Gene Therapy Oversight: Lessons for Nanobiotechnology

U.S. Food and Drug Administration, FDA Nanotechnology: FAQs, available at <http://www.fda.gov/nanotechnology/faqs.html> (last visited May 13, 2009) per notes 155, 236 below. See also U.S. Environmental Protection Agency, Nanotechnology: An EPA Research Perspective, available at <http://es.epa.gov/ncer/nano/factsheet/nanofactsheetjune07.pdf> (last visited September 8, 2009). The FDA does not have its own formal definition of nanotechnology, but the agency contributed to the NNI definition. Id.

See National Institutes of Health, Office of Portfolio Analysis & Strategic Initiatives, “Nanomedicine,” available at <http://nihroadmap.nih.gov/nanomedicine> (last visited September 10, 2009).

See, e.g., Wu X. , “Immunofluorescent Labeling of Cancer Marker Her2 and Other Cellular Targets with Semiconductor Quantum Dots,” Nature Biotechnology 21, no. 1 (2003): 41–46 (describing how this group is using quantum dots for cancer research); Loo C. , “Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy,” Nano Letters 5, no. 4 (2005): 709–711.

Press Release, Arrowhead Research Corp., “Arrowhead Research Subsidiary, Insert Therapeutics, Treats First Patient with Nano-Engineered Anti-Cancer Therapeutic,” July 19, 2006, available at <http://www.arrowheadresearch.com/publications/060719041827.html> (last visited September 10, 2009).

U.S. Department of Energy, Office of Science, “Gene Therapy,” available at <http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml> (last visited September 10, 2009).

See Mastrobattista E. , “Artificial Viruses: A Nanotechnological Approach to Gene Delivery,” Nature Reviews: Drug Discovery 5, no. 2 (2006): 115–121, at 115 (stating that despite the “large number of ongoing trials, success with gene therapy has been limited” and summarizing “some successful applications of gene-delivery systems in gene-therapy clinical trials”).

See infra, text at notes 170–177.

Chowdhury E. H. Akaike T. , “A Bio-Recognition Device Developed onto Nano-Cyrstals of Carbonate Apatite for Cell-Targeted Gene Delivery,” Biotechnology & Bioengineering 90, no. 4 (2005): 414–421, at 414.

See, e.g., Bharali D. J. , “Organically Modified Silica Nanoparticles: A Nonviral Vector for In Vivo Gene Delivery and Expression in the Brain,” Proceedings of the National Academy of Sciences 102, no. 32 (2005): 11539–11544.

See, e.g., Eliyahu H. , “Novel Dextra-Spermine Conjugates as Transfecting Agents: Comparing Water-Soluble and Micellar Polymers,” Gene Therapy 12, no. 6 (2005): 494–503, at 494.

See id.

Id. (“The ideal gene delivery system must protect the nucleic acid from degradation, have the ability to deliver it to target cells, and should induce efficient gene expression in the presence of body fluids such as serum and interstitial fluids, concomitant with being nontoxic, nonimmunogenic, and stable during storage and treatment.”).

See Chowdhury Akaike , supra note 9, at 414.

Id. This is what caused Jesse Gelsinger's death in 1999. See Smith L. Byers J. F. , “Gene Therapy in the Post-Gelsinger Era,” JONA's Healthcare Law, Ethics & Regulation 4, no. 4 (2002): 104–110, at 104; Science Blog, “Researchers Use Nano-Particles to Deliver Gene Therapy,” available at <http://www.scienceblog.com/cms/researchers_use_nano-particles_to_deliver_gene_therapy> (last visited September 10, 2009) (“[V]iral-based gene delivery systems…have to infect the cell membrane to introduce the genes that can help cure disease in cells. [The viruses] lucky enough to make it through the tough membranes to infect the damaged cells do so in a very unpredictable manner. And in some cases, that unpredictability of the new gene interrupts an important healing sequence, harming the cell by potentially causing mutations leading to cancer, and even triggering a dormant oncogene — oncogene is a gene that helps cells undergo dramatic change — in the body resulting in an incurable lifethreatening disease.”).

See Chowdhury Akaike , supra note 9, at 414; see also Brunetti-Pierri N. , “Acute Toxicity After High-Dose Systemic Injection of Helper-Dependent Adenoviral Vectors into Nonhuman Primates,” Human Gene Therapy 15, no. 1 (2004): 35–46, at 43–44.

See Chowdhury Akaike , supra note 9, at 414.

Mastrobattista , supra note 7, at 115. Mastrobattista also list “limited DNA-carrying capacity, lack of target-cell specificity, and immunogenicity” as limitations of viral vectors. Id. See also Chowdhury Akaike , supra note 9, at 414.

See, e.g., Mastrobattista , supra note 7.

Eliyahu , supra note 11, at 494, citing Templeton N. S. , “Liposomal Delivery of Nucleuc Acids In Vivo,” DNA & Cell Biology 21, no. 12 (2002): 857–867.

See, e.g., Eliyahu , supra note 11; Roy I. , “Optical Tracking of Organically Modified Silica Nanoparticles as DNA Carriers: A Nonviral, Nanomedicine Approach to Gene Delivery,” Proceedings of the National Academy of Sciences 102, no. 2 (2005): 279–284, at 279.

Roy , supra note 21, at 279.

Introgen Therapeutics, Inc., <http://www.introgen.com> (last visited September 10, 2009).

Science Daily, “Intravenous Nanoparticle Gene Therapy Shows Activity in Stage IV Lung Cancer,” available at <http://www.sciencedaily.com/releases/2007/04/070417162301.htm> (last visited September 10, 2009).

See id. The University of Texas System owns stock in Introgen.

Hayes M. E. , “Genospheres: Self-Assembling Nucleic Acid-Lipid Nanoparticles Suitable for Targeted Gene Delivery,” Gene Therapy 13, no. 7 (2006): 646–651, at 646.

Id., at 650.

Roy , supra note 21, at 279.

“Using Nanoparticles, In Vivo Gene Therapy Activates Brain Stem Cells,” July 26, 2005, available at <http://www.nanotechwire.com/news.asp?nid=2156> (last visited September 10, 2009).

Roy , supra note 21, at 279.

Id., at 279–280.

Panyam J. Labhasetwar V. , “Biodegradable Nanoparticles for Drug and Gene Delivery to Cells and Tissue,” Advanced Drug Delivery Reviews 55, no. 3 (2003): 329–347, at 334, 339. This research involved biodegradable nanoparticles that encapsulated DNA. The nanoparticles protect the DNA from degradation due to certain enzymes. “PLGA” stands for poly-(d,1-lactide-co-glycolide), a biocompatible, biodegradable polymer.

Id., at 334.

See id., at 334–335.

Guo S. , “Specific Delivery of Therapeutic RNAs to Cancer Cells via the Dimerization Mechanism of phi29 Motor RNA,” Human Gene Therapy 16, no. 9 (2005): 1097–1110, at 1097; Khaled A. , “Controllable Self-Assembly of Nanoparticles for Specific Delivery of Multiple Therapeutic Molecules to Cancer Cells Using RNA Nanotechnology,” Nano Letters 5, no. 9 (2005): 1797–1808, at 1797.

Guo , supra note 40, at 1097; Khaled , supra note 40, at 1797.

Guo , supra note 40, at 1098.

See, e.g., Greber D. Fussenegger M. , “Mammalian Synthetic Biology: Engineering of Sophisticated Gene Networks,” Journal of Biotechnology 130, no. 4 (2007): 329–345, at 329.

ETC Group, “Extreme Genetic Engineering: An Introduction to Synthetic Biology,” January 2007, available at <http://www.etcgroup.org/upload/publication/602/01/synbioreportweb.pdf> (last visited September 10, 2009).

Id.; Doktycz M. J. Simpson M. L. , “Nano-Enabled Synthetic Biology,” Molecular Systems Biology 3, no. 125 (May 2007): 1–10, at 1.

ETC Group, supra note 45, at 1; see also id., at 5 (“Synthetic biology may be the converging technology, par excellence.”).

Id., at 1.

Isaacs F. J. , “RNA Synthetic Biology,” Nature Biotechnology 24, no. 5 (2006): 545–554, at 545.

See id.

See, e.g., Serrano L. , “Synthetic Biology: Promises and Challenges,” Molecular Systems Biology 3, no. 158 (December 2007): 1–5, at 3.

See id.

National Institutes of Health, Recombinant DNA Advisory Committee, Meeting Minutes, September 17–18, 2007, available at <http://oba.od.nih.gov/oba/rac/minutes/RAC_minutes_09–07.pdf> (last visited September 10, 2009).

Id., at 30.

National Institutes of Health, Recombinant DNA Advisory Committee Agenda, 113th Meeting, June 17–18, 2008, available at <http://oba.od.nih.gov/oba/RAC/meetings/Jun2008/June-08Agenda.pdf> (last visited September 10, 2009).

Id., at 3.

National Institutes of Health, Recombinant DNA Advisory Committee, Meeting Minutes, June 17–18, 2008, at 20–21, available at <http://oba.od.nih.gov/oba/RAC/meetings/jun2008/RAC_Minutes_06–08.pdf> (last visited September 10, 2009).

Id., at 22.

Id., at 23.

Swazey J. P. , “Risks and Benefits, Rights and Responsibilities: A History of the Recombinant DNA Research Controversy,” Southern California Law Review 51, no. 6 (1978): 1019–1078, at 1021.

Fredrickson D. S. , The Recombinant DNA Controversy - A Memoir: Science, Politics, and the Public Interest 1971–1981 (Washington, D.C.: ASM Press, 2001): At 8–9.

Swazey , supra note 60, at 1021.

See Fredrickson , supra note 61, at 8–9; Swazey , supra note 60, at 1021. But the reality was that “[no] one could be certain what that combination of genes might do, and the possibilities ranged from nothing at all to some nightmarish version of contagious cancer.” Rogers M. , Biohazard (New York: Knopf, 1977): at 37.

See Fredrickson , supra note 61, at 9; Swazey , supra note 60, at 1021; see also Rogers , supra note 65, at 36–37.

Fredrickson , supra note 61, at 9; Swazey , supra note 60, at 1021.

Fredrickson , supra note 61, at 8–9.

Id.; Swazey , supra note 60, at 1021.

Fredrickson , supra note 61, at 10; Swazey , supra note 60, at 1021; see also Rogers , supra note 65, at 38.

Swazey , supra note 60, at 1022.

Fredrickson , supra note 61, at 11.

Id., at 12.

Id., at 14.

Id. “[S]eventy-eight of the ninety-odd participants voted to send a letter of concern to the prestigious National Academy of Sciences.” Rogers , supra note 65, at 42.

Id., at 14.

Singer M. Söll D. , “Guidelines for DNA Hybrid Molecules,” Science 181, no. 4105 (1973): 1114.

Fredrickson , supra note 61, at 15.

Fredrickson , supra note 61, at 16; Berg P. , “Potential Biohazards of Recombinant DNA Molecules,” Science 185, no. 4148 (1974): 303.

Swazey , supra note 60, at 1024–1025.

Fredrickson , supra note 61, at 17.

Berg P. , “Summary Statement of the Asilomar Conference on Recombinant DNA Molecules,” Proceedings of the National Academy of Sciences 72, no. 6 (1975): 1981–1984, at 1981.

Fredrickson , supra note 61, at 18–27.

Berg , supra note 83, at 1981.

Id., at 1981–1982. Biological barriers include (1) “fastidious bacterial hosts unable to survive in natural environments; and (2) nontransmissible and equally fastidious vectors…able to grow only in specified hosts.” Id. at 1982.

Berg , supra note 80, at 303; Fredrickson , supra note 61, at 31–32. NIH had the statutory authority to form the RAC under 42 U.S.C. § 282(b)(6), which stated that the Director of NIH may “establish such technical and scientific peer review groups and scientific program advisory committees as are needed.” 42 U.S.C. § 282(b) (6); Rainsbury J. M. , “Biotechnology on the RAC: FDA/NIH Regulation of Human Gene Therapy,” Food & Drug Law Journal 55, no. 4 (2000): 575–600, at 576 n.5.

Fredrickson , supra note 61, at 33. The first RAC members (by institutional affiliation and expertise) were: NIH Deputy Director for Science, Chair; Yale, molecular genetics; University of Michigan, molecular genetics; University of Alabama, microbiology; Rockefeller University, cell biology; University of Washington, microbiology; University of California at La Jolla, molecular biology; Stanford, molecular biology; Hopkins Johns , molecular biology; Brookhaven National Lab, molecular biology; University of Wisconsin, phage expert; Harvard, molecular biology; Evergreen State College, biology; Scripps Research Foundation, microbiology; Chief of Viral Diseases, National Institute of Allergy & Infectious Diseases; University of Texas, Austin, government/public affairs (added late 1975); and Georgetown University, ethics (added early 1976). Id., at 34.

Areen J. , “Regulating Human Gene Therapy,” West Virginia Law Review 88, no. 2 (1985): 153–171, at 156, quoting Califano J. , Governing America: An Insider's Report from the White House and the Cabinet (New York: Simon and Schuster, 1981): at 203.

Id., quoting Califano , supra note 93, at 203 (internal quotation marks omitted).

Fredrickson , supra note 61, at 36.

Recombinant DNA Research Guidelines, 41 Federal Register 27,902 (July 7, 1976); see Fredrickson , supra note 61, at 39.

Fredrickson , supra note 61, at 40.

Fredrickson took over as NIH Director on July 1, 1975. The NIH Almanac: Historical Data, available at <http://www.nih.gov/about/almanac/historical/directors.htm> (last visited September 10, 2009).

Fredrickson , supra note 61, at 44; Recombinant DNA Research Guidelines, supra note 96, at 27,902. RAC went through three versions of the guidelines after Asilomar. Fredrickson D. S. , “A History of the Recombinant DNA Guidelines in the United States,” in Morgan J. Whelan W. J. , eds., Recombinant DNA and Genetic Experimentation (New York: Pergamon Press, 1979): At 151, available at <http://profiles.nlm.nih.gov/FF/B/B/K/C/_/ffbbkc.pdf> (last visited September 10, 2009) (stating that Fredrickson “could not even have explained the crucial distinctions between Federal guidelines and regulations“).

Fredrickson , “A History of the Recombinant DNA Guidelines in the United States,” supra note 99, at 151–152.

Fredrickson , supra note 61, at 51.

Id., citing Memorandum from Susan K. Feldman to Director, National Institutes of Health, Definition and Procedures Regarding Regulations for Research on Recombinant DNA Molecules: Information (January 13, 1976) (on file with the National Institutes of Health Central Files, Com 4-4-7-1A).

Id., at 50.

Id., at 51.

Fredrickson , supra note 61, at 272.

Id., at 272.

Thompson L. , “Human Gene Therapy: Harsh Lessons, High Hopes,” FDA Consumer Magazine 34, no. 4 (2000): 19–24, available at <http://www.fda.gov/fdac/features/2000/500_gene.html> (last visited May 14, 2009).

Rainsbury , supra note 90, at 578.

Fredrickson , supra note 61, at 272–274; Rainsbury , supra note 90, at 578.

President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Splicing Life: A Report on the Social and Ethical Issues of Genetic Engineering with Human Beings (Washington, D.C.: U.S. Government Printing Office, 1982): At 3–5, available at <http://bioethics.gov/reports/past_commissions/splicinglife.pdf> (last visited September 10, 2009) [hereinafter Splicing Life].

Id., at 3–5.

Hearings on Human Genetic Engineering Before the Subcommittee on Investigations and Oversight for the House Comm. on Science and Tech., 97th Cong., 2d Sess. 441–454 (November 16–18, 1982) [hereinafter Hearings on Human Genetic Engineering]; Rainsbury , supra note 90, at 578–581.

Hearings on Human Genetic Engineering, supra note 114.

Rainsbury , supra note 90, at 579.

Id., at 579.

Office of Technology Assessment, Human Gene Therapy: Background Paper (December 1984) (on file with OTA, Washington, D.C.) [hereinafter OTA, Human Gene Therapy]; Rainsbury , supra note 90, at 578–581.

OTA, Human Gene Therapy, supra note 118; Rainsbury , supra note 90, at 578–581.

OTA, Human Gene Therapy, supra note 118; Rainsbury , supra note 90, at 578–581.

44 Federal Register 17,844 (1984); Rainsbury , supra note 90, at 578–581; Working Group on a Response to the Splicing Life Report, April 11, 1983. On the evolution from Working Group to Human Gene Therapy Subcommittee, see National Institutes of Health, Office of Science Policy, “Gene Therapy for Human Patients: Information for the General Public,” April 1990, available at <http://oba.od.nih.gov/rdna_rac/rac_general_public.html> (last visited May 15, 2009).

Rainsbury , supra note 90, at 578–581.

Human Gene Therapy Subcommittee, National Institutes of Health Recombinant DNA Advisory Committee, “Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Protocols,” DNA Technical Bulletin 1, no. 4 (1986): 221–242 [hereinafter NIH Points to Consider].

See Rainsbury , supra note 90, at 577. DHHS had promulgated regulations for oversight of human subjects research. Areen , supra note 92, at 159, citing 45 C.F.R. § 46 (1983). At the heart of the regulations was review by the Institutional Review Board (IRB) at the researcher's home institution.

NIH Points to Consider, supra note 123; Gage J. L. , “Government Regulation of Human Gene Therapy,” Jurimetrics 27, no. 2 (1987): 200–218, at 207–209; 50 Federal Register 2,942 (1985).

Rainsbury , supra note 90, at 581; Friedmann T. Noguchi P. Mickelson C. , “The Evolution of Public Review and Oversight Mechanisms in Human Gene Transfer Research: Joint Roles of the FDA and NIH,” Current Opinion in Biotechnology 12, no. 3 (2001): 304–307, 304.

51 Federal Register 23,309 (June 26, 1986) (“Nucleic acids or viruses used for human gene therapy will be subject to the same requirements as other biological drugs.”).

U.S. Food and Drug Administration, Center for Drugs and Biologics, “Points to Consider in Human Somatic Cell Therapy and Gene Therapy (1991),” Human Gene Therapy 2, no. 3 (1991): 251–256 [hereinafter FDA Points to Consider].

See 42 U.S.C. § 262 (a).

21 U.S.C. § 321 (g) (1).

21 U.S.C. § 321 (h).

FDA Points to Consider, supra note 128.

See Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products, 58 Federal Register 53,248–53,301 (October 14, 1993).

Id., at 53,249 (“Gene therapy products are 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. Some gene therapy products…fall within the definition of biological products and are subject to the licensing provisions of the PHS Act, as well as to the drug provisions of the act.”)

Id., at II (B)(2).

U.S. Food and Drug Administration, “Cellular & Gene Therapy Products,” available at <http://www.fda.gov/Biologics-BloodVaccines/CellularGeneTherapyProducts/default.htm> (last visited September 10, 2009).

Rainsbury , supra note 90, at 582–583.

Merrill R. A. , “Gene Therapy, Law, and FDA Role in Regulation,” in Murray T. H. Mehlmann M. J. , eds., Encyclopedia of Ethical, Legal, and Policy Issues in Biotechnology, vol. 1 (New York: John Wiley & Sons, 2000): 321–329, at 324.

Rainsbury , supra note 90, at 582–585; see also Merrill , supra note 140, at 324.

See Rainsbury , supra note 90, at 582–585.

Id., at 583.

Id., at 583–584.

Naumann A. B. , “Federal Regulation of Recombinant DNA Technology: Time for a Change,” High Technology Law Journal 1, no. 1 (1986): 61–98, at 71.

Rainsbury , supra note 90, at 585.

Merrill , supra note 140, at 324.

See Rainsbury , supra note 90, at 585–586; see also Merrill , supra note 140, at 324.

Rainsbury , supra note 90, at 586.

Merrill , supra note 140, at 325.

Rainsbury , supra note 90, at 586.

Id., at 586.

Noguchi P. D. , “From Jim to Gene and Beyond: An Odyssey of Biologics Regulation,” Food & Drug Law Journal 51, no. 3 (1994): 367–373, 369.

National Institutes of Health, Recombinant DNA Research: Actions under the Guidelines, 60 Federal Register 20,726 (April 27, 1995). See also 62 Federal Register 4,782 (January 31, 1997); Noguchi , supra note 154, at 369–370.

Noguchi , supra note 154, at 369.

See Rainsbury , supra note 90, at 588 (“External pressure on NIH to eliminate the RAC, or at least to streamline RAC's review process, was predicated largely on the assumption that dual FDA/RAC investigation of clinical protocols was a rate-limiting step in the development of novel genetic therapies.”).

National Institutes of Health, Recombinant DNA Research: Notice of Intent To Propose Amendments to the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) Regarding Enhanced Mechanisms for NIH Oversight of Recombinant DNA Activities, 61 Federal Register 35,774 (July 8, 1996).

Fredrickson , supra note 61, at 286.

Friedmann Noguchi Michelson , supra note 126, at 305.

Merrill , supra note 140, at 328 (noting that of the 61 comments the NIH received addressing the proposal to eliminate the RAC, 41 were opposed).

62 Federal Register 4,782 (January 31, 1997).

Friedman Noguchi Michelson , supra note 126, at 305.

62 Federal Register 59,032 (October 31, 1997).

On FDA authority, see U.S. Food and Drug Administration, supra note 137; see also Merrill , supra note 140, at 322.

Merrill , supra note 140, at 328.

See NIH Guidelines for Research Involving Recombinant DNA Molecules (April 2002) Appendix M-1-C-4, available at <http://oba.od.nih.gov/rdna/nih_guidelines_oba.html> (last visited September 10, 2009) [hereinafter NIH Guidelines, 2002].

Smith L. Byers J. F. , “Gene Therapy in the Post-Gelsinger Era,” JONA's Healthcare Law, Ethics, & Regulation 4, no. 4 (2001): 104–110, at 104.

Somia N. Verma I. , “Gene Therapy: Trials and Tribulations,” Nature Reviews Genetics 1, no. 2 (2000): 91–99, at 95.

Zallen D. T. , “U.S. Gene Therapy in Crisis,” Trends in Genetics 16, no. 6 (2000): 272–275, 274.

Silberner J. , “A Gene Therapy Death,” Hastings Center Report 30, no. 2 (2000): 6.

See Zallen , supra note 173, at 274.

Id. Furthermore, “only 5% (39/691) of observed serious adverse events, including deaths, were ever reported to NIH.” Id.

See Andriessen J. J. E. Fahlbruch B. , How to Manage Experience Sharing: From Organizational Surprises to Organizational Knowledge (Amsterdam: Elsevier, 2004): at 299.

Zallen , supra note 173, at 274.

Rainsbury , supra note 90, at 594.

65 Federal Register 60,328 (October 10, 2000).

See Note , “Guiding Regulatory Reform in Reproduction and Genetics,” Harvard Law Review 120, no. 2 (2006): 574–596, 580 (observing that the RAC “serves as a deliberative body for considering novel ethical questions raised by new types of gene transfer research”).

Friedmann Noguchi Michelson , supra note 126, at 305.

Only about 20–30% of submitted protocols are selected for public review. See King N. M. P. , “RAC Oversight of Gene Transfer Research: A Model Worth Extending?” Journal of Law, Medicine & Ethics 30, no. 3 (2002): 381–389, at 385.

Friedmann Noguchi Michelson , supra note 126, at 306.

King , supra note 184, at 385.

See Friedmann Noguchi Michelson , supra note 126, at 306.

Cornetta K. Smith F. O. , “Regulatory Issues for Clinical Gene Therapy Trials,” Human Gene Therapy 13, no. 10 (2002): 1143–1149, 1146.

See 66 Federal Register 57,970 (November 19, 2001).

See Coronetta Smith , supra note 189, at 1146; see also NIH Guidelines 2002, supra note 169 (“Principal Investigators must submit, in accordance with this section…a written report on: (1) any serious adverse event that is both unexpected and associated with the use of the gene transfer product (i.e., there is reasonable possibility that the event may have been caused by the use of the product; investigators should not await definitive proof of association before reporting such events).”). See also 21 C.F.R. 312.32 (c) (1) (outlining the FDA's SAE reporting requirements).

NIH Guidelines, 2002, supra note 169, at Appendix M-1-C- 4-b.

Weiss R. , “Gene Research Rule Proposed,” Washington Post, December 13, 2000, at A2.

See King , supra note 184, at 385.

Id., at 385–386.

See 66 Federal Register 4,688 (January 18, 2001).

See Andriessen Fahlbruch , supra note 178, at 301.

See, e.g., National Institutes of Health, “Financial Conflicts of Interest and Research Objectivity: Issues for Investigators and Institutional Review Boards,” #OD-00-040, June 2000, available at <http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-00-040.html> (last visited September 10, 2009).

Kolemainen S. M. , “The Dangerous Promise of Gene Therapy,” available at <http://www.actionbioscience.org/biotech/kolehmainen.html> (last visited September 10, 2009).

Cornetta Smith , supra note 189, at 1144.

See 42 U.S.C. § 262 (a).

See 21 C.F.R. § 600.3 (s).

Cornetta Smith , supra note 189, at 1145.

FDA/CBER, Human Gene Therapy and the Role of the Food and Drug Administration, available at <http://www.fda.gov/cber/infosheets/genezn.htm> (last visited May 22, 2009).

FDA/CBER, Gene Therapy Patient Tracking System, Final Document, June 27, 2002, available at <http://www.fda.gov/cber/genetherapy/gttrack.htm> (last visited May 15, 2009).

See King , supra note 184, at 385.

National Institutes of Health, Office of Science Policy, “Frequently Asked Questions about the NIH Review Process for Human Gene Transfer Trials,” available at <http://oba.od.nih.gov/rdna/rdna_faq.html> (last visited September 10, 2009).

See id.

U.S. Food and Drug Administration, FDA 101: Human Gene Therapy, available at <http://www.cardiumthx.com/flash/pdf/genetherapy022608.pdf> (last visited September 10, 2009).

U.S. Food and Drug Administration, “Human Gene Therapy and the Role of the Food and Drug Administration,” available at <http://www.fda.gov/cber/infosheets/genezn.htm> (last visited May 15, 2009).

Marshall E. , “Second Child in French Trial Is Found To Have Leukemia,” Science 299, no. 5605 (2003): 320, 320.

Recombinant DNA Advisory Committee, Meeting Minutes (February 10, 2003), available at <http://www4.od.nih.gov/oba/RAC/minutes/RAC_minutes_02–03.pdf> (last visited November 30, 2006); Marshall , supra note 216, at 320.

Marshall , supra note 216, at 320.

See Cornetta K. , “Regulatory Issues in Human Gene Therapy,” Blood Cells, Molecules & Diseases 31, no. 1 (2003): 51–56, at 53.

Marshall , supra note 216, at 320; Cornetta , supra note 219, at 53.

Recombinant DNA Advisory Committee, Minutes of Meeting (February 10, 2003), at 3, available at <http://www4.od.nih.gov/oba/RAC/minutes/RAC_minutes_02–03.pdf> (last visited May 19, 2009).

CBS News Online, “Gene Therapy Questions after Woman's Death,” September 16, 2007, available at <http://www.cbsnews.com/stories/2007/09/16/health/main3265175.shtml?source=RSSattr=Health_3265175> (last visited September 10, 2009).

Weiss R. , “Gene Therapy Study Is Allowed to Resume,” Washington Post, November 26, 2007, at A3.

Kaiser J. , “Gene Transfer an Unlikely Contributor to Patient's Death,” Science 318, no. 5856 (2007): 1535, at 1535.

Hampton T. , “Arthritis Gene Therapy Trial Resumes,” JAMA 299, no. 1 (2008): 28.

Mastrobattista , supra note 7, at 115.

Science Daily, supra note 24.

U.S. Congress, Office of Technology Assessment, New Developments in Biotechnology - Background Paper: Public Perceptions of Biotechnology (Washington, D.C.: U.S. Government Printing Office, May 1987): At iii [hereinafter OTA, New Developments].

Id., at 5.

Id., at 4.

See Center for Genetics and Society, Detailed Survey Results, 1992 – March of Dimes, available at <http://www.genetic-sandsociety.org/article.php?id=404#1993time> (last visited September 10, 2009).

Center for Genetics and Society, Detailed Survey Results, December 1993 – Time/CNN, supra note 242. See also Elmer-Dewitt P. , “The Genetic Revolution: New Technology Enables Us to Improve on Nature: How Far Should We Go?” Time 143, no. 3 (1994): 46–53.

See Center for Genetics and Society, Detailed Survey Results, 1996 – National Center for Genome Resources, supra note 235. See also Singer E. , “The Polls–Trends: Genetic Testing, Engineering, and Therapy Awareness and Attitudes,” Public Opinion Quarterly 62, no. 4 (1998): 633–664; Rabino I. , “Gene Therapy: Ethical Issues,” Theoretical Medicine and Bioethics 24, no. 1 (2003): 31–58.

Macer D. R. J. , “Public Acceptance of Human Gene Therapy and Perceptions of Human Genetic Manipulation,” Human Gene Therapy 3, no. 5 (1992): 511–518, at 514.

OTA, New Developments, supra note 229, at 26.

Id., at 25.

See Center for Genetics and Society, Detailed Survey Results, October 2002 – Genetics and Public Policy Center, supra note 235.

See Rainsbury , supra note 90, at 596.

In addition to sources discussed below, see, e.g., Cook-Deegan R. M. , “Human Gene Therapy and Congress,” Human Gene Therapy 1, no. 2 (1990): 163–170; Areen J. , “The Greatest Rewards and the Heaviest Penalties,” Human Gene Therapy 3, no. 3 (1992): 277–278; Zallen D. T. , “Public Oversight Is Necessary if Human Gene Therapy Is To Progress,” Human Gene Therapy 7, no. 7 (1996): 795–797; Friedmann T. , “Principles for Human Gene Therapy Studies,” Science 287, no. 5461 (2000): 2163–2165; Zallen , supra note 173; Kresina T. F. , “Federal Oversight of Gene Therapy Research,” in Kresina T. E. , ed., An Introduction to Molecular Medicine and Gene Therapy (New York: Wiley-Liss, Inc.: 2001): 303–317; Baruch S. , Human Germline Genetic Modification: Issues and Options for Policymakers , Genetics and Public Policy Center, Washington, D.C., 2005, available at <http://www.dnapolicy.org/images/reportpdfs/HumanGermlineGenetic-Mod.pdf> (last visited September 10, 2009).

Splicing Life, supra note 111, at 82–88.

Walters L. Palmer J. G. , The Ethics of Human Gene Therapy (New York: Oxford University Press, 1997): at 148.

Id., at 151.

Id., at 147–152.

Id., at 151.

King , supra note 184.

Id., at 386.

Wolf S. M. , “Ban Cloning? Why NBAC Is Wrong,” Hastings Center Report 27, no. 5 (1997): 12–15.

See, e.g., King , supra note 184, at 381–382.

Walters Palmer , supra note 245, at 151.

Kessler D. A. , “Regulation of Somatic-Cell Therapy and Gene Therapy by the Food and Drug Administration,” New England Journal of Medicine 329, no. 16 (1993): 1169–1173.

Indeed, given differences between IRBs and IBCs, one could argue this is a four-way system. For an article raising concerns over the IBC system, see Race M. S. Hammond E. , “An Evaluation of the Role and Effectiveness of Institutional Biosafety Committees in Providing Oversight and Security at Biocontainment Laboratories,” Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science 6, no. 1 (2008): 19–35.

See Jasanoff S. , The Fifth Branch: Science Advisors as Policymakers (Cambridge: Harvard University Press, 1990). See also, e.g., Croley S. P. , “Theories of Regulation: Incorporating the Administrative Process,” Columbia Law Review 98, no. 1 (1998): 1–168.

See Croley , supra note 259.

Garfinkel M. S. , Synthetic Genomics: Options for Governance , October 2007, available at <http://www.jcvi.org/cms/fileadmin/site/research/projects/synthetic-genomics-report/synthetic-genomics-report.pdf> (last visited September 10, 2009).

Id., at 42–44.

Kessler , supra note 257, at 1735.

FDA Science Board, Subcommittee on Science and Technology, FDA Science and Mission at Risk, November 2007.

Id., at 24, 27.

See Kuzma J. , “An Integrated Approach to Oversight Assessment for Emerging Technologies,” Risk Analysis 28, no. 5 (2008): 1197–1220, at 1217. The survey is available in the online version of the article. Id.

Paradise J. , “Developing U.S. Oversight Strategies for Nanobiotechnology: Lessons from Past Oversight Experiences,” Journal of Law, Medicine & Ethics 37, no. 4 (2009): 688–705.

See Karkkainen B. C. , “Information as Environmental Regulation: TRI and Performance Benchmarking, Precursor to a New Paradigm?” Georgetown Law Journal 89, no. 2 (2001): 257–370, at 287.

See Lin A. C. , “Size Matters: Regulating Nanotechnology,” Harvard Environmental Law Review 31, no. 2 (2007): 349–408, at 361.

Bowman D. M. Hodge G. A. , “A Small Matter of Regulation: An International Review of Nanotechnology Regulation,” Columbia Science & Technology Law Review 8 (2007): 1–36, 13.

See, e.g., Jacobstein N. , “Foresight Guidelines for Responsible Nanotechnology Development,” Institute for Molecular Manufacturing, 2006, available at <http://www.imm.org/policy/guidelines/> (last visited September 10, 2009).

See Hansen David , “Nanotech Strategy,” Chemical & Engineering News 86, no. 9 (2008): 29–30.

See National Science and Technology Council, Subcommittee on Nanoscale Science, Engineering, and Technology, National Nanotechnology Initiative: Strategy for Nanotechnology-Related Environmental, Health, and Safety Research , February 2008, at 3, available at <http://www.ostp.gov/galleries/NSTC/NNI_EHS_Research_Strategy.pdf> (last visited September 10, 2009).

See id., at 46.

Id., at 44.

Chemical News Engineering , “Nanotech Strategy: Prioritizing Federal Efforts for Studying Health and Safety of Nanomaterials Evolves,” available at <http://pubs.acs.org/cen/government/86/8609gov2.html> (last visited September 10, 2009).

See Marchant G. E. Sylvester D. J. , “Transnational Models for Regulation of Nanotechnology,” Journal of Law, Medicine & Ethics 34, no. 4 (2006): 714–725, at 714.

See, e.g., Lin , supra note 269, at 351 (“[N]anotechnology poses distinct and serious concerns that warrant legislation specific to the manufacture and use of nanomaterials.”); Marchant Sylvester , supra note 276, at 723 (discussing transnational regulation, and finding that “nanotechnology will likely require its own unique approach”).

See, e.g., Davies J. C. , “Managing the Effects of Nanotechnology,” Woodrow Wilson International Center for Scholars, January 2006, at 10 (while noting that new regulatory frameworks may be needed, describing only how current regulatory law can be applied to nanotechnology); Tomasco P. J. Note , “Manufactured Nanomaterials: Avoiding TSCA and OSHA Violations for Potentially Hazardous Substances,” Boston College Environmental Affairs Law Review 33, no. 1 (2006): 205–245, at 238.

See Greenwood M. , “Thinking Big About Things Small: Creating an Effective Oversight System for Nanotechnology,” March 2007, at 10, available at <http://www.nanotechproject.org> (last visited May 15, 2009).

See, e.g., Davies , supra note 280, at 10, 12 (demonstrating that both the Toxic Substances Control Act and the Occupational Safety and Health Act are broad enough to apply to nanotechnology); Lin , supra note 267, at 362, 370 (same). The EPA has also specifically addressed how it accommodates nanotechnology. See, e.g., U.S. Environmental Protection Agency, “Nanotechnology under the Toxic Substances Control Act,” available at <http://www.epa.gov/oppt/nano> (last visited September 10, 2009) (outlining the adequacy of the Toxic Substances Control Act to protect against release of hazardous nanomaterials into the environment); U.S. Environmental Protection Agency, “Nanoscale Materials Stewardship Program,” available at <http://www.epa.gov/oppt/nano/stewardship.htm> (last visited September 10, 2009) (describing a program launched in January 2008 inviting participants to voluntarily report use of nanoscale materials in manufacturing).

FDA, Nanotechnology: A Report of the U.S. Food and Drug Administration , July 25, 2007, at 4, available at <http://www.fda.gov/nanotechnology/taskforce/report2007.pdf> (last visited September 10, 2009).

Id., at ii.

FDA Regulation of Nanotechnology Products, available at <http://www.fda.gov/nanotechnology/regulation.html> (last visited May 15, 2009).

Id., at 30.

Id., at 32.

Maynard A. D. , “Nanotechnology: Assessing the Risks,” Nano Today 1, no. 2 (2006): 22–33, at 32.

Vinardell M. P. , “In Vitro Cytotoxicity of Nanoparticles in Mammalian Germ-Line Stem Cell,” Toxicological Sciences 88, no. 2 (2005): 285–286.

Bell T. E. , Understanding Risk Assessment of Nanotechnology , at 2, available at <http://www.nano.gov/Understanding_Risk_Assessment.pdf> (last visited September 10, 2009).

Maynard , supra note 288, at 24.

See id., at 31 (“[S]pecific information on hazard, exposure, dose, response, and other compartments within risk assessment frameworks is lacking.”)

Ryman-Rasmussen J. P. , “Penetration of Intact Skin by Quantum Dots with Diverse Physicochemical Properties,” Toxicological Sciences 91, no. 1 (2006): 159–165.

Oberdorster G. , “Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles,” Environmental Health Perspectives 113, no. 7 (2005): 823–839.

Maynard , supra note 288, at 27.

Tran C. L. , “Inhalation of Poorly Soluble Particles. II.: Influence of Particle Surface Area on Inflammation and Clearance,” Inhalation Toxicology 12, no. 12 (2000): 1113–1126.

See Oberdorster G. , “Translocation of Inhaled UIltrafine Particles to the Brain,” Inhaled Toxicology 16, nos. 6/7 (2003): 437–445, at 441; Elder A. , “Translocation of Inhaled Ultrafine Manganese Oxide Particles to the Central Nervous System,” Environmental Health Perspectives 114, no. 8 (2006): 1172–1178.

See Maynard A. Kuempel E. D. , “Airborne Nanostructured Particles and Occupational Health,” Journal of Nanoparticle Research 7, no. 6 (2005): 587–614.

See Wang Z. L. , “Nanostructures of Zinc Oxide,” Materials Today 7, no. 6 (June 2004): 23–33 (illustrating the synthesis of a wide variety of nanostructures from ZnO).

See, e.g., Warheit D. B. , “Comparative Pulmonary Toxicity Assessment of Single-Wall Carbon Nanotubes in Rats,” Toxicological Sciences 77, no. 1 (2004): 117–125; Kagan V. E. , “Nanomedicine and Nanotoxicology: Two Sides of the Same Coin,” Nanomedicine: Nanotechnology, Biology and Medicine 1, no. 4 (2005): 313–316.

35 U.S.C. §§ 200–212.