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= Field Definition =
===Introduction to Genetic and Genomic Diagnostics===


==What are Genetic 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 research and development in the biotechnology industry.  Over the last 30 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.


===Definitions===
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 techquies.  Thus, the acutal methods that are developed are not often based on new measurement or sampling techniques, but rather, newly discovered links between genotype and phenotype.
We're interested in studying genetic diagnostics (GDx). GDx are clinical diagnostics based on the analysis of human DNA to determine genotype and corresponding health states, such as disease diagnosis, prognosis, recurrence, and differential drug response. (see SACGHS Patent report, pg 5).


GDx are often classified as molecular diagnostics (or esoteric tests), a category of relatively novel diagnostics based on biochemistry developed over the last 30 years. Molecular diagnostics analyze molecular components of the body, such DNA, RNA, proteins, and some small molecules. Importantly, while other standard diagnostics, such as immunochemistry tests, may in fact be based on molecular techniques, the are generally not classified as molecular diagnostics. Molecular diagnostics typically test for rare or unusual health conditions and are more sophisticated or involve increased complexity and human involvement than routine tests, although molecular tests are becoming more routine.
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 diabeties, 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.


Molecular diagnostics are a kind of In-Vitro Diagnostic (IVD). (Other classes of IVDs are General/Clinical chemistry, Immunochemistry, Hematology/Cytology, Microbiology/Infectious Disease, & Molecular, Genomic, Proteomic, & Metabolomics).
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 suprise that these companies seek robust legal protection for their investments in the form of intellectual proeprty ("IP"). 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.


=== [[Diagnostic_Kits/Glossary|Research Vocabulary]] ===
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 beind 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.  
Under this section, you can find a variety of key concepts related to the Diagnostic Kits sector and relevant to its understanding.


==What's the market like?==
==Resources==
The following resources may helpful for understanding key concepts discussed in our research:


Although market data is readily available for molecular / esoteric diagnostics, it usually is not broken into further sub-categories, making it difficult to find market information specifically for genetic tests.
===[[Diagnostic_Kits/Glossary|Research Vocabulary]]===
===[[Diagnostic Kits/Bibliography by Resource Type | Bibliography by Resource Type]]===
===[[Diagnostic Kits/Bibliography by Research Question | Bibliography by Research Question]]===


Currently there are genetic tests clinically available for over 1574 diseases according to genetests.org.
==Defining Genetics and Genomics==
Understanding the definitions of "Genetics" and "Genomics" and how these terms are used in practice is a helpful precursor to discussing the broader issues presented in the diagnostics sector.  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.  For instance, in a 2008 report, The Secretary’s Advisory Committee on Genetics, Health, and Society (pg. 17) defined this class of tests as those that involve generally the analysis of human DNA, RNA, genes, or gene products to detect mutations, genotypes, and phenotypes related to disease and health. As of 10/22/2009, http://genetests.org lists 1557 disease conditions for which clinical genetic tests are commercially available, and the number is growing by at least 7% per year. However, despite this growth, fewer tests and therapeutics are reaching the market than would be expected based on major scientific achievement and investment in the field. This phenomenon is termed the "pipeline problem" in the literature. We will explore this phenomeon under the Section XXX


The SACGHS Oversight report (pg 65) describes the two paths genetic diagnostics typically follow from the research bench to clinical practice: a complete in vitro diagnostic kit may be developed and sold commercially to multiple laboratories, or laboratories may develop and validate a test solely for use internally, often with the use of analyte-specific reagents; these tests are called laboratory-developed tests (LDTs). The two paths are subject to different regulatory requirements; generally, IVD kits are more stringently regulated by FDA, which considers kits as in vitro diagnostic devices and may require premarket review or approval.
A more rigorous definition can be done by approaching this challenge from a [technology-historical] perspective we may find some guidance.  For instance, "The invention of the [[A_brief_history_of_license_practices_in_BGP_-_the_case_of_PCR PCR - Polymerase Chain Reaction]], back in 1985, and the rapid pace at which novel genetic defects have been identified since 'positional cloning' came of age in the early 1990s, have greatly increased the possibilities for genetic diagnosis. Over the past two decades, the number of diagnostic tests has steadily increased." [2]


Both types of diagnostic, IVDs and LDTs, must be analyzed in CLIA-certified labs.  Clearing FDA premarket review or approval is generally much more resource-intensive than developing an LDT, so new discoveries are often find their way to market first as LDTs.
==Understanding Genetic and Genomic Diagnostic Distinctions==
A third kind of genetic diagnostic product has developed over the last decade: direct-to-consumer (DTC) genetic tests. Most are ignored clinically are are often derided by medical professionals as "recreational genomics." <ref>[http://www.genomicslawreport.com/index.php/2009/10/23/medical-vs-recreational-genomics-drawing-a-line-in-the-sand/ Medical vs. “Recreational” Genomics: Drawing a Line in the Sand] - Genomics Law Report</ref>
Genetics involves scientific studies of single genes and their effects. Genes (units of heredity) 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, but environmental differences also play a part. Examples of single gene disorders that would be considered as "genetics" include cystic fibrosis and PKU (phenylketonuria). More at Genome.gov and at CDC.gov Genetics.  


==Who sells genetic diagnostics?==
Thus, genetic diagnostics (or "GDx") assay a relatively small piece of DNA and/or make a relatively small number of measurement to determine genotype and identify genetic variation known to be related to disease, it's prognosis, drug response, and other heath states. [1]. Over the last 30 years, improvements in sequencing technology have led to massive increases in test throughput, resulting in an accelerating discovery of new genetic targets for diagnostics and a new class diagnostics, genomic diagnostics, based themselves on the high-throughput techniques. 


Where are genetic diagnostic products, be they IVDs, LDTs, or DTC tests, developed, produced, and used?
Genomic diagnostics are capable of many more measurements than genetic diagnostics, often the complete sequence of several genes to the entire genome, or of hundreds of thousands of SNPs from a genomic sample. In this sense, genomic tests "provide comprehensive genetic risk profiles for many diseases or targeted genetic risk profiles for specific conditions (e.g., breast cancer)" (Scientific Foundations for Personal Genomics paper) and are often based on 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 (see DTC+Genomics cell in the table for examples). For instance, Myriad Genetic's BRCAanalysis diagnostic is based on direct sequencing of BRCA1 and BRCA2 genes.


I don't have any solid archetypal examples of GDx development from the 3 categories, which is to say, I don't fully understand how basic research, often consisting of genotype-phenotype association studies, is turned into a new diagnostic product.
Direct sequencing of whole genes is thus the preferred technique for providing comprehensive risk profiles for specific diseases. 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


Who produces existing tests? As far as I can tell, there are two main national testing providers, which resell smaller company's IVDs as kits, produce their own IVD kits, and offer a variety of LDTs, as well as thousands of smaller CLIA-certified labs operating independently and in association with hospitals and doctors offices and offering a subset of the services.
However, in practice, "Genomic Diagnostics" still is something of a misleading term, because the genomic diagnostics that are available today are based on second generation sequencing platforms on which whole-genome sequencing is still quite expensive.  Consequently, "genomic diagnostics" today refers to tests that involve the measurement of fractions of the complete genome of a person that are significantly larger than what is typically analyzed with typical genetic tests, although that fraction may be much less than the complete genome.  A more accurate term would be "multiplex genetic tests": genetic diagnostics that are highly parallelized and have a relatively high-throughput, but are not based on a complete genome sequence.


The two largest national independent clinical laboratories, Quest Diagnostics and LabCorp, sold 2.78 billion worth of genetic & esoteric tests in 2008 (from annual reports; not clear if that revenue is from IVDs or LDTs or both).
In-Vitro Diagnostic Multivariate Index Assays (IVDMIA) are a specific class of diagnostic in which multiple data points, for instance from a variety of mutations in a set of genes or the expression levels of those genes, are measured and then combined 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.


The most prominent DTC companies operate their own CLIA-certified labs. Users purchase the test, use a sampling kit at home (often a buccal swab), and mail the sample kit to the DTC company's lab, which is where the test is conducted. Results are shared online or via a counselor retained by the company. Physicians are often not involved, unlike other GDx products.
Ultimately, manufacturers would like to develop, and clinicians would like to use, diagnostics based on multiplex genetic measurements or whole genome sequencing (link to "two types of genomics"), which would be more cost-effective than multiple single tests. (SACGHS Patents line 1459)


So besides DTC products, which are used at home, in most cases samples are collected at a Doctor's office or at a hospital and then sent to an independent testing provider, either one of the two main reference lab or a smaller-CLIA lab.
==Understanding the Diagnostics Market==
Although market data is readily available for molecular / esoteric diagnostics, it usually is not broken into further sub-categories, making it difficult to find market information specifically for genetic tests.


=Essay=
# [[Page for Joint Creation of Blog Post]]


=Study of the field=
Generally speaking, these two kind tests - genomics and genetics -  are delivered to users in three different ways: Laboratory Developed Tests services (LDT), In Vitro Diagnostics Kits (IVD), Direct to Consumers (DTC) or Over the Counter Diagnostic Kist (OTC) The table below provide a general framework for this categorization.
 
Analysis of the field with basis on [https://cyber.law.harvard.edu/commonsbasedresearch/Field_Research_Methodology Field Research Methodology]
 
# [[Overview of Economics of Intellectual Property in Kits]]
# [[Give an overall picture of the Kits' sector]]
# Outputs and Products of the field: [[data, narratives and tools produced by the Kits' sector]]
# Legal tools available for and in use by the actors of Kits' sector: [[IP in Kits]]
# [[competitive advantages in Kits]]
# [[IP Profile of Biggest for-profit companies in Kits]]
# [[IP Profile of non-profit companies in Kits]]
# [[IP Profile of Universities working in Kits]]
# [[IP Profile of Associations in Kits]]
# [[Commons based cases in Kits]]
# [[Peer-Production Business models in Kits]]
# [[Open Business models in Kits]]
 
 
= Bibliographies =
== [[Diagnostic Kits/Bibliography by Resource Type | Bibliography by Resource Type]] ==
== [[Diagnostic Kits/Bibliography by Research Question | Bibliography by Research Question]] ==
==test section==


{| class="wikitable" style="text-align:center;" border=1
{| class="wikitable" style="text-align:center;" border=1
|+ Diagnostic Kits Available on Market
|+ '''Diagnostic Kits Available on Market'''
|-
|-
! Marketing Method !! Examples of Genetic Tests !! Examples of Genomic Kits
! Marketing Method !! Examples of Genetic Tests !! Examples of Genomic Kits
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! DTC (clinical)
! DTC (clinical)
| DNA Direct
| DNA Direct
| [http://www.dnapolicy.org/news.release.php?action=detail&pressrelease_id=137 URL]
| http://www.dnapolicy.org/news.release.php?action=detail&pressrelease_id=137
|-
|-
! DTC (recreational)
! DTC (recreational)
Line 86: Line 66:
|}
|}


=Navigation=
 
==Navigation==
Back to [[Main Page]]
Back to [[Main Page]]


[[Category:Diagnostic_Kits]]
[[Category:Diagnostic_Kits]]

Revision as of 14:37, 30 April 2010

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 research and development in the biotechnology industry. Over the last 30 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 techquies. Thus, the acutal 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 diabeties, 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 suprise that these companies seek robust legal protection for their investments in the form of intellectual proeprty ("IP"). 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 beind 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.

Resources

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

Research Vocabulary

Bibliography by Resource Type

Bibliography by Research Question

Defining Genetics and Genomics

Understanding the definitions of "Genetics" and "Genomics" and how these terms are used in practice is a helpful precursor to discussing the broader issues presented in the diagnostics sector. 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. For instance, in a 2008 report, The Secretary’s Advisory Committee on Genetics, Health, and Society (pg. 17) defined this class of tests as those that involve generally the analysis of human DNA, RNA, genes, or gene products to detect mutations, genotypes, and phenotypes related to disease and health. As of 10/22/2009, http://genetests.org lists 1557 disease conditions for which clinical genetic tests are commercially available, and the number is growing by at least 7% per year. However, despite this growth, fewer tests and therapeutics are reaching the market than would be expected based on major scientific achievement and investment in the field. This phenomenon is termed the "pipeline problem" in the literature. We will explore this phenomeon under the Section XXX

A more rigorous definition can be done by approaching this challenge from a [technology-historical] perspective we may find some guidance. For instance, "The invention of the A_brief_history_of_license_practices_in_BGP_-_the_case_of_PCR PCR - Polymerase Chain Reaction, back in 1985, and the rapid pace at which novel genetic defects have been identified since 'positional cloning' came of age in the early 1990s, have greatly increased the possibilities for genetic diagnosis. Over the past two decades, the number of diagnostic tests has steadily increased." [2]

Understanding Genetic and Genomic Diagnostic Distinctions

Genetics involves scientific studies of single genes and their effects. Genes (units of heredity) 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, but environmental differences also play a part. Examples of single gene disorders that would be considered as "genetics" include cystic fibrosis and PKU (phenylketonuria). More at Genome.gov and at CDC.gov Genetics.

Thus, genetic diagnostics (or "GDx") assay a relatively small piece of DNA and/or make a relatively small number of measurement to determine genotype and identify genetic variation known to be related to disease, it's prognosis, drug response, and other heath states. [1]. Over the last 30 years, improvements in sequencing technology have led to massive increases in test throughput, resulting in an accelerating discovery of new genetic targets for diagnostics and a new class diagnostics, genomic diagnostics, based themselves on the high-throughput techniques.

Genomic diagnostics are capable of many more measurements than genetic diagnostics, often the complete sequence of several genes to the entire genome, or of hundreds of thousands of SNPs from a genomic sample. In this sense, genomic tests "provide comprehensive genetic risk profiles for many diseases or targeted genetic risk profiles for specific conditions (e.g., breast cancer)" (Scientific Foundations for Personal Genomics paper) and are often based on 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 (see DTC+Genomics cell in the table for examples). For instance, Myriad Genetic's BRCAanalysis diagnostic is based on direct sequencing of BRCA1 and BRCA2 genes.

Direct sequencing of whole genes is thus the preferred technique for providing comprehensive risk profiles for specific diseases. 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, in practice, "Genomic Diagnostics" still is something of a misleading term, because the genomic diagnostics that are available today are based on second generation sequencing platforms on which whole-genome sequencing is still quite expensive. Consequently, "genomic diagnostics" today refers to tests that involve the measurement of fractions of the complete genome of a person that are significantly larger than what is typically analyzed with typical genetic tests, although that fraction may be much less than the complete genome. A more accurate term would be "multiplex genetic tests": genetic diagnostics that are highly parallelized and have a relatively high-throughput, but are not based on a complete genome sequence.

In-Vitro Diagnostic Multivariate Index Assays (IVDMIA) are a specific class of diagnostic in which multiple data points, for instance from a variety of mutations in a set of genes or the expression levels of those genes, are measured and then combined 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.

Ultimately, manufacturers would like to develop, and clinicians would like to use, diagnostics based on multiplex genetic measurements or whole genome sequencing (link to "two types of genomics"), which would be more cost-effective than multiple single tests. (SACGHS Patents line 1459)

Understanding the Diagnostics Market

Although market data is readily available for molecular / esoteric diagnostics, it usually is not broken into further sub-categories, making it difficult to find market information specifically for genetic tests.


Generally speaking, these two kind tests - genomics and genetics - are delivered to users in three different ways: Laboratory Developed Tests services (LDT), In Vitro Diagnostics Kits (IVD), Direct to Consumers (DTC) or Over the Counter Diagnostic Kist (OTC) The table below provide a general framework for this categorization.

Diagnostic Kits Available on Market
Marketing Method Examples of Genetic Tests Examples of Genomic Kits
Products sold in Kits ? Myriad, oncotypeDX,
LDTS genetests.org deCodeMe, navigenics, DNA Direct, pathway, counsyl
DTC (clinical) DNA Direct http://www.dnapolicy.org/news.release.php?action=detail&pressrelease_id=137
DTC (recreational) ? 23andme


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