Diagnostic Kits

Introduction to Genetic and Genomic Diagnostics

The field of Biotechnology is a critical US industry, by some estimates approaching 2% of the US GPD and growing 15% per year. Genetic and Genomic research represent a core focus of R&D in the biotechnology industry. Over the last 40 years, improvements in sequencing technology have led to massive increases in test precision and overall throughput capacity. These advances have bolstered the breadth of genetic and genomic research, and have allowed these fields to transcend from mere laboratory concepts to a number of practical, real world applications.

Today, these research efforts have contributed clinical diagnostic methods of testing that are capable of providing information specific to the genetic characteristics of an individual. The logical core of diagnostics is the link between a health state, such as a disease or drug response, and particular genetic sequence (often a mutation therein). Once this link is clinically established, a test can readily be developed based on existing techniques. Thus, the actual methods that are developed are not often based on new measurement or sampling techniques, but rather, newly discovered links between genotype and phenotype.

Through these tests a clinician can perceive a wealth of information, including an individual's disposition to develop complex diseases over time, such as cancer, heart disease, asthma, and diabetes, and allow the clinician to advise practical changes in lifestyle to minimize health future health risks or maximize preventative medical care. In cases where disease may already be present, some tests are useful for determining more efficient methods of treatment that are specific to that individual. The diagnostic tests range from single tests which evaluate a single gene and its affects to others, which are more comprehensive, and can evaluate samples on the genomic level, which are capable of analyzing multiple genetic factors.

These tests represent valuable assets to the companies who develop them and bring them to market in the form of consumer product offerings. Currently, diagnostic tests are being marketed to the public in a three different ways: Laboratory Developed Test Services, In Vitro Diagnostic Kits, and Tests Sold Directly to Consumers. It should be no surprise that these companies seek robust legal protection for their investments through intellectual property ("IP") law. For instance, many companies obtain patents for their inventions that grant them a legal mechanism to exclude others from utilizing their research and development efforts. However, these protections occasionally affect research and development efforts of others in these fields negatively.

Emerging research in genetic and genomic diagnostics presents unique challenges for IP considerations. Changes in laboratory research due to actual or anticipated patent or license enforcement could signal the failure of protections secured through intellectual property to spur the innovations such protections are intended to promote. These issues are at the center of our research efforts under the Industrial Cooperation Project at the Harvard University's Berkman Center for Internet & Society. This research is part of a broader project being led by Professor Yochai Benkler. Through the research, we seek to understand the approaches to innovation with genetic diagnostic kits, and look specifically to the barriers to use and innovation.

Defining Genetics and Genomics

Occasionally, the terms "Genetics" and "Genomics" are used interchangeably within the context of genetic testing. More specifically, both terms are sometimes used to refer to the testing of specific genes or the indexing of multiple tests of single genes. Although we note there is a difference in these terms, we use this term synonymously, except where specifically noted otherwise.

The difference between these terms is scientifically important because they refer to distinct concepts. These terms are often confused because the distinctions between "genetic" and "genomic" diagnostics are rarely delineated well, if at all. Consequently, discussions of their market, innovation cycles and the impact of intellectual property in the emergence of open or closed arrangements of cooperation is less than precise.

Understanding Genetic and Genomic Diagnostic Distinctions

In simple terms, "Genetics" can be defined as the scientific study of single genes and their effects. Genes are units of heredity that carry the instructions for making proteins, which direct the activities of cells and functions of the body. Genetics is also term that refers to the study of genes and their role in inheritance - the way certain traits or conditions are passed down from one generation to another. Genes influence traits such as hair and eye color as well as health and disease development. Genetics determines much, but not all, of a person's appearance and health status. Environmental factors also play a part. Many disorders of the human body, such as disease and illness, are linked to abnormal gene function. For example, single gene disorders include cystic fibrosis and PKU (phenylketonuria). For more examples, see National Human Genome Research Institute and The Centers for Disease Control and Prevention.

Thus, "Genetic Diagnostics" is clinical testing of singular genes, by assaying a relatively small sample containing DNA, to determine genotype and identify genetic abnormalities known to be link to disease. Additionally, these tests can determine the prognosis of disease, potential responses to drug treatment, and other factors related to the state of health of the sample provider.

On the other hand, "Genomics" is a relatively new term that describes the study of all of a person's genes including interactions of those genes with each other and the person's environment. Genomics involves the scientific study of complex diseases such as heart disease, asthma, diabetes and cancer because they are caused more by a combination of genetic and environmental factors. Genomics is offering new possibilities for therapies and treatment of some diseases, as well as new diagnostic methods. The major tools and methods related to Genomics studies are bioinformatics, genetic analysis, measurement of gene expression, and determination of gene function. More at Genome.gov and at and at CDC.gov Genomics and Health Resources and CDC.gov Genomics Translation Resources

However, the phrase "Genomic Diagnostics" tends to be used differently than the scientific meaning of "Genomics." The majority of Genomic Diagnostics that are available today are based on second generation sequencing platforms. Today, this type of diagnostic refers to the testing of fractions of the complete human genome of a person. These tests evaluate mutiple genes and are significantly larger than what is typically analyzed in a typical "Genetic Diagnostic." Although whole genome sequencing is possible, these tests are quite expensive and the term "Genomic Diagnostic" is used to refer to the tests of portions, or fractions, of the entire genome. Perhaps, a more apt term to define this type of diagnostic, is "multiplex genetic tests," because they represent genetic diagnostics that are highly parallelized and have a relatively high-throughput, but are not based on a complete genome sequence.

"Genomic Diagnostics", as in the popular usage of the term, are capable of many more measurements than genetic diagnostics. Often these tests completely sequence several genes to the entire genome, or of hundreds of thousands of SNPs from a genomic sample and tend to use microarrays (sometimes called SNP chips or gene chips) or second generation (still called "next-generation" sequencing circa 2010), high-throughput DNA sequencing. Microarrays are widely used in direct-to-consumer genomic diagnostics designed to provide risk profiles for many genetic diseases at once. These tests are highly useful for more complex diseases that caused by multiple genetic abnormalities, rather than single abnormal genes. In this sense, Genomic diagnostics "provide comprehensive genetic risk profiles for many diseases or targeted genetic risk profiles for specific conditions." (Scientific Foundations for Personal Genomics paper) Examples of disease caused by multiple genetic disorders include asthma, heart disease, autism, cancer, and hypertension.

Types of Diagnostics Tests

Genetic and Genomic Diagnostics are conducted through a variety of different testing procedures. Primarily, diagnostics utilize biochemical, cytogenetic, molecular, or a combination of these methods, to analyze DNA, RNA, chromosomes, proteins, and metabolites.

Diagnostics may be conducted as Clinical Tests, Research Tests, Investigative, or Recreational Tests. Note that these terms are distinct from the technical methods used in a diagnostic. Rather than describing the procedure, they describe the utility, clinical validity, or purpose of a test.

Test Type	Purpose of Test
Clinical Tests	Clinical level tests are used to examine sample specimens of individual patients for diagnosis, prevention, or treatment of genetic related disorders. The test results are reported from the laboratory back to the patient in writing. Laboratories who conduct these types of tests must be approved by the Clinical Laboratory Improvement Amendments (or "CLIA") program.
Research Tests	Research tests are conducted in laboratories and research centers to study and understand genetic conditions or to develop clinical level tests. These tests are not subject to CLIA approval and are conducted for internalized research purposes to develop advances in testing.
Investigative and Recreational Tests	Investigative and Recreational tests are considered valuable tests, but are those that have not gained either scientific validity or acceptance in the medical community. In short, these tests often are perceived to lack the accuracy of clinical level tests. Moreover, laboratories conducting these tests are not subject to CLIA approval.

Testing Methods

[detailed information on the technical aspects of tests]

In-Vitro Diagnostic Multivariate Index Assays ("IVDMIAs") are another specific class of diagnostics which expound on Genetic and Genomic diagnostics as discussed above. These tests utilize multiple data points from a variety of mutations in a set of genes, or the expression levels of those genes, and then combined the results into a single score or metric by an (often proprietary) algorithm. The FDA defines IVDMIAs as "test systems that employ data, derived in part from one or more in vitro assays, and an algorithm that usually, but not necessarily, runs on software to generate a result that diagnoses a disease or condition, or is used in the cure, mitigation, treatment, or prevention of disease."(FDA 1610). Note that an IVDMIA could be based around a microarray or direct sequencing; they defining characteristic is the combination of the multiple measurements into a single score by a cryptic algorithm.

Clinical Diagnostics Testing

Application of Test Results

Genetic and Genomic clinical tests are being offered to the public for a variety of purposes. The following table illustrates typical purposes of testing.

Test Objective	Description
Diagnostic	These tests are used to confirm when a person has signs or symptoms of a genetic disease. The tests are tailored for diagnosing a particular disease. This includes diseases such as Down Syndrome and Duchenne Muscular Dystrophy. These types of diseases are linked to specific genetic disorders. If signs are present, such as the physical attributes associated with Down Syndrome, a genetic test can be used to determine if the patient has the extra copy of Chromosome 21.
Predictive	A predictive genetic test indicates a person's propensity to develop a disease before any symptoms are present. These types of tests are used for certain cancers, such as breast, colon, and ovarian cancer. The results of the tests can predict, with a margin of error, a person's percentage likelihood of developing these diseases over their lifetimes. Usually, externalized factors, such as age and lifestyle, are taken into consideration with the results to bolster test accuracy.
Presymptomatic	Presymptomatic tests are similar to predictive tests. These tests are used to determine risk for genetic conditions that are already known to be present in their family, but show no symptoms. Diseases such as Huntington's and Grave's disease are among commonly screened in presymptomatic testing. The test results allow doctors to give medical advice, and take preventative actions, to decrease the likelihood of occurrence or increase the chances of successful treatment.
Preconception/Carrier	Preconception or Carrier Tests can determine if individuals "carry" a alterations in their genes that are associated with an "autosomal recessive order." In short, people have a higher likelihood of developing certain diseases if they inherit two copies of altered chromosomes from their parents. If two people each have a copy of one chromosome, their children have a much higher likelihood of developing diseases such as Cystic Fibrosis and Tay-Sachs Disease.
Prenatal	Prenatal tests are used to test fetuses during the course of pregnancy. These tests are especially useful for scenarios where a fetus has a higher likelihood of developing diseases. For instance, if both parents are carriers of genes related to autosomal recessive disorders, or where family history indicates a likelihood of development of Huntington's and Grave's disease.
Newborn	Similarly, newborn babies may also be screened after birth, or at an early age, when circumstances indicate a likelihood of development. For instance, one test analyzes blood samples for abnormal or missing genes or the presence of Phenylkentonuria (PKU), a type of metabolic disease that can cause severe mental retardation without early treatment.
Pharmacogenic	Pharmacogenic screening is a type of genetic test that may indicate a person's response to certain types of drug treatment. This type of test can enable practitioners to select the best methods of treatment after a disease as already been diagnosed.

The Paradigms of Genetic Test Marketing to Patients and Consumers

Clinically Ordered Tests and Direct-Access Tests

Traditionally, the pathway for a patient or consumer to access genetic testings was through a medical professional, such as a physician, who orders a test in the course of medical care to for the purposes of diagnosis or disease prevention. Today, patients and consumer can also directly access genetic testing services directly through laboratories or over-the-counter purchase mail-in kits from drug stores. Within this new paradigm, patients and consumers typically mail a specimen, like a buccal swab or smear, in a container to a laboratory or company which then processes the test and provides test results. Occasionally, consumers and patients in some states can order lab tests directly through a testing center without the need of a lab test order by a medical professional -- availability of this test depends on state and local regulations, as many areas do not permit patients to order their own tests.

One significant difference between the physician-ordered tests and those either directly-accessed or ordered by a consumer is that test results are often not interpreted by a medical professional. Instead, the company or laboratory who provides the testing services are communicate the test results combined with their own analytic interpretations directly to the consumer. Many commentators criticize direct-access tests because they lack the personalized approach to result interpretation by a professional, especially in instances where results indicate a percentage calculation which indicates potential health risks or status. More specifically, in many cases genetic testing services do not account for externalized environmental factors which are known to affect the probability of a person's health status.

Additionally, although the links between many genetic tests and occurrence of diseases are widely accepted in the scientific and medical communities, many genetic tests are not stringently regulated or approved by the FDA for use in the diagnosis or prevention of disease. In some circumstances, the methods of testing may also vary widely. Many commentators, including a U.S. committee on genetics from the Department of Health and Human Services, are concerned that the differences of how test is prepared or conducted ultimately affects the accuracy and proficiency of test results. Moreover, these discrepancies are often not well communicated to the consumers.

Since the awareness - and in particular, the almost prolific discussion in popular media - of genetic tests continues to increase, the future may hold more stringent regulations of genetic product marketing by the FDA and the FTC.

Who Offers Genetic and Genomic Tests?

Generally speaking, genomic and genetic diagnostic tests are available to the public in three different ways: Laboratory Developed Tests services (LDT), In Vitro Diagnostics Kits (IVD), and Direct to Consumers (DTC) as "over the counter" kits.

Market Participants in Personal Genomics

Sequencer Manufacturers

• Illumina
• Solexa
• 454
• CompleteGenomics.com
• PacificBio
• Helicos

Full Genome Sequencing providers

• Knome.com: full genomic sequencing and 2 years research updates; personal genetic counseling. Only $68,500.
• EveryGenome.com: $48,000 full genome sequencing by Illumina. Requires physician request.
• PersonalGenomes.org: Plans to offer free genomic sequencing to 100,000 volunteers. Currently working on the first 100. Jason Bobe works here.

Recreational and Clinical Genomic diagnostics

• Coriell Personal Medicine Collaborative - cpmc.coriell.org: Free Affymetrix GeneChip SNP sequencing, but only for "potentially medically actionable" conditions. Currently this list includes 10 conditions, and will grow as the Informed Cohort Oversight Board approves more conditions.
• 23andMe.com: Offers ancestry and health genomic analysis with an Illumina 550,000 SNP chip for between $399-$499. Results are not clinically useful.
• DeCODEme.com: $195 - $985 for up to 48 genetic conditions using a 100,000 SNP chip. In Bankruptcy proceedings.
• Counsyl.com: offers a (I presume) a chip-based screen for 100 genetic disease markers, including some for cystic fibrosis. Trying to sell both direct to consumers and clinically and aiming for insurance coverage. DTC costs $349. Not sure how they ensure the results are clinically useful.
• Navigenics.com: offers chip-based testing for 28 different conditions along with personal genetic counseling for $999. Not sure how they ensure the results are clinically useful. Want to be clinically used.
• PathwayGenomics.com: offers carrier testing for 61 genetic diseases, metabolism genes for 9 different drugs, as well as ancestry analysis for $199-$399. Not sure how they ensure the results are clinically useful.
• DNADirect.com - not sure what their product is.
• GenomicHealth.com / OncotypeDX.com : 21-gene expression assay that predicts recurrence of certain kinds of breast cancer. Considered a multivariate assay and regulated by the FDA; has more clinical data than most other genetic diagnostics demonstrating it's clinical validity and utility. Covered my insurance more often than other tests.

Reference labs

"The major national reference labs including Quest, LabCorp, Specialty/Ameripath, Mayo and others account for at least 60% of the market for esoteric test services. The remaining 40% is shared by a group of some 3000 small, local market laboratories. The major reference labs have built a comprehensive menu of specialized test services and continue to expand their offerings via collaborations with leading medical research centers. They offer a huge presence in the market and manage distribution networks that touch just about every medical specialty. Thus many CLIA-registered company sponsored test services avail themselves of the marketing resources offered by the national reference labs."

Quest and Labcorp are the two most dominant national reference labs. Financial information can be gotten from the SEC by using the Standard Industrial Classification 8071: Services - medical laboratories, which includes Quest, Lab-Corp, Bio-Reference, Athena, and ~120 others.

• Quest (wikipedia) DGX stock symbol. (SEC CIK#: 0001022079 )
  • 2008 10-K - Annual Report
    • Net Sales of gene-based & esoteric tests: $1,400 Million (20% of total revenue).

• LabCorp wikipedia. LH stock symbol. (SEC CIK# 0000920148)
  • 2008 10-K - Annual Report
    • Net Sales of Genomic & Esoteric tests: $1,478.3 Million (+5.9% from 2007)
    • Volume of Genomic & Esoteric tests: 23.7 Million
    • Patents, licences, and technology "2008 gross carrying amount": 94.7 million

• Bio-Reference Laboratories INC (SEC CIK# 0000792641)
  • 2008 10-K - Annual Report
    • Net revenue from esoteric tests (50%): $150.5 Million

• Athena Diagnostics INC (SEC CIK# 0001161704)

Study of the field

General Analysis of the field based on our ICP Main Questions

1. Overview of Economics of Intellectual Property in Kits
2. Give an overall picture of the Kits' sector
3. Outputs and Products of the field: data, narratives and tools produced by the Kits' sector
4. Legal tools available for and in use by the actors of Kits' sector: IP in Kits
5. competitive advantages in Kits
6. IP Profile of Biggest for-profit companies in Kits
7. IP Profile of non-profit companies in Kits
8. IP Profile of Universities working in Kits
9. IP Profile of Associations in Kits
10. Commons based cases in Kits
11. Peer-Production Business models in Kits
12. Open Business models in Kits

Resources

The following resources may helpful for understanding key concepts discussed in our research:

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