United States Country Report (Diagnostic Kits)

The Secretary of the U.S. Department of Health and Human Services charged an advisory committee, named the Secretary’s Advisory Committee on Genetics, Health, and Society (“SACGHS”), to investigate a number of questions “related to the adequacy and transparency of the current oversight system for genetic testing” and to examine “current patent policy and licensing practices for their impact on access to genetic technologies.” After an extensive period of investigation, the SACGHS completed a number of reports, including: the U.S. System of Oversight and Genetics Testing (the “SOGT Report”) report on April 30, 2008, and the Revised Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (the “GPLPPA Report”) completed in draft form as of February 2010.

Guide to U.S. Reports

Report Title	Abbreviation	Date of Publication	Subject Matter Covered
U.S. System of Oversight and Genetics Testing Report	SOGT Report	April 30, 2008	Preliminary Report on the status of government oversight and application of genetic information for patient care and management.
Revised Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests	GPLPPA Report	February 2010 (draft)	Report following the SACGHS investigation covering the effects of patent licensing practices on research, and patient and clinical access to genetic tests.

The SOGT Report

The SACGHS SOGT Report is a helpful precursor to understanding SACGHS’s follow up report on the state of gene patenting and licensing practices in the industry as well as the other Country Advisory Reports. This section will highlight and summarize some of the pertinent findings from the SOGT Report, and, in particular, focus on the science, technology, development and market offerings of genetic tests available as explained within the Report. As the title suggests, the 190-page SOGT Report is an in depth report on the status of government oversight of genetic testing and the application of genetic information for patient care and management. The SOGT Report includes an extensive discussion of the current trends in genetic testing, including: the underlying science, technology and testing methodologies used, clinical and non-clinical diagnostic applications, validity and proficiency of testing, the application of state and federal regulations over testing, and public availability of testing. The SOGT Report concludes with a series of recommendation based on the SACGHS committees’ findings.

For the purposes of the SOGT Report, SACGHS defines a genetic or genomic test as “an analysis of human chromosomes, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), genes, and/or gene products (e.g., enzymes and other types of proteins) that is primarily used to detect heritable or somatic mutations, genotypes, or phenotypes related to disease and health.” The purposes of genetic and genomic tests, include “predicting risk of disease, screening newborns, directing clinical management, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations.” Notably, the SOGT Report excludes tests conducted for “forensic or identity purposes, and tests conducted purely for research” from these definitions.

Genetic and genomic tests are conducted using “biochemical, cytogenic, and molecular methods or a combination of these methods to analyze DNA, RNA, chromosomes, proteins, and certain metabolites.” According to the Report, biochemical tests do not directly evaluate DNA, but rather measure the products of genes – enzymes and hormones. These tests are used after the newborn period for “screening and diagnosis” of certain metabolic disorders using specimens that consist of amniotic fluid, maternal serum, or chroionic villi. Cytogenic tests evaluate samples for changes in the number of or structure of chromosomes. Today, cytogenic tests represent the “first tier of genetic testing for assessment of a child with multiple congenital abnormalities,” developmental delays, prenatal detection of abnormalities, or evaluation of cancerous tumors. Molecular testing is among the most complex of genetic and genomic tests and is specifically used to evaluate DNA or RNA for alterations such as “nucleotide substitutions, deletions, or insertions for changes in the amount of DNA.” The underlying technology used in the sequencing of DNA and RNA typically utilizes methods of amplification and hybridization through the use of polymerase chain reactions (PCR), and variants on PCR methodology, and microarrays. These technologies can also be combined with biochemical and cytogenetic tests to determine a wide range of detecting various genetic anomalies, mutations, protein functionality, single nucleotide polymorphisms (SNPs) and microdeletions in samples. In summary, the technology described above can be used to develop tests that identify specific genetic characteristics, such as patterns of SNPs, gene expression, which are associated with specific health conditions or diseases.

Manufacturers and providers of all genetic and genomic tests and testing services tend to classify tests in two ways: as in vitro diagnostic (“IVDs”) tests, and, as laboratory-developed tests (“LDTs”). The ultimate purpose of the test or method of product marketing (e.g., for clinical diagnostics or direct-to-consumer testing) is not distinguished at this level. The distinction between an IVD and a LDT is mostly relevant for how the test is ultimately developed and conducted in, or commercially sold to, a laboratory and what level of federal regulation applies.

IVDs are manufactured primarily as “kits” which include a set of a analyte-specific reagents (ASRs), which constitute the “active ingredients” that necessary for conducting a test, and a set of test instructions on how to perform the test. IVD kits are sold as commercial products by device manufacturers to laboratories who conduct the tests independently. In contrast, LDTs are tests which have been developed within a laboratory, using ASRs which have been developed internally or, occasionally bought from external suppliers. LDT is only used within the laboratory in which they were developed, and are not sold to other laboratories.

A subset of both IVDs and LDTs, known as in vitro diagnostic multi-variate assays (“IVDMIAs”), represent a genetic test for diagnostic purposes that can be defined as “a device that combines the values of multiple variables using an interpretation fluctuation to yield a single, patient-specific results (e.g., a classification, score, or index).” IVDMIAs are used for the diagnosis of disease and other conditions, and will test multiple genetic variables (e.g., more than one gene) in a single test, for multiple genetic conditions. A computer algorithm is applied to the test results, this produces a somewhat comprehensive report that quantifies an index or score report covering a range of genetic conditions.

IVD and LDT Regulation

For U.S. regulatory purposes, IVDs are more stringently regulated than are LDTs. The Food and Drug Administration (“FDA”) regulates IVDs as “medical devices” and depending on the complexity of the IVD, may require pre-market approval, certain levels of quality control, clinical and analytical utility, and accuracy of results prior to the sale of an IVD. Although the FDA has asserted that LDTs are within their regulatory purview, most LDTs do not presently garner the same level of regulatory scrutiny as IVDs and are subject to little regulation when a laboratory utilizes internally developed ASRs. However, the FDA does regulate the sale of ASRs to laboratories. Whether considered an LDT or IVD, IVDMIAs have been clarified by the FDA to be medical devices and are subject to stringent regulation.

Beyond the FDA, the Centers for Medicare and Medicaid Services (“CMS”) impose federal regulatory requirements on all laboratories that conduct testing through the Clinical Laboratories Improvement Amendments (“CLIA”). In short, CLIA imposes requirements on laboratories to meet certain quality assurances and proficiency standards. Laboratories that conduct any type of testing, whether they are classified as IVDs or LDTs, as long as they test human specimens for the purpose of assessing health, diagnosis and treatment, or genetic testing are subject to these regulations and require CLIA certification. Once an LDT or IVD has been developed, and satisfies any applicable regulatory requirements, it can be used for a variety of purposes, depending on their clinical and analytical utility. Genetic tests can broadly be used for clinical diagnostic purposes, or for the purposes of conducting further research (e.g., to develop a new genetic test or just to study the field), and they can be used for investigative purposes (e.g., non-clinical applications for consumers). Notably, tests which are used solely for the purpose of conducting further research, or for investigative purposes, are not stringently regulated. Many of the genetic tests available fall into this regulation-exempt category.

Establishing the clinical validity (which means, how consistently and accurately the test detects or predicts the intermediate or final outcomes of interest. At http://www.cdc.gov/genomics/gtesting/ACCE/index.htm) of a genetic test is a complex process, and according to the SOGT, such validity may not be firmly established before the test is being offered as a product or service. This is especially prevalent in the case of direct-to-consumer test offerings. At present, there does not seem to be a centralized organization which requires certification of clinical validity for all genetic tests. Instead, certification of clinical validity is voluntary or required, in limited circumstances, through specific organizations which are related to particular diseases or health conditions. Although the FDA and CMS have some premarket approval requirements for regulating IVDs and LDTs, many tests which fall into the category of LDTs are not stringently regulated prior to being offering in the market. For a small number tests with firmly established clinical validity, the classic route of offering testing to the public goes through a medical professional, such as a doctor or clinician. However, certain tests, some with clinical validity and others without, are offered directly to consumers through laboratories or companies. This is the case for many LDT-type tests.

The Impact of Gene Patents and Licensing Practices on Patient Access to Genetic Tests – the GPLPPA Report (when wikifing this part....I think there should be sections to each of the problems they found...so the reading is easy)

The GPLPPA Report

Following the SACGHS SOGT Report, SACGHS produced the GPLPPA Report which was the result of the committee’s investigation on the effects of patent licensing practices on patient and clinical access to genetic tests. The GPLPPA Report was substantially based on a comprehensive literature review, commissioned case studies, and expert consultations. The Report went through several revisions, including a first draft in December 2008, a revision in October 2009, and a final draft in February 2010.

The scope of the report focused on “genetic tests that rely on analysis of nucleic acid molecule to determine human genotype, whether used for diagnostic, predictive, or other clinical purposes.” It is particularly important to note the difference of this definition as compared to the range of genetic tests available (e.g., IVDs and LDTs) that were discussed in the SOGT Report, because the GPLPPA Report appears to eschew IVDs and LDTs with low acceptance in terms of clinical validity. This is significant, because those tests represent the majority of genetic test offerings available in the market today. Instead, the GPLPPA focused on a smaller number of tests that have strong correlations and wide use in clinical settings. However, it may be the case that these types of tests represent the majority of diagnostic methods which are patented in the U.S., and for that reason, are especially important to consider in the context of patient access to testing services. (link back concepts from this paragraph into the the definitions/research vocabulary part here)

In the course of investigating the issues of patenting and licensing practices, the GPLPPA Report focused on eight case studies of ten clinical conditions and their related patents and genetic tests for those conditions. In particular, these case studies focused on:

• Inherited susceptibility to breast/ovarian cancer and colon cancer;
• Hearing loss;
• Cystic fibrosis
• Inherited susceptibility to Alzheimer disease
• Hereditary hemochromatosis;
• Spinocerebellar ataxias;
• Long QT syndrome; and
• Canavan disease and Tay-Sachs disease.

According to the GPLPPA Report, the types of patent claims that serve as the basis for the exclusive rights for genetic testing typically fall into one of four categories: (1) composition of matter claims covering isolated nucleic acid molecules, (2) process claims that cover methods for detecting particular nucleic acid sequences or mutations using probes, primers or some other method, (3) claims to processes that associate a genotype with a phenotype, and (4) patents that claim genetic test kits or claims covering platform technology used for genetic testing.

Gene Patents are Difficult to Invent Around

With respect to patent claims on genes and associations, the GPLPPA Report concluded that “[i]t is generally difficult if not impossible to ‘invent around’ patent claims on genes and associations” because inventing around a patented technology “involves making an invention that accomplishes the same thing as the original patented invention but does not infringe the original invention.” Due to the number of patents covering genes that already exist, in many cases an unpatented substitute may not be available. (explain...something like: “This is because the patented gene is the core element to determine the existence of a certain condition”) Moreover, associated patent claims are often dependent on a method of “associating a particular genetic marker with a phenotype” but when no substitute marker exists, “it is impossible to invent around an association patent claim.”

To support this conclusion, GPLPPA Report discusses a recent study , which investigated U.S. and European patent claims relating to genetic testing to “see how many could be circumvented or invented around.” After reviewing 267 patent claims related to 22 inherited diseases, the study concluded that “64 percent of the patent claims were either difficult or impossible to circumvent.” Another point of interest is that the study concluded the most difficult claims to circumvent consisted of methods of detecting particular sequences. About half of the claims covering isolated gene molecules were considered difficult to circumvent.

Additionally, the GPLPPA notes that the technical difficulties of patent circumvent only represent one aspect of the problem for researchers attempting to create new genetic tests. Although a technology may be considered easy to circumvent, that does not account for the time, effort, or financial burden which must be expended in order to successful circumvent a patent. For these reason, the ability to license an invention is especially important for practitioners, researchers, and developers.

US Constitution, IP Clause, and Gene Patents

The GPLPPA Report evaluated the effect of patents and licenses in light of the purposes delineated in the U.S. Constitution’s “intellectual property” clause. On this point, the GPLPPA Report notes that “the purpose of the U.S. Patent System is to promote ‘the progress of science and useful arts.” With this in mind, the GPLPPA considered the affects of the genetic patent in claims on: (1) the concept of a patent as an incentive for further inventions, (2) patents as an incentive to disclose new discoveries, and (3) patents as an incentive for test development. Additionally, the GPLPPA Report considers other benefits which might be offered through the patent system.

Considering the primary goals of the patent system as an incentive mechanism for new inventions, further improvements on inventions, and for the disclosure of inventions, the GPLPPA Report reached a number of conclusions. First, “biotechnology researchers have strong incentives to invent that are independent of patents,” because they are often motivated “by the desire to advance understanding, help their patients by developing treatments for disease, advance their careers, and enhance their reputations.” Although, patents can attract “outside investment” and can also “motivate established companies to invest their own existing resources in pursuing particular lines of genetic research,” the “Federal Government is the major funder of basic research and likely the funder of basic genetic research.” On this note, the GPLPPA Report concludes that “the role of patents in stimulating genetic research thus appears to be limited to stimulating private funding that is supplemental to the significant Government funding.”

Invention Disclosure Incentives

In terms of invention disclosure incentives , the GPLPPA Report notes that “it is doubtful that inventors would keep genetic discoveries secret if they could not patent them.” Moreover, the report notes that there are some sources of data from literature sources that suggest “patents may actually diminish the production of public genetic knowledge.” This leads to the conclusion that patents as an disclosure mechanism are not particularly strong, since absent patent protection, inventions would likely be disclosed anyway.

Patents as Incentives to Bring Innovations to Market

On the final type of incentive, which considers patent grants as necessary to incentivize developers to transform inventions into marketable products, the GPLPPA noted that “case studies show that laboratories lacking exclusive rights associated with genetic testing for particular conditions have regularly developed genetic test for those conditions.” In other words, in certain cases patents were not necessary to encourage developers to bring a genetic test to market. The Report also points out that “[w]hen relevant patents were granted, the patent-rights holder enforced their patents rights to narrow or clear the market of” competing tests. The GPLPPA Report uses several examples of instances where patent holders used their exclusive rights to effectively shutdown genetic tests offered by competitors. The Report concludes that “patent-derived exclusive rights are neither necessary nor sufficient conditions for the development of genetic test kits and testing services.”

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In consideration of other benefits offered by patents, the GPLPPA Report investigated claims that patents offer “significant incentives to educate physicians and patients and that such patent-driven educational efforts can have the benefit of increasing the awareness” of available genetic tests. (what is patent-driven educational efforts in this sense???? explain). However, the GPLPPA notes that there are additional concerns that are raised by these practices, including “overutilization, inappropriate testing and patient harm.”

Effects of Patents and Patient Access to Tests

Next, the GPLPPA Report analyzed how patents and associated licensing practicing affect the price of genetic tests and clinical access to genetic tests. SACGHS was concerned that test pricing that might be higher than those that “would exist in a competitive market.” Study results in this area were somewhat inconclusive, because of difficulties relating to the “contribution of various factors, including [the relation of] overhead costs to price.” In conclusion, the GPLPPA found that “although case studies identified patents and exclusive licenses that appear to be causing high-prices for some genetic tests, no evidence was found that patents and exclusive licenses have consistently led to higher prices.”

On the other hand, the GPLPPA Report does conclude that “the patenting and licensing of genetic tests has limited the ability of clinical laboratories to offer genetic testing” which can, “in turn, affect patient access, the quality of genetic tests and innovations in testing.” This finding was based on studies which showed that some patent holders were using their exclusive rights, and limited licensing practices, to prevent other laboratories from offering testing. In these cases, the patent holders had effectively become the providers of testing. Interestingly, these limitations did not seem to affect the ability of a patient to access genetic testing when the patent rights were licensed broadly. But, where patent holders had used their exclusive rights to “narrow[] or clear[] the market of competing tests,” there were some problems, such as periods of time were testing was only available from academic research laboratories, and not CLIA-certified laboratories.

A second problem indicated when there is little or no licensing of a patented invention is where limited providers of genetic testing do not accept a particular insurance provider, “including Medicaid or Medicare” or other private insurance providers. The result is that patients who are unable to get coverage may be forced to pay considerable amounts of money to obtain access to testing. (example of how much they should pay?) The third problem affecting patient access is that where a patent-holder is the sole provider of testing, a patient cannot use another testing provider to confirm the results by the first testing provider. This essentially acts as a complete barrier to second-opinions on test results. The Report did note, however, that this phenomenon is not well documented.

IP and Quality of Tests

Restrictive licensing practices, patent blocks, or holdouts may also potentially impact the quality of testing services currently available. Principally, this affects tests where a patent holder is not actively allowing licenses to other entities and, consequentially, has become the sole administrator of a genetic test. The GPLPPA Report notes that this has the potential to affect the quality of testing available because there are no other entities available to independently verify testing results. Similarly, if more laboratories were available, greater competition might have the effect of improving assay proficiency for a particular test. Despite this, the GPLPPA Report concludes that the best method of ensure test proficiency is by establishing standards and requiring testing providers to meet those standards. In the case of sole testing providers, this would alleviate concerns over lack of confirmatory tests provided by other laboratories. Moreover, the committee concluded that this would have the additional effect of ensuring quality for all genetic, including for tests that are licensed across a field.

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