarket Approval of the Replacement Heart Valve,); 51 Fed. Reg. 5296 (Feb. 12, 1986) (to be codified at 21 C.F.R. pt. 870). 196 CTR. FOR BIOLOGICS EVALUATION & RESEARCH, U.S. DEP’T OF HEALTH & HUMAN SERV., GUIDANCE FOR INDUSTRY: PUBLIC HEALTH ISSUES POSED BY THE USE OF NON-HUMAN PRIMATE XENOGRAFTS IN HUMANS (1999), http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm092866.pdf. 197 U.S. DEP’T OF HEALTH AND HUMAN SERVS., PHS GUIDELINE ON INFECTIOUS DISEASE ISSUES IN XENOTRANSPLANTATION (2001), http://www.fda.gov/downloads/BiologicsBloodVaccines/Guidance ComplianceRegulatoryInformation/Guidances/Xenotransplantation/UCM092858.pdf. 198 CTR. FOR BIOLOGICS EVALUATION & RESEARCH, U.S. DEP’T OF HEALTH & HUMAN SERVS., GUIDANCE FOR INDUSTRY: SOURCE ANIMAL, PRODUCT, PRECLINICAL, AND CLINICAL ISSUES CONCERNING THE USE OF XENOTRANSPLANTATION PRODUCTS IN HUMANS (2003), http://www.fda.gov/downloads/ BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/uc m092707.pdf. 199 Hutt, supra note 54 at 1189–90. 632 FOOD AND DRUG LAW JOURNAL VOL. 71 of CRISPR-Cas technology to modify the genome of non-human cells for clinical applications is likely to fall within FDA’s oversight of xenotransplantation. C. Other Considerations in Support of FDA Regulation There are other considerations in support of FDA regulation of CRISPR-Cas technology beyond the existence of applicable regulatory frameworks. FDA has great flexibility and expansive oversight over pharmaceutical drugs and medical devices. FDA believes that the FDCA and the PHSA provide it with immense discretion in interpreting the statutory provisions relating to drugs, medical devices, and biologics to fulfil its duty to protect public health. As such, FDA has relied on the FDCA and PHSA to regulate several clinical procedures and products, including cloning, with no explicit legislative grant, or judicial challenge. FDA can in theory create regulations to address the safety issues associated with CRISPR-Cas technology with little to no backlash. Moreover, FDA oversight extends to both public and private institutions. This is especially important with respect to CRISPR-Cas technology, which is easy to use, widely available, and inexpensive. Private institutions such as fertility clinics, are capable of using it without reliance on federal funding. Hence, federal legislation may be ineffective if it prohibits only funding of specific research activities. FDA authority over private institutions allow it to regulate the private sector in situations in which federal legislative prohibitions do not explicitly address. FDA does not need to decide the moral and ethical limits of CRISPR-Cas application in order to regulate it. It did not need to in order to regulate cloning. When Zoon, then-Director of FDA’s Center for Biologics Evaluation and Research testified to the Oversight and Investigations Subcommittee of the House Committee on Energy and Commerce in March 2001 regarding FDA’s regulation of cloning, she explained that FDA’s role was based on “significant scientific concerns regarding safety” and FDA’s assessment of its role is a “scientific one.”200 Accordingly, as scientists, bioethicists, and other stakeholders debate the ethical, moral, and social implications of CRISPR-Cas applications, FDA can proceed with regulations if there are safety concerns based on scientific data. D. The Third Time is a Charm FDA can learn from its previous experiences to guide its regulation of CRISPR-Cas technology. First, FDA should announce its oversight extends to applications for CRISPR-Cas sooner rather than later. It took FDA a decade to claim jurisdiction over rDNA technology and gene therapies; in contrast, FDA asserted authority over human cloning within a few years. A swift jurisdictional claim would provide leadership and direction in a time of great controversy, and would allay at least the safety concerns of industry members and the public at large. Second, FDA should ensure that it abides by the APA, and in particular, employ a notice-and-comment rulemaking approach to creating its regulations. Some have criticized FDA’s approach to creating its regulations for human cloning for not satisfying the requirements of the APA.201 Furthermore, the quality and effectiveness of the regulations are likely to be enhanced

200 Merrill, supra note 120, at 103. 201 Id. at 124–31.

2016 FDA REGULATION OF CRISPR 633 if FDA gathers information from the different interest groups to formulate its final rules. Third, FDA should provide clear standards for its regulatory approach. Its regulations for both rDNA applications and human cloning were criticized for lack of clarity and guidance.202

VI. SUMMARY

The CRISPR-Cas technology is truly a revolutionary biotechnology breakthrough. Its applications are innumerable, not only for clinical use in humans, but also for use in plants and animals. It will be impossible to police its use because of its low cost and easy accessibility. A regulatory framework, however, can ensure safe use and minimal risk to individuals and society. The FDCA and PHSA seemingly have provided FDA with broad discretion on regulating pharmaceutical products and medical devices for the purpose of protecting public health. FDA can rely on these remedial statutes to regulate CRISPR-Cas biotechnology without legislative reform. Moreover, precedent supports FDA regulation of CRISPR-Cas technology, which is most likely to be used as a form of gene therapy, with potential application to assisted reproduction. Existing FDA regulatory frameworks and mechanisms may be applicable. These frameworks, however, may need to be revised to address specific safety concerns associated with CRISPR-Cas system. So long as FDA’s approach satisfies the requirements of the APA, FDA can extend its oversight to clinical applications of CRISPR-Cas, with industry support and no judicial challenge.

202 Rainsbury, supra note 57, at 581; Merrill, supra note 120, at 131.