Regulation of Next Generation Sequencing

Lander E. S. Linton L. M. and Birren B. , Initial Sequencing and Analysis of the Human Genome, Nature 409, no. 6822 (2001): 860–921; Celera Genomics' results from its parallel project were published at the same time: Venter J. C. Adams M. D. and Myers E. W. , The Sequence of the Human Genome, Science 291, no. 5507 (2001): 1304–1351.

Conley J. M. Doerr A. K. and Vorhaus D. B. , Enabling Responsible Public Genomics, Health Matrix 20, no. 2 (2010): 325–385, at 330–331.

See Shendure J. and Adain Lieberman E. , The Expanding Scope of DNA Sequencing, Nature Biotechnology 30, no. 11 (2012): 1084–1094 (noting that, between 2005 and 2012, the cost of DNA sequencing has dropped from $1,000 per megabase to ten cents per megabase); Hayden E. C. , Technology: The $1000 genome, Nature 507, no. 7492 (2014): 294–295; Biesecker L. G. , Opportunities and Challenges for the Integration of Massively Parallel Genomic Sequencing into Clinical Practice: Lessons from the ClinSeq Project, Genetics in Medicine 14, no. 4 (2012): 393–398.

Seeinfra notes 23 through 26.

See, e.g., Heger M. , FDA Official Discusses Issues with Regulating NGS Dx Tests, Genome Web (2012), available at <http://www.genomeweb.com/sequencing/fda-official-discusses-issues-regulating-ngs-dx-tests> (last visited July 8, 2014).

42 U.S.C. § 263a.

Sanger F. Nicklen S. and Coulson A. R. , DNA Sequencing with Chain-Terminating Inhibitors, Proceedings of the National Academy of Sciences of the United States of America 74, no. 12 (1977): 5463–5467. In the same year, Allan Maxam and Walter Gilbert published an alternative approach in which terminally labeled DNA fragments were subject to base-specific chemical cleavage and the reaction products were separated by gel electrophoresis. See Maxam A. and Gilbert W. , A New Method for Sequencing DNA, Proceedings of the National Academy of Sciences of the United States of America 74, no. 2 (1977): 560–564. The Sanger method, which was subsequently refined and commercialized, became the dominant method in both research and clinical diagnostics. See Voelkerding K. Dames S. and Durtschi J. , Next Generation Sequencing: From Basic Research to Diagnostics, Clinical Chemistry 55, no. 4 (2009): 641–658.

Wright C. Burton H. and Hall A. , Next Steps in the Sequence: The Implications of Whole Genome Sequencing for Health in the UK, PHG Foundation (2011), available at <http://www.phgfoundation.org/reports/10364/> (last visited July 8, 2014).

Id.

Id.

Id.

Id.

Id.

See id.; see also Ware J. S. Robers A. M. and Cook S. A. , Next Generation Sequencing for Clinical Diagnostics and Personalised Medicine: Implications for the Next Generation Cardiologist, Heart 98, no. 4 (2012): 276–281; Voelkerding , supra note 8.

Metzker M. L. , Sequencing Technologies – The Next Generation, Nature Reviews Genetics 11, no. 1 (2010): 31–46.

This white paper uses the term next generation sequencing to refer to rapid DNA sequencing methods that determine the four bases of the human genome in a strand of DNA. Specifically, NGS involves the use of 2nd/3rd/4th-generation sequencing technologies to perform genome-wide sequencing of multiple genes or alleles spread across the genome for clinical (prognostic, diagnostic, therapeutic) purposes. This definition encompasses the sequencing of multiple genes or complete genomes.

See Metzker , supra note 15.

See Voelkerding , supra note 7.

Id., at 40.

See Metzker , supra note 15; see also Voelkerding , supra note 8; Shendure and Lieberman Aiden , supra note 3.

See Voelkerding , supra note 7.

Bras J. Guerreiro R. and Hardy J. , Use of Next-Generation Sequencing and Other Whole-Genome Strategies to Dissect Neurological Disease, Nature Reviews: Neuroscience 13, no. 7 (2012): 453–464.

Seee.g., Ma Q. C. Ennis C. A. and Aparicio S. , Opening Pandora's Box – The New Biology of Driver Mutations and Clonal Evolution in Cancer as Revealed by Next Generation Sequencing, Current Opinion in Genetics & Development 22, no. 1 (2012): 3–9.

Calvo S. E. Compton A. G. and Hershman S. G. , Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing, Science Translational Medicine 4, no. 118 (2012): 118ra10.

Seee.g., Chiu R. W. Akolekar R. and Zheng Y. W. , Non-Invasive Prenatal Assessment of Trisomy 21 by Multiplexed Maternal Plasma DNA Sequencing: Large Scale Validity Study, British Medical Journal (Clinical Research ed.) 342 (2011): c7401.

Biesecker L. G. Burke W. and Kohane I. , Next-Generation Sequencing in the Clinic: Are We Ready? Nature Reviews. Genetics 13, no. 11 (2012): 818–824.

See Biesecker , supra note 3.

Id.

See Biesecker , supra note 26.

Id.

Id.

Id.

Id.

See Biesecker , supra note 3.

Id.

Id.

See CLIA, supra note 6.

Id. § 263a(a).

Id. § 263a(b).

Id. § 263a(f).

See42 C.F.R. Part 493 (1990).

H.R. Rep. No. 100-899, at 28 (1988).

42 C.F.R. § 493.17 (1993).

42 U.S.C. § 263a(d)(3) (2013).

42 C.F.R. § 493.15(b) (1993). Waived tests are simple laboratory examinations and procedures that (1) are cleared by FDA for home use; (2) use methodologies that are so simple and accurate as to render the likelihood or erroneous results negligible; or (3) pose no reasonable risk of harm to the patient if the test is performed incorrectly. The specific CLIA-waived tests are: Dipstick or tablet reagent urinalysis (non-automated) for: bilirubin, glucose, hemoglobin, ketone, leukocytes, nitrite, pH, protein, specific gravity, and urobilinogen; Fecal occult blood; Ovulation tests – visual color comparison tests for human luteinizing hormone; Urine pregnancy tests – visual color comparison tests; Erythrocyte sedimentation rate – non-automated; Hemoglobin – copper sulfate – non-automated; Blood glucose by glucose monitoring devices cleared by the FDA specifically for home use; Spun microhematocrit; and Hemoglobin by single analyte instruments with self-contained or component features to perform specimen/reagent interaction, providing direct measurement and readout. 42 C.F.R. § 493.15(c) (1993). FDA has granted waived status to certain IVDs based on these criteria. See CLIA – Tests waived by FDA from January 2000 to present, available at <http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfclia/testswaived.cfm?start_search=A> (last updated July 8, 2014).

See generally 42 C.F.R. Part 493, Subpart M (1992).

Testimony of Thomas Hamilton, Director, Survey and Certification Group, CMS before the House Subcommittee on Criminal Justice, Drug Policy, and Human Resources of the Committee on Government Reform (June 27, 2006), available at <http://www.cms.hhs.gov/apps/media/press/testimony.asp?Counter=1892&intNumPerPage=10&checkDate=&checkKey=&srchType=1&numDays=3500&srchOpt=0&srchData=&keywordType=All&chkNewsType=7&intPage=&showAll=&pYear=&year=&desc=false&cboOrder=date>.

List of Exempt States Under the Clinical Laboratory Improvement Amendments (CLIA), available at <http://www.cms.hhs.gov/CLIA/downloads/Exempt.States.List.pdf>.

See Genetics and Public Policy Center, Survey of Direct-to-Consumer Testing Statutes and Regulations (June 2007), available at <http://www.dnapolicy.org/resources/DTCStateLawChart.pdf> (last visited July 8, 2014).

Seegenerally Transcript, CDRH Public Meeting on Ultra High Throughput Sequencing for Clinical Diagnostic Applications – Approaches to Assess Analytical Validity (June 23, 2011), available at <http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM266607.pdf> (last visited July 8, 2014).

The Medical Device Amendments of 1976 Pub. L. No. 94-295,90 Stat. 539 (codified as amended at the Federal Food, Drug and Cosmetic Act of 1938, 21 U.S.C. § 301 et seq.) (Nov 27, 2013).

See generally 21 U.S.C. et seq.

See The Safe Medical Devices Act of 1990, Pub. L. No, 101–629, 104 Stat. 4511 (codified as amended at 21 U.S.C. § 301 et seq.); The Medical Device Amendments of 1992, Pub. L. No. 102-300, 106 Stat. 238 (codified as amended at 21 U.S.C. § 301 et seq.)

See The Medical Device User Fee and Modernization Act of 2002 (MDUFMA), Pub. L. No. 107-250, 116 Stat. 1588 (codified as amended at 21 U.S.C. § 360i); Food and Drug Administration Amendments Act (FDAAA), Pub. L. 110–85 (2007); Food and Drug Administration Safety and Innovation Act (FDASIA), Pub. L. No. 112-144, 126 Stat. 993 (2012).

21 U.S.C. § 360c(a)(1)(A) (2012).

Id. § 360c(a)(1)(B).

Id. § 360c(a)(1)(C).

Goldberger B. A. , The Evolution of Substantial Equivalence in FDA's Premarket Review of Medical Devices, Food and Drug Law Journal 56, no. 3 (2001): 317–318.

See21 U.S.C. § 360(j)-(k), 360c(f); 21 C.ER. § 807.92 (2012).

The FDA Modernization Act of 1997 (FDAMA), 105 Pub. L. No. 105-115, 111 Stat. 2296 (codified as amended at 21 U.S.C. § 360c(f)(2)) (2012).

See21 U.S.C. § 360c(f)(2)(A)(iv) (2012).

21 U.S.C. § 321(h)(2) (2013).

21 C.F.R. § 809.3(a) (2013).

See Medical Devices: Immunology and Microbiology Devices; Classification of Gene Expression Profiling Test System for Breast Cancer Prognosis, Federal Register 72 (May 9, 2007): 26, More recently, in November 2013 FDA cleared Illumina's MySeq DxTM Cystic Fibrosis Clinical Sequencing Assay using a classification regulation first promulgated in 2005 for Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection systems. See 510(k) Summary for MySeq DxTM Cystic Fibrosis Clinical Sequencing Assay (K132750), at <http://www.accessdata.fda.gov/cdrh_docs/pdf13/K132750.pdf> (last visited July 8, 2014); 21 C.F.R. § 866.5900.

See21 U.S.C. § 360j(g); 21 C.F.R. pt. 812 (2013).

Compliance with the requirements described here also establishes an exemption to the investigational new drug (IND) requirement applicable to devices that are considered drugs or biological products. See 21 C.F.R. §§ 312.2(b)(2)–(3), 601.21 (2013).

21 C.F.R. § 809.10(c)(2)(i) (2013); see also, e.g., Warning Letter from Stephen I. Gutman, Dir., Office of In Vitro Diagnostic Device Evaluation and Safety, CDRH, to Mr. Carl Hull, CEO, Applied Imaging Corp. (March 28, 2003), available at <http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2003/ucm147393.htm> (last visited July 8, 2014).

Seee.g., Warning Letter from Lillian J. Gill , Acting Dir., Office of Compliance, CDRH, to Surendra K. Gupta, PhD, President, GDS Tech., Inc. (October 27, 1994); Warning Letter from Lillian J. Gill, Dir., Office of Compliance, CDRH, to Thomas D. Brown, President, Abbott Labs (November 5, 1998), available at <http://www.fda.gov/downloads/ICECI/EnforcementActions/WarningLetters/1998/UCM066894.pdf> (last visited July 8, 2014).

See21 U.S.C. § 360j(g)(3); 21 C.F.R. pts. 50, 56 (2013).

21 C.F.R. § 812.2(c)(3) (2013); see also id. § 812.3(k) (defining the term noninvasive); FDA, Guidance for Industry and FDA Staff: In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions (June 25, 2010), available at <http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071230.pdf> (explaining what constitutes confirmation of the diagnosis by another, medically established diagnostic product or procedure) (last visited July 8, 2014).

N.Y. Dist., FDA, to Paul Reiter, President, Millennium Biotechnology, Inc. (January 12, 2009) (stating that IVDs were not RUO, despite manufacturer's assertion that they were for research use only, when there was no evidence that they were labeled that way), available at <http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm162698.htm> (last visited July 8, 2014).

Id. § 809.10(c)(2)(ii) (2013).

An analogous scheme exists for investigational use only (IUO) IVDs. These are IVDs that are being shipped or delivered for product testing prior to full commercial marketing (for example, for use on specimens derived from humans to compare the usefulness of the product with other products or procedures which are in current use or recognized as useful)…. Id. § 809.10(c)(2)(ii). IUO products, like RUO products, must not be used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure, and must be labeled with the statement, For Investigational Use Only. The performance characteristics of this product have not been established.

See CDRH/CBER, Draft Guidance for Industry and FDA Staff: Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions (June 1, 2011), available at <http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM257460.pdf> (last visited July 8, 2014).

See21 C.F.R. § 801.4 (2013). Section § 801.4 implements 21 U.S.C. § 352(f), which provides that a device is misbranded if it lacks adequate directions for use. Section 801.4 states: The words intended uses or words of similar import in 801.5, 801.119, and 801.122 refer to the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised…. if a manufacturer knows, or has knowledge of facts that would give him notice that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a device which accords with such other uses to which the article is to be put.

See FDA RUO/IUO Draft Guidance at 10.

Id; See US Food and Drug Administration, Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Guidance for Industry and Food and Drug Administration Staff, November 25, 2013, available at <http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM376118.pdf> (last visited July 8, 2014).

Federal Register 62 (November 21, 1997): 62,243, 62,249; see Citizen Petition, FDA Docket 1992P-0405, submitted by Hyxnan, Phelps & McNamara, P.C. (Oct. 22, 1992); See Washington Legal Foundation, Re: Citizen Petition, available at <http://www.fda.gov/ohrms/dockets/dockets/06p0402/06p-0402-cp00001-01-vol1.pdf> (last visited April 29, 2014).

Federal Register 75 (June 17, 2010): 34,463, 34,463.

See Warning Letter from Steven I. Gutman , M.D., M.B.A., Dir., OIVD to David P. King, Pres. & CEO, Laboratory Corp. of America (Sept. 29, 2008), available at <http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm1048114.htm> (stating that test intended to be used as a tool to identify high-risk women who might have ovarian carcinoma, which had been designed, developed, and validated by investigators at Yale University and for which materials specifications and performance characteristics were developed by Yale investigator was not within the scope of laboratory developed tests over which the agency has traditionally declined active regulation); Letter from Steven I. Gutman, M.D., MBA, Dir., OIVD to Jeffrey R. Luber, Pres., EXACT Sciences Corp. (Oct. 11, 2007), available at <http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2007/ucm076536.htm> (last visited July 8, 2014) (stating that colorectal screening test designed, developed, validated, and marketed by EXACT Sciences and offered by LabCorp facilities, and for which EXACT Sciences provided instructions for use, validation information, and performance claims was not within the scope of laboratory developed tests over which the agency has traditionally declined active regulation); Letter from Steven I. Gutman, M.D., MBA, Dir., OIVD to Peter J. Levine, Pres./CEO, Correlogic Systems, Inc. (July 12, 2004) (stating, with respect to an ovarian cancer detection assay, that FDA would regulate the software developed at Correlogic's reference laboratory and licensed/transferred to the customer laboratories but would not, consistent with its policy of enforcement discretion, seek to regulate the activities of the clinical laboratories or of Correlogic's reference laboratory).

Seee.g., Citizen Petition Submitted by Daniel Popeo, Chairman & General Counsel, and Richard Samp, Chief Counsel, Washington Legal Foundation (September 28, 2006) (FDA Docket No. 2006-P-0402) (challenging FDA's jurisdiction over LDTs); Secretary's Advisory Committee on Genetic Testing Meeting Transcript 51 (October 26, 1999) (statement of David Feigal, Director, CDRH) (recognizing that the in-house development of tests by clinical laboratories could be considered part of the practice of clinical pathology medicine and … not something that FDA has jurisdiction over).

Javitt G. H. and Carner Strong K. , Must FDA Engage in Rule-making to Regulate Laboratory-Developed Tests? The Food and Drug Law Institute's Food and Drug Policy Forum 1, no. 17 (September 14, 2011).

Seee.g., Ashford M. , At Dx Conference, FDA's Gutierrez Sheds Further Light on Plans for Risk-Based LDT Regulation, GenomeWeb Pharmacogenomics Reporter (September 7, 2011), available at <http://www.genomeweb.com/mdx/dx-conference-fdas-gutierrez-sheds-further-light-plans-risk-based-ldt-regulation> (last visited July 8, 2014) (Gutierrez told attendees that risk classification for LDTs will mirror largely what the FDA already does for in vitro diagnostics. ‘Anything already defined class III [as an IVD] will stay as class III [if an LDT makes the same claim],' he said.)

Federal Register 62 (1997): at 62,249.

Id.

Id., at 62,249, 62,252 (1997).

Federal Register 61 (March 14, 1996): 10,484, 10,484.

FDA, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays 4 (July 26, 2007).

Id., at 4–6.

Id., at According to the trade press, FDA plans to delay development of a final guidance on IVDMIAs, and instead focus more broadly on the agency's role in ensuring the safety and efficacy of all laboratory-developed tests. See T. Ray, FDA Shelves IVDMIA Final Guidelines in Order to Focus on Overall LDT Regulation, GenomeWeb Pharmacogenomics Reporter (June 17, 2010), available at <http://www.genomeweb.com/dxpgx/fda-shelves-ivdmia-final-guidelines-order-focus-over-all-ldt-regulation> (last visited July 8, 2014).

See Federal Register 65 (Apr. 7, 2000): 18230, 18231,18234 (codified at 21 C.F.R. § 809.40 (2000)).

See Untitled Letter from Wood James , Deputy Director, Patient Safety and Prod. Quality, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), CDRH, to James Plante, Founder and CEO, Pathway Genomics Corp. (May 10, 2010); Untitled Letter from Alberto Gutierrez, OIVD, CDRH, to deCODE Genetics (June 10, 2010) [hereinafter deCODE Genetics Letter]; Untitled Letter from Alberto Gutierrez, OIVD, CDRH, to 23andMe, Inc. (June 10, 2010) [hereinafter 23andMe Letter]; Untitled Letter from Alberto Gutierrez, OIVD, CDRH, to Navigenics (June 10, 2010).

See Warning Letter to 23andMe (November 22, 2013).

See Transcript, FDA Public Meeting on Oversight of LDTs 75 (July 19, 2010) (presentation of Elizabeth Mansfield, Director for Personalized Medicine, OIVD), available at <http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM226203.pdf> (last visited July 8, 2014).

Federal Register 75 (2010): at 34,464.

Seee.g., Presentation of Gutierrez Alberto , What about Public Health! AACC Webinar, October 5, 2011; see Ashford , supra note 83.

See CDRH, Documents CDRH is Considering for Development (FY2012), available at <http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm109196.htm#5> (last visited July 8, 2014).

See CDRH Fiscal Year 2013 (FY 2013) Proposed Guidance Development, available at <http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/MDUFAIII/ucm321367.htm#list13> (last visited July 8, 2014). The agenda does include, on the B list, a draft guidance for Direct to Consumer (DTC) Genetic Testing: IVDs. (last visited April 29, 2014).

Pub. L. No. 112-144, § 1143, 126 Stat. 1130 (July 9, 2012). Note: As this issue was going to press, FDA notified Congress that it intended to issue draft guidance outlining a risk-based framework for LDTs.

Gargis A. S. Kalman L. and Berry M. W. , Assuring the Quality of Next-Generation Sequencing in Clinical Laboratory Practice, Nature Biotechnology 30, no. 11 (2012): 1033–1036.

42 C.F.R. § 493.1253(b) (2003).

See Gargis , supra note 100.

Id.

Id.

Id.

Id.

Id.

SeeFederal Register 76 (May 19, 2011): 28990; Transcript, CDRH Public Meeting on Ultra High Throughput Sequencing for Clinical Diagnostic Applications – Approaches to Assess Analytical Validity (June 23, 2011), available at <http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM266607.pdf> (last visited July 8, 2014).

Seee.g., Federal Register 76 (May 19, 2011): at 28,990 (stating that the purpose of the FDA public meetings is to start discussion on approaches that can provide the most useful information in establishing safety and effectiveness of genomic sequencing technologies when used clinically (emphasis added)).

See Transcript, CDRH Public Meeting on Ultra High Throughput Sequencing, supra note 108, at 10.

See Heger , supra note 6.

See Transcript, CDRH Public Meeting on Ultra High Throughput Sequencing, supra note 107, at 76.

See21 U.S.C. § 321(h) (June 22, 2009).

Seee.g., Ass'n of Am. Physicians & Surgeons Inc. v. FDA, 226 F. Supp. 2d 204, 217–18 (D.D.C. 2002) ([E]ven the FDA has repeatedly stated that it may only regulate claimed uses …, not all foreseeable or actual uses.); see also Millet, Pit and Seed Co., Inc. v. United States, 436 F.2d 1039 (6th Cir. 1980) ([W]e do not agree with the apparent theory of the government that if any consumers use a product as a drug, such use, if known by the seller, is determinative on this issue. Carried to its logical extreme, this would mean that every merchant who sells carrots to the public with knowledge that some of his consumers believe that the ingestion of carrots prevents eye diseases and hold the carrots out for use as a drug, as that term is defined in the Act.). A few cases have recognized an exception to the broad principle that manufacturer claims are the basis for assessing a product's intended use for purposes of the FDCA. Courts have held that FDA is entitled to regulate a product as a drug or medical device based on nearly exclusive use of the product for its drug- or device-like properties. See Action on Smoking & Health v. Harris, 655 F.2d 236 (D.C. Cir. 1980); see also Clinical Reference Lab., Inc. v. Sullivan, 791 F. Supp. 1499, 1507 ( Kan D. 1992), aff'd in part, 21 F.3d 1026 (10th Cir. 1994) ([I]ntended use may also be shown by the product's actual use.); United States v. 22 Rectangular or Cylindrical Finished Devices, … The Ster-O-Lizer MD-200, 714 F. Supp. 1159 ( Utah D. 1989) (mem. op.)

See21 U.S.C. § 321(h) (June 22, 2009).

See FDA, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices (May 11, 2005), available at <http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089593.pdf> (last visited July 8, 2014).

Id., at 5.

21 U.S.C. § 321(h) (June 22, 2009).

21 U.S.C. § 396 (Nov 21, 1997) (Nothing in this chapter shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship.)

Federal Register 73 (February 8, 2008): at 7,500.

21 C.F.R. pt. 820 (2013).

Federal Register 73 (Feb. 8, 2008): at 7,500.

Federal Register 76 (Feb. 15, 2011): 8649 (codified at 21 C.F.R. § 880.6310 (2011)).

21 C.F.R. § 862.2100 (2013).

Rehm H. L. Bale S. J. Bayrak-Toydemir P. , ACMG Practice Guidelines: ACMG Clinical Laboratory Standards for Next-Generation Sequencing, Genetics in Medicine 15, no. 9 (2013): 733–747.

42 C.F.R. Part 493, Subpart M (1992).

For example, as of July 2013, fourteen states licensed genetic counselors, and another four states passed bills that eventually will require licensure. See National Society of Genetic Counselors, States Issuing Licenses for Genetic Counselors (last updated March 21, 2014), available at <http://nsgc.org/p/cm/ld/fid=19\> (last visited July 8, 2014). The states that currently require licenses include California, Delaware, Illinois, Indiana, Massachusetts, Nebraska, New Mexico, Ohio, Oklahoma, Pennsylvania, South Dakota, Tennessee, Utah, and Washington. Id. The states that have passed bills to eventually require licensure include Hawaii, New Hampshire, New Jersey, and North Dakota. Id.

Nekrutenko A. and Taylor J. , Next-Generation Sequencing Data Interpretation: Enhancing Reproducibility and Accessibility, Nature Reviews Genetics 13, no. 9 (2012): 667–672.

Id.