HUMBER COLLEGE- SCHOOL OF HEALTH SCIENCES

Direct-to-Consumer Genetic Testing

REGA 505 Biotechnology (Regulatory Affairs Program)
Professor: Peivand Pirouzi Submitted by: Mukesh Kumar A and Shivam Ohri December 2, 2012

Overview The significant advance of the genome understanding and the approach to study the genome in detail has reduced the cost of genetic testing; leading to the expansion of genetic testing service from the small controlled laboratory environment to the commercial domain. Direct-to-consumer genetic testing (DTC-GT), also known as personal genomic profiles, is referred as the process to market genetic tests to the consumers directly without the involvement of the any independent health care provider, and the respective results are given to the consumer directly. These DTC-GT involves a variety of genetic testing and a broader type of genetic testing can be a carrier testing for disease such as cystic fibrosis and hemochromatosis; some other implications are ancestral analysis, pre-conception screening and even nutrigenetics23.

The Human Genome Project (HGP) completion in 2003 led to the scientific advances and expanded the science of genetic contribution to humans and related disease; it led to the development of molecular diagnostic tests for prevention of the disease. A company marketing the DTC-GT kits mainly functions through internet. A consumer can order a specimen collection kit online, provide a saliva or a cheek swab sample using the test kit and send it back to the source company for genotyping. The company conducts genotyping tests and posts the test results on a secure website, to which the consumer has the access4. This paper goes through the key methods for genetic testing, industry overview and various regulatory and industry challenges.

Methods and Technology Currently, DTC-GT is grouped into three classes: Target Genotyping of specific variant, wide single nucleotide polymorphism (SNP) chips, and Whole-genome sequencing (WGS). The Target Genotyping of specific variant type provides information on variants relevant to one or more specific disease or traits2. DNA sequencing is the process of determining the exact order of the 3 billion chemical building blocks (called bases and abbreviated A, T, C, and G) that make up the DNA of the 24 different human chromosomes24. By sequencing the DNA sequences it has helped reveal the estimated 20,000-25,000 human genes within our DNA, as well as the regions controlling them. There are several ways and methods for sequencing, namely Sanger sequencing the first method to sequence, pyro sequencing. Third generation technologies aim to increase throughput and decrease the time to result and cost by eliminating the need for excessive reagents and harnessing the processivity of DNA polymerase.24 There are many sequencing methods but require much more detailed explanation than the scope of this paper. The first Human Genome took 13 years for sequencing and assembly of the sequences and cost about 13 billion dollars.24 As technology improved, the cost of whole genome sequencing has drastically come down and is much more affordable than before. To site a few examples: Illumina reduced the price of Whole Genome sequencing from $48000 to $19,500 in 2010 and cost of whole genome sequence for serious patients is $9500.29 However, the industry goal of whole genome sequencing is to bring the price closest to $1000 per genome so it is affordable by the common man and can be used in hospitals and clinics routinely.24

On the other hand, the current most affordable method for Direct to Consumer Genetic testing is by using microarray technology to identify Single Nucleotide Polymorphisms (SNPs, pronounced snips). A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide A, T, C or G in the genome differs between members of a biological species or paired chromosomes in a human. An SNP array is a type of DNA , which is used to detect polymorphisms within a population.26 The basic principles for SNP arrays are the convergence of DNA hybridization, fluorescence microscopy, and solid surface DNA capture. The three mandatory components of the SNP arrays are: 1. 2. 3. The array that contains immobilized nucleic acid sequences of target; One or more labeled allele-specific oligonucleotide (ASO) probes; A detection system that records and interprets the hybridization signal.

To achieve relative concentration independence and minimal cross-hybridization, raw sequences and SNPs of multiple databases are scanned to design the probes. Each SNP on the array is interrogated with different probes.26 But why are SNPs so important to identify as DNA markers in the first place? SNPs are highly conserved throughout evolution and within a population, the map of SNPs serves as an excellent genotypic marker for research.26 This approach is based on the assumption that variation of the SNPs is associated with certain diseases and supported by peerreviewed scientific studies. There are some estimated 12 million SNPs in the human genome.24 Due to the importance of SNPs, the International HapMap Consortium and others are part of an ongoing effort to identify SNP loci, genotype them in individuals of

various ancestries, and uncover their correlation structure in the genome. In comparison with Whole Genome Sequencing, it is easier and cheaper to scan SNPs than sequencing the whole genome. 23&Me offers their whole genome SNP scan for as low as $299.28 As an example of how SNPs influences a disease condition is the Apolipoprotein (Apo E) gene that is associated with Alzheimers disease.25 Two variations of the SNPs of Apo E results in three possible alleles for this gene: E2, E3 and E4. Each allele results in a peptide sequence that is different by one amino acid; the consequence of this alteration are proteins that differ in structure & function which could lead to different conditions. Each individual inherits one maternal copy of Apo E and one paternal copy of ApoE, and an individual that inherits a copy of E4 allele is predisposed to developing Alzheimers disease while someone inheriting the E2 allele is less likely to develop Alzheimers. 25 It is easier to find SNPs for disease genes that are segregated in a Mendelian order. However, the scenario is not always as simple as the above example and certain diseases are a combination of various genes, lifestyle patterns, epigenetic factors and environment factors.25 However, identifying SNPs that correlate to diseases come with their own challenges. Most of these challenges are associated with the study conducted on them. The sample size in associated published studies is very small.30 Majority of studies have design flaws, lacked adequate statistical support, and were not reproducible in subsequent studies. Therefore they failed to confirm putative genetic association. 26

Sequencing Industry The sequencing market is most prominent in the US although some of the other countries are Canada, Germany and the UK.24 The global market for sequencing products was valued at $2.3 billion in 2010 and nearly $3 billion in 2011. The market is forecast to grow at a compound annual growth rate of 17.5% to reach $6.6 billion by 2016. 33 Sequencing instruments and consumables made up the largest market segment in 2011, with revenues of nearly $1.6 billion. The segment is expected to grow to $2.2 billion in 2016, an annual growth of 7.3%.33 Sequencing services comprise the fastest-growing market segment, totaling $987.6 million in 2011 and expected to each nearly $3.5 billion in 2016, a CAGR of 29.0%.33 An overview of three main genome-profiling companies The estimated market for the three most prominent genome-profiling companies (23andme, deCODE and Navigenics) was around US $1020 million in 2009.27 These companies represent the scientific world to provide a consumer oriented service.24 23&me was Founded by Anne Wojicki and Linda Avey in 2006.24 The company was named Times invention of the year in 2008.17 In collaboration with Illumina, the company conducts the sequencing and genotyping activities. 23&Me genotypes not only health related genes but also genealogy patterns and recreational genes. The company recently surpassed 100,000 subscribers.28 23andMe has pioneered the social networking aspect of its service, encouraging customers to compare genes to friends and family and join a community effort called Research 2.0.

The second major player is deCode Genetics that provides the deCodeME service. Founded by Kari Stefannsson, the Mission of the company was to use Icelands genetics resources to discover disease genes, develop diagnostic tests and design new drugs. 32 The company built a vast genealogical database by taking advantage of Icelanders proud tradition of recording family histories dating back to medieval dates. Iceland served as an ideal place for such a project due to its relatively small population of just over 300,000 people with 95% being native Icelanders.24 This helps the company conduct original research on complex traits. The third major player considered here is Navigenics that provides a completely health focused service but at a relatively higher price than other listed services.31 It focuses strictly on treatable diseases and does not convey predisposition to a disease for which there is no beneficial medical or lifestyle intervention. Its service called the Health Compass, combines a genetic health assessment with the latest discoveries in science and medicine with genetic counseling. The Health Compass currently presents information on 21 diseases.24 Challenges Besides the technical challenges relating to identification of SNP markers as mentioned before, these companies face various economic and regulatory challenges. Presently, only a little is known about the actual number of genetic tests sold by all DTC genetic testing companies and there is limited consumer acceptance of these services. A few studies have shown that only a relatively small percentage of the US population is aware of the availability of direct-to- consumer genetic tests and only a fraction of these have

purchased such tests. The major concerns related to DTC-GT are: analytic validity, clinical validity, clinical utility, physical involvement, and access to accurate and truthful information. The Government Accountability Office (GAO) published its first report in 2006 and questioned whether a genetic test provides meaningful, scientifically based information that was entirely accurate. The results are complex to be interpreted and even a physician may require the support of a genetic counselor. These are expressed in terms of probability ratios that may vary from company to company depending on the type and number of SNP markers used.24 These companies therefore market their services as medical informational services and not as medical test.31 In general, the DTC model creates concerns for potential consumers regarding credibility of tests, security of DNA use, privacy of genetic risk information, and lack of confidence in non face-to-face genetic counselling, that affect the consumer acceptability. Faced by tough economic challenges during the Global Financial Crisis (GFC), deCode Genetics filed for bankruptcy in 2009 but has re-emerged since then.27 Many sequencing related dotcom companies have high turnover rates and websites once originated with novel ideas are no longer marketed. Various companies also struggled with intellectual property protection. Furthermore, companies testing only a few mutations (with each mutation corresponding to one trait) may have had difficulties competing with companies like 23andme, which offer full genome scans.27 These companies face varying regulatory requirements across different countries as well as different provinces in US. With the publication of the Secretary's Advisory Committee

on Genetics, Health, and Society (SACGHS) report in 2008, public health officials in New York and California sent warning letters to a number of genetic testing companies that they were operating without necessary state licenses. This report recommended the creation of a mandatory, publicly available, Web-based registry for laboratory tests in order to enhance the transparency of genetic testing and assist efforts in reviewing the clinical validity of laboratory tests. Certain provinces make it mandatory for kits to be ordered and results to be interpreted by a physician (which is the case in some states in the USA such as Connecticut and Michigan) and makes the process even more unsustainable for these companies.27 The Regulatory framework in US There are three federal regulatory areas that regulate Direct-to-consumer Genetic Testing: Food and Drug Administration (FDA), Federal Trade Commission (FTC), and Clinical Laboratory Improvement Amendments (CLIA). The FDA has the rights to regulate the medical devices as defined in the regulations. DTC-GT kits can be marketed as IVDsTest Kits (Medical Device) and Home Brews tests. Due to uniqueness of these tests, these companies functions outside the guidelines of the federal regulations. The FDA regulates the manufacturing of reagents and the test kits to perform testing however majority of the companies market these kits as Home Brews that are not within in the FDAs definition of medical devices. Thus, the FDA does not regulate the clinical validity, clinical utility or analytic validity of these tests. The Federal Trade Commission (FTC) is responsible to regulate unfair practices affecting commerce and controls false or misleading advertisings. If a company that advertises

false or misleading information, the FTC can enforce action against it and prohibit the company from advertising such claims. The Centre for Disease Control (CDC) and the Centers for Medicare and Medicaid Services govern all reagents and the protocols used in genetic tests by laboratories which offer clinical testing services. The Clinical Laboratory Improvement Amendment Act (CLIA, enacted in 1988) allows the government to certify laboratories testing for the prevention, diagnosis, or treatment of any disease1. 23andMe began using a CLIAcertified laboratory until 2008 and made such a change in response to evolving regulatory requirements17. The In-vitro Medical Devices (IVMDs) are classified in terms of their complexity and assesses safety, quality and effectiveness of the device. However, discussions between FDA and manufacturers are on-going to develop a risk based and fair regulatory framework for such kits. Currently, 25 states and District of Columbia permit DTC-GT without restriction and 13 states completely prohibit it. Lastly, Genetic Information Nondiscrimination Act (GINA, enacted in 2008) was passed to protect from discrimination based on genetic information and prohibits employers and health insurers from requesting, requiring, purchasing or using genetic information. Canadian Regulatory Framework In Canada, In-vitro Diagnostic Devices (IVDDs) are regulated under the Food and Drug Act, and are classified as Class III medical devices if intended for genetic testing. Medical devices cannot be sold or imported without the licence, and manufacturer has to provide safety, efficacy and quality evidence. However, Health Canada classifies DTC-

GT as Personal Used Kits that are not subject to federal regulations. The only regulatory safeguard is under Customs Regulations, that can restrict imports, especially the ones ordered online. Although testing services are not regulated under the act, sample collection kits are regulated as Pregnancy test kit (Class II Medical Devices) and Blood collection device (lancet), which are Class II Medical Devices. The genetic tests developed in-house are not regulated by Health Canada although clinical laboratories are regulated under the provincial jurisdiction. These are accredited to programs based on ISO 15189: Medical Laboratories which describes particular requirements for quality and competence. Conclusion In summary, the costs of both sequencing and genotyping services are drastrically lowering as technology improves. The trend is in progression towards whole genome sequencing as it provides even more detailed information. Genetic testing is a breakthrough in science, and and can provide The new current business opportunities framework in is

pharmacogenomics

nutrigenomics.

regulatory

underdeveloped and conatins loopholes for testing and interpretation of such results. Transparency, providers information safety, and test and lab quality are all important aspects to be considered for further regulatory development. Promoting transparency will enable permit providers and consumers to make informed decisions about DTC genetic testing; companies will provide all relevant information about offered tests in a readily accessible and understandable manner. Some of these tests may lack analytical or clinical validity; hence, professional organisations should educate their members regarding the types of genetic tests offered. These tests are of immense importance as they can

diagnose disease factors early and serve as a prevention tool to save healthcare costs to an individual as well as the respective government. References 1. Drabiak-Syed, Katherine . "Direct-to-Consumer Genetic Testing (DTC): PredictER
Law and Policy Update."http://bioethics.iu.edu/ (Indiana University centre of Bioethics). Indiana University, 8 2010. Web. 1 Dec 2012. <http://bioethics.iu.edu/programs/predicter/legal-updates/dtcgenetics/>.

2. Leachman, Sancy A, Daniel G MacArthur, Misha Angrist, Stacy W Gary, Angela R

Bradbury, Daniel B Vorhaus, and et al. "Direct-to-Consumer Genetic Testing: Personalized Medicine in Evolution."asco.org. American Society of Clinical Oncology. Web. 1 Dec 2012. <http://www.asco.org/ASCOv2/Home/Education & Training/Educational Book/PDF Files/2011/zds00111000034.PDF>.

3. Hudson, Kathy, Gail Janitt, Wylie Burke, and Peter Byers. "ASHG Statement* on
Direct-to-Consumer Genetic Testing in the United States." The National Center for Biotechnology Information (www.ncbi.nlm.nih.gov. The American Journal of Human Genetics (Volume 81) . Web. 1 Dec 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950839/pdf/AJHGv81p635.pdf >.

4. Ries, Nola M., and Edna Einsiedel. "Online Direct-to-Consumer Genetic Testing
Issues & Policy Option."Geneomecanada.ca. Genome Canada, 24 2010. Web. 1 Dec 2012. <http://www.genomecanada.ca/medias/pdf/en/GPS-Policy-briefJune2010.pdf>.

5. Ray, Turna. "In Wake of 'Flawed' GAO Report, Consumer Genomics Firms Call for
Regulatory Plan for DTC Industry." www.genomeweb.ca. Pharmacogenomics

Reporter, 28 2010. Web. 1 Dec 2012. <http://www.genomeweb.com/dxpgx/wakeflawed-gao-report-consumer-genomics-firms-call-regulatory-plan-dtc-industry>.

6. Vorhaus, Dan. "What Five FDA Letters Mean for the Future of DTC Genetic
Testing."www.genomicslawreport.com. Genomics Law Report, 11 2010. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2010/06/11/what-fivefda-letters-mean-for-the-future-of-dtc-genetic-testing/>.

7. Vorhaus, Dan. "Breaking: FDA Moves to Broadly Regulate

LDTs." www.genomicslawreport.com. Genomics Law Report, 16 2010. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2010/06/16/breaking-fdamoves-to-broadly-regulate-ldts/>.

8. Vorhaus, Dan. "Personal Genemics Follows Pathway to corner Drugstore; Is

Regulation Next ? ."www.genomicslawreport.com. Genomics Law Report, 11 2010. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2010/05/11/pathwaywalgreens-and-dtc-regulation/>.

9. Vorhaus, Dan. "Evaluating the NIH's New Genetic Testing

Registry." www.genomicslawreport.com. Genomics Law Report, 18 2010. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2010/03/18/evaluatingthe-nihs-new-genetic-testing-registry/>.

10. Ray, Turna. "Vorhaus, Dan. "Evaluating the NIH's New Genetic Testing Registry."
www.genomicslawreport.com. Genomics Law Report, 18 2010. Web. 1 Dec 2012. .."www.geneomecanada.ca. Pharmacogenomics Reporter, 12 2009. Web. 1 Dec 2012. <http://www.genomeweb.com/dxpgx/new-oivd-director-says-fda-mayneed-go-back-square-one-ivdmia-guidance>.

11. Vorhaus, Dan. "23andMes New Game Plan: What it Means for the Company and for
DTC Genetic Testing." www.genomicslawreport.com. Genomics Law Report, 15 2009. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2009/11/15/23andme-newmodel-overview/>.

12. Vorhaus, Dan. " Pathway Genomics Launches and a Look Back at Two Years of DTC
Genomics."www.genomicslawreport.com. Genomics Law Report, 15 2009. Web. 1 Dec 2012. <http://www.genomicslawreport.com/index.php/2009/07/15/pathway-genomicslaunches-and-a-look-back-at-two-years-of-dtc-genomics/>.

13. Ray, Turna. "Navigenics Agrees Not to Market Genetic Testing Services Directly to
NY Residents."www.genomeweb.ca. Pharmacogenomics Reporter, 20 2010. Web. 1 Dec 2012. <http://www.genomeweb.com/dxpgx/navigenics-agrees-not-marketgenetic-testing-services-directly-ny-residents>.

14. Pollack, Andrew. "California Licenses 2 Companies to Offer Gene

Services." www.nytimes.com. The New York Times, 19 2008. Web. 1 Dec 2012. <http://www.nytimes.com/2008/08/20/business/20gene.html?_r=3&>.

15. Pollack, Andrew. "Gene Testing Questioned By Regulators." www.nytimes.com. The

New York Times, 26 2008. Web. 1 Dec 2012. <http://query.nytimes.com/gst/fullpage.html?res=9501E1DB1238F935A15755C0 A96E9C8B63&sec=&spon=&pagewanted=all>.

16. United States. Centers of Medicare nad Medicaid Services.Clinical Laboratory

Improvement Amendments (CLIA) . Baltimore: , 2012. Print. <http://www.cms.gov/Regulations-andGuidance/Legislation/CLIA/index.html?redirect=/clia>.

17. Wojcicki, Anne. "Sorry for the Delay: A Message from 23andMe Founders Anne
Wojcicki and Linda Avey." www.23andme.com. The 23andMeBlog, 01 2008. Web. 1 Dec 2012. <blog.23andme.com/23andme-and-you/sorry-for-the-delay-a-messagefrom-23andme-founders-anne-wojcicki-and-linda-avey/>.

18. Goetz, Thomas. "23AndMe Will Decode Your DNA for $1,000. Welcome to the Age of
Genomics."www.wired.com. Wired Magazine, 17 2007. Web. 1 Dec 2012. <http://www.wired.com/medtech/genetics/magazine/1512/ff_genomics?currentPage=all>.

19. Langreth, Robert. "Personal Genome Race Goes Into Overdrive." www.forbes.com.
World's Business Leader, 16 2007. Web. 1 Dec 2012. <http://www.forbes.com/2007/11/16/personal-genome-services-techcx_rl_1116decode.html>.

20. Castle, David, and Nola M. Ries. "Elsevier." Elsevier. (2007): 139 & 141 . Web. 1 Dec.
2012. <http://genetica.ufcspa.edu.br/nutric/conteudo/nutrigenomic 3.pdf>.

21. Kutz, Gregory. "GAO (United States Government Accountability Office)." GAO (United
States Government Accountability Office). (2006): 1-19. Web. 1 Dec. 2012. <http://www.gao.gov/new.items/d06977t.pdf>.

22. United States. Federal Trade Commission. At-Home Genetic Tests: A Healthy Dose of
Skepticism May Be the Best Prescription. Washington, DC: , 2010. Web. <http://www.ftc.gov/bcp/edu/pubs/consumer/health/hea02.shtm>.

23. Nelson, Tanya N., Linlea Armstrong, Julie Richer, Jane Evans, Julie Lauzon, Barbara
McGillivray, Hlne Bruyre, and Shelley Dougan. "CCMG Statement on Direct-toConsumer Genetic Testing."www.ccmg-ccgm.org. Canadian College of Medical Genetics, 20 2011. Web. 1 Dec 2012. <http://www.ccmg-

ccgm.org/_includes/ckfinder/userfiles/files/Policies, Reports and Position Statements/Position Statements/PosStmt_EPP_DTC_FINAL_20Jan2011.pdf>.

24. Davies, Kevin. The $1000 Genome: The revolution in DNA sequencing and New era of
personalized medicine. 1st . New York: Free Press, 2010. 85-134. Print.

25. Ganguli, Mary, Vijay Chandra, and et al. "Apolipoprotein E Polymorphism and
Alzheimer Disease."www.wpic.pitt.edu. American Medical association, n.d. Web. 2 Dec 2012. <http://www.wpic.pitt.edu/research/dementia_epidemiology/IndoUS/ScientificRe ports/Manuscripts/Ganguli 2000 APOE.pdf>.

26. Bell, John I. "Single nucleotide polymorphisms and disease gene

mapping." www.arthritis-research.com. Nuffield Department of Clinical Medicine, 09 2002. Web. 2 Dec 2012. <http://arthritis-research.com/content/pdf/ar555.pdf>.

27. Borry, Pascal, Martina C. Cornel, et al. United States. National Centre for
Biotechnology Information.Where are you going, where have you been: a recent history of the direct-to-consumer genetic testing market. Bethesda, MD: , 2010. Web. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063844/pdf/12687_2010_Articl e_23.pdf>.

28. H, Scott. "23andCuriosity." The 23andMe blog. 23andMe (Health and Traits), 2 2012.
Web. Web. 6 Dec. 2012. <http://blog.23andme.com/health-traits/23andcuriosity/>.

29. Wetterstrand KA. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing
Program (GSP) Available at: www.genome.gov/sequencingcosts. Accessed [6 Dec. 2012].

30. LaFramboise, Thomas. "Single nucleotide polymorphism arrays: a decade of

biological, computational and technological advances." Single nucleotide polymorphism arrays: a decade of biological, computational and technological advances. 37.13 (2009): 4181-4193. Web. 6 Dec. 2012. <http://nar.oxfordjournals.org/content/37/13/4181.full>.

31. . "Applying Preventive Genomics Medicine in Clinical Practice

." www.naviggenics.com. Navigenics, n.d. Web. 6 Dec 2012. <http://www.navigenics.com/visitor/for_physicians/>.

32. . "Selection of risk associated genetic variants (SNPs)." www.decodeme.com.

Decodeme, n.d. Web. 6 Dec 2012. <http://demo.decodeme.com/health-watchinformation/snp-selection>.

33. BCC Research, . "Top Ten Companies in DNA Sequencing." www.reportnreports.com.

BCC Research , 30 2012. Web. 6 Dec 2012. <http://www.reportsnreports.com/reports/195954-top-ten-companies-in-dnasequencing.html>.