By Turna Ray
Among the smorgasbord of comments submitted by various stakeholders to the National Institutes of Health about the development of a voluntary genetic testing registry, a few themes have emerged, revealing the circumstances under which test makers would be willing to participate and when they would be less inclined to do so.
Comments from numerous stakeholders were submitted in response to a request for information that the NIH issued in May asking stakeholders to weigh in with ideas about how the voluntary registry should be structured. The repository, slated for launch next year, will have its home at the National Library of Medicine, and will be implemented by the National Center for Biotechnology Information (PGx Reporter 06/02/10).
Drug developers, laboratories, diagnostics firms, payors, and various interest groups that commented on the genetic testing registry agree that an open repository such as the one being envisioned by the NIH would offer the public a way to get information on the uses, limitations, and regulatory status of genetic tests. Additionally, stakeholders agreed that the registry — depending on its structure and the types of data included — could be a way to curate information on investigational markers and emerging technologies, which would facilitate more collaborations between the government, industry, and academia.
However, drug developers and test makers also have their reasons for not wanting to participate in the registry.
For example, diagnostic firms and laboratories don't want to post clinical validity or clinical utility data while that data is still emerging for a particular test. Moreover, several test developers said they would rather keep information about cost and reimbursement off the registry — a view counter to that of two professors from the Duke Center for Public Genomics, who said that including reimbursement and test cost data in the registry would be in the best interest of patients.
Pharma and biotechnology companies, meantime, want to see a broad range of genetic and genomic tests included in the registry as a way to assess the field and minimize their risk when investing in companion diagnostics development. However, recognizing the dual regulatory pathway for test kits approved by the US Food and Drug Administration and laboratory-developed tests overseen by CMS, there is a concern among drugmakers that the public will compare FDA-approved tests to non-FDA approved tests.
Wary of such comparisons, drug firms would not want to participate if the registry did not differentiate between FDA-approved and non-approved tests, warned Pfizer in its comments to the NIH.
Meanwhile, payors and researchers have weighed in with different interests in mind.
Recognizing that the registry will invariably be used by health regulators to keep an eye on claims made by developers of genetic tests, Blue Cross Blue Shield Association wrote that in order to really get a handle on how the genetic testing marketplace is evolving, participation in the repository should be mandatory.
Providers of information technology management services and entities conducting genomic data reviews extended offers to the NIH to use their expertise to build the registry.
For example, the NIH Pharmacogenomics Research Network, which works with the Pharmacogenomics KnowledgeBase to curate and review PGx markers for an online repository, suggested that the NIH include links to its gene/drug reviews.
Information technology and services provider McKesson, which two years ago began providing a master catalog for commercial diagnostic tests, also suggested that NIH link the genetic testing registry to its catalog of 2,000 test codes, 400 clinical evidence summaries, and customer feedback.
Value for Drug Developers
Pharma and biotech companies are interested in the genetic testing registry insofar as it relates to their ability to use companion diagnostics in the development of drugs.
Drugmakers have been on the front lines pushing for regulatory oversight of all genetic tests, regardless of whether they are developed at a lab or by a diagnostics company. Their reasons are two-fold. First, regulatory oversight of all genetic tests decreases the risk of investing in the development of a test that will be used to make treatment decisions. Second, drugmakers don't want to pay to get a companion diagnostic for a drug OK'd by the FDA if laboratory test developers can beat them to the market by independently developing a similar test and avoid FDA oversight altogether.
To ameliorate this uneven playing field with regard to FDA's inconsistent regulation over LDTs, Genentech submitted a Citizen Petition to the FDA in 2008, advising the agency to regulate all predictive genetic tests used to stratify patients for treatment-related decisions. The Citizen Petition was a key factor in the agency's decision to lift enforcement discretion over LDTs and try to level the playing field for all test developers, whether commercial diagnostic firms, pharma/biotech, or laboratories (PGx Reporter 12/17/08).
As FDA mulls what its new regulations will look like, the agency has stated that it plans to consult the NIH's genetic testing registry in order to keep an eye on the genetic testing industry. What specific areas the NIH and FDA plan to coordinate within the registry is not yet known, however (PGx Reporter 07/20/10).
Based on comments from pharma and biotech firms on the genetic testing registry, it seems drug developers favor a registry that encompasses a broad swath of the diagnostics industry.
Boehringer Ingelheim, a company that is developing personalized drugs with the help of companion tests, recommended that NIH include "all genetic tests" in the registry, whether approved by the FDA or laboratory-developed tests currently under the oversight of the Centers for Medicare & Medicaid Services.
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Meanwhile, the Biotechnology Industry Organization would like NIH to make it mandatory for tests posing higher public health risks to be listed in the registry. "While we support the creation of a voluntary genetic test registry, BIO supports ongoing efforts to make registration mandatory for certain moderate- to high-risk categories of tests," BIO wrote in its comments. BIO represents more than 1,200 biotech firms, academic institutions, and state biotech centers in the US and abroad.
Most companion diagnostics are likely to fall in the moderate- to high-risk category, since they are tied to a drug.
Pfizer sees the value of the registry in "assisting regulatory agencies in evaluating tests and developing appropriate pathways for oversight." The company, which has inked several drug/diagnostic co-development deals with test developers in the area of cancer and infectious diseases, encouraged the NIH "to consult both CMS and FDA through the process of developing" the registry.
While Pfizer would like to see both FDA-approved tests and LDTs overseen under CLIA listed in the registry, the drug developer advised the NIH to separate tests by their regulatory status. Under Pfizer's proposed plan, while the "FDA-approved" test section would be mandatory and modeled after the [email protected] website, the section for non-approved tests would remain voluntary and be similar to clinicaltrials.gov.
"Our recommendation is based on concern that the quality of analytical and clinical validity and clinical utility data submitted for the latter category of tests should not be viewed as necessarily comparable to data for products that have undergone FDA review and approval," Pfizer said in its comments. "If the proposed registry treats all submitted tests equally and there is no vetting of data or information to support these validity and utility claims, users could be misled into thinking a test is more robust than it actually is."
Finally, firms that have invested in getting FDA approval would be discouraged to voluntarily participate if their tests are included in the same website as non-approved tests, Pfizer cautioned.
"As a consequence of regulatory oversight, we are concerned that there could be inappropriate comparison of data from FDA-regulated versus non-FDA-regulated tests, and that makers of FDA-approved tests might even be discouraged from submitting their tests if they felt disadvantaged in how they could portray their products due to labeling constraints," Pfizer observed, adding that firms with FDA-approved tests are limited by the test labeling on the claims they can make, whereas non-FDA approved tests are not limited in the same way.
"Low participation by makers of FDA-approved tests would create an unfortunate gap in the database," the company cautioned.
Test Makers Speak Out
The device manufacturer interest group AdvaMed advised the NIH to limit the registry to only include genetic tests until the reliability of the data submitted to the repository can be established.
"Rather than encompassing every 'genetic' test that involves enzymes, proteins, and metabolites, AdvaMed recommends that NIH limit the scope of the database to tests that involve analysis of human chromosomes, deoxyribonucleic acid, ribonucleic acid, and genes," the group wrote. AdvaMed represents manufacturers of diagnostics, medical devices, and medical information systems, which produce 90 percent of the healthcare technology products purchased in the US each year.
Furthermore, AdvaMed advised that NIH only collect the most basic test information: test name; manufacturer/institution name and contact information; regulatory status; and the option to link to clinical trials data or FDA approval summaries.
"Only after appropriate safeguards are in place to verify the accuracy and reliability of the data entered into the database should data be accessible for use," AdvaMed wrote. "After such systems and safeguards are in place, AdvaMed would recommend that the additional relevant data fields to include would be: indications for use; warnings and limitations; specimen requirements; availability; and accessibility."
Given the evolving nature of diagnostic technologies, diagnostic companies and laboratory test developers seem averse to submitting clinical validity and clinical utility parameters for genetic tests to the registry, since those numbers are likely to change as test providers continue to improve upon their offerings.
Clinical Data's PGxHealth, for example, recommended that the NIH model the registry after GeneTests in requesting submission of "objective" information about a lab's products.
"Some of the fields proposed for the genetic testing registry would include information that tends to be both subjective and ever-evolving, such as that pertaining to clinical validity and utility. This information more properly belongs in either (or both) expert-written summaries, such as GeneReviews, or on the websites of each laboratory; links to these external resources could then be provided from within the GTR," PGxHealth wrote.
The company further cautioned that presenting "subjective data" in the same database as "objective data" could be "unintentionally misleading."
Similarly, Illumina expressed concern that diagnostic firms submitting early clinical validity data for genetic tests still undergoing clinical trials may invite more regulatory scrutiny.
Due to this risk, "test developers may opt to withhold submitting data until more clinical validity and utility is demonstrated — which would limit the informational resource that the site could have been able to provide for researchers," Illumina wrote to the NIH.
Furthermore, Illumina's comments suggested that the company would be unwilling to voluntarily submit to the registry test cost information. Given that reimbursement is granted to genetic tests on a case-by-case basis, Illumina asserted that cost should not be a required field in the registry.
"There are too many factors that can greatly skew the cost, which could contribute to significant inaccuracies," Illumina said.
Finally, test makers represented by AdvaMed appear concerned that the NIH lacks focus in terms of who the registry is meant to serve. In its comments, AdvaMed points out that many different audiences are listed in the NIH RFI, including lab professionals, policymakers, and payors.
"The way one would present the database information so that patients will understand the data would be very different from the way one would present the information to researchers and clinical laboratory professionals," the group wrote. "AdvaMed is concerned about the complexity that may result in targeting the information for use among so many different parties."
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The scope of the registry in terms of its audience and use needs further clarification, according to some stakeholders, particularly in terms of whether the FDA can use voluntary data submissions in regulatory decision making.
As long as the registry is housed at the NIH, Life Technologies believes the registry should remain voluntary, in order not to be overly burdensome to test providers. However, if the registry is made mandatory, as some have suggested, then Life Technologies recommends it be housed at the FDA and used as a tool for regulatory oversight.
For the time being, since the NIH has proposed a voluntary registry, several test providers suggested that companies and labs should be able to leave certain fields blank, but should have to give a reason for why they did so, such as noting that the data is not provided, not applicable, or no evidence is available.
The Question of DTC Genomics
When the NIH first expressed its intent to develop a voluntary genetic testing registry, many questioned whether direct-to-consumer genomics firms would be included in this database.
While that remains to be seen, at least one DTC genomics firm, 23andMe, responded to NIH's RFI. 23andMe suggested that genealogy and ancestry tests be left out of the testing registry, while tests related to diseases and health conditions be included.
Tests for genealogical and ancestry discovery "require an entirely separate design process," 23andMe wrote. Additionally, the company added that certain non-disease condition tests, such as those gauging consumers' eye color or hair curl, "seem low priorities" given the health and disease focus of the registry.
Furthermore, 23andMe suggested that the NIH think ahead to how the registry might handle whole-genome sequencing tests as they become more integrated into clinical use.
"According to the definition of 'genetic test' in the RFI … the GTR will need to accommodate information regarding genotype-based, sequencing-based, and copy number variant-based tests (including comparative genomic hybridization), among others," 23andMe said. "Ideally the GTR will be flexible enough to handle the data elements associated with each of these categories."
Furthermore, 23andMe, as well as several other commenters, suggested the registry inform the public when certain tests are based on "variants of unknown significance."
"Consumers of genetic tests will find the GTR most helpful if the GTR is capable of communicating that some tests may produce results where accuracy cannot be evaluated or health significance is unknown," the company advised.
Finally, since 23andMe provides its customers with information about specific populations in which a variant has been validated, the company suggested that the NIH inform the public of similar information in the registry. "It may be helpful to have an explicit 'subpopulations for which test has been validated' data element since this question will come up for many tests," 23andMe said.
For the Public's Benefit
Although diagnostic firms would like to keep cost and reimbursement data off the genetic testing registry for competitive reasons, two Duke professors, Robert Cook-Deegan and Misha Angrist, urged the NIH to include this information.
Cook-Deegan, director of Duke University's Center for Genome Ethics, Law and Policy; and Angrist, assistant professor at Duke's Institute for Genome Sciences & Policy, noted that in a survey they performed for the Secretary's Advisory Committee on Genetics, Health, and Society, they found that many patients "worried about cost and insurance coverage in addition to their actual clinical results."
Cook-Deegan and Angrist noted that many people they surveyed "were not aware of their testing alternatives, either from other commercial labs or university labs. Very few knew about business arrangements, costs, or even opportunities to get help seeking coverage and reimbursement for tests that could alter the course of their lives."
Therefore, they noted, "in the interest of transparency, we urge NIH to include pricing and insurance coverage information in the genetic testing registry, or at least linkages to resources that clinicians and patients can use to find out information about the tests they might use."
Furthermore, they urged for the open sharing of genotype-phenotype data, particularly when one company or laboratory is the sole provider of a test, such as Myriad Genetics. If companies are permitted to withhold such data by citing them as proprietary assets, then this information will be "unavailable to health professionals or patients who need the information to interpret test results," Cook-Deegan and Angrist wrote.
In the same vein, the Duke researchers also urge the NIH to include information about gene patents in the registry. In other work they performed for SACGHS (PGx Reporter 10/14/09), they "found an alarming lack of transparency among holders of gene patents, which, in some cases, has led to misunderstandings, intimidation, and de facto monopolies," Cook-Deegan and Angrist wrote. "Some companies do not even list their licensed patents, and almost none indicate what uses are exclusively or not exclusively licensed (and thus available for others to use or license)."
The professors acknowledged that with the ongoing litigation concerning Myriad's patents on certain BRCA mutations, the law in the area is in flux. Still, they urged the NIH to list data on gene patents so that consumers, researchers, and test developers can get a better picture of the genetic testing industry and its workings.
A genetic testing registry "is an opportunity for transparency not only with respect to clinical, pricing, and insurance data, but intellectual property as well," Cook-Deegan and Angrist wrote.