Evaluating the NIH’s New Genetic Testing Registry

This morning the NIH announced plans to create a publicly accessible registry of genetic tests.  The Genetic Testing Registry (GTR) is expected to be available in 2011 and will contain information voluntarily submitted by genetic test providers.  The news is significant and carries implications for clinical genetic testing laboratories, personal genomics service providers and individual purchasers of genetic tests.

Many details of the GTR are yet to come, with NIH promising to “engage stakeholders – such as genetic test developers, test kit manufacturers, health care providers, patients and researchers – for their insights on the best way to collect and display test information.”  While the GTR isn’t expected to launch until next year, and there is time to fill in the details, the questions and answers section of the GTR’s new website helpfully addresses several of the most important features of the registry.

This post looks at what we know about the GTR today, and considers what the GTR’s ultimate implementation might mean for the development and regulation of genetic testing.  (Note that the inset orange questions, and the text that immediately follows each question, is taken directly from the GTR question and answer page.)

Background Reading: the SACGHS Recommendation.  As a matter of background, the announcement of the GTR is important, but not surprising.  The past several years have seen a number of individuals and organizations advocate for a genetic test registry.  Many of these are summarized on the GTR’s background reading page, with the most prominent being the report by the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) titled “U.S. System of Oversight of Genetic Testing” (pdf).  The report, which was published in April of 2008, is a comprehensive review of the genetic testing landscape.  Included among its several policy recommendations was the following:

To enhance the transparency of genetic testing and assist efforts in reviewing the clinical validity of laboratory tests, HHS should appoint and fund a lead agency to develop and maintain a mandatory, publicly available, Web-base registry for laboratory tests.

As the SACGHS report and the GTR announcement both point out, the recent proliferation of genetic tests and genetic testing laboratories has made it difficult for stakeholders – including healthcare payors, healthcare providers, patients and consumers and even genetic test providers themselves – to keep track of all of the available tests.  The GTR announcement represents a first attempt to address that problem.

An Opt-In Approach (Voluntary vs. Mandatory).

Is participation in the GTR mandatory?

No. Participation in the Registry is not mandatory. Providers of genetic tests are encouraged to submit test information voluntarily.

That the GTR is voluntary, and not mandatory, is without question its most significant departure from the SACGHS recommendations.  In preparing its recommendation the SACGHS specifically addressed this issue:

…SACGHS reviewed proposals for a voluntary or mandatory test registry and considered the benefits and burdens of each type of system.  The committee decided that a mandatory, publicly available, Web-based registry that is well staffed to maintain an accurate and current database would offer the best approach to addressing [the] information gaps in the availability of tests and their analytical and clinical validity.

Although the SACGHS report acknowledged that “short-term voluntary approaches” to test registration might be appropriate, it also clearly indicated that the fundamental objective was the creation of a permanent and mandatory test registry.

This important distinction has not been lost on others.  In a press release celebrating the GTR, the advocacy group Genetic Alliance (whose founder, Sharon Terry, has been one of the most outspoken advocates for a mandatory registry, including making the case several months ago in this very space) applauded the NIH’s announcement while simultaneously looking forward “to the registry becoming mandatory so that we are all apprised of the quality and availability of genetic testing across the nation.”

Another long-time advocate of a mandatory genetic test registry (see here, here and here) is new NIH chief of staff Kathy Hudson, who is without question one of the key figures behind today’s announcement.  According to ScienceInsider, “Hudson once pressed for a mandatory registry, but admits it’s not clear whether NIH has the authority to require that companies submit data on their tests.”  The NIH may not have the authority, but it is working together with the FDA and CMS to implement the GTR (more on this below), and both of those agencies have much more clearly established authority to directly regulate genetic testing companies.

While there’s no obvious indication that the GTR is intended to be an interim stop on the road to a mandatory test registry, such a conversion is certainly a possibility at some point in the future, particularly if the GTR proves successful but ultimately incomplete in a voluntary iteration.

A Limitation on Included Tests (Laboratory Tests vs. Genetic Tests).

What is the scope of the GTR?

The GTR will collect and provide information on genetic tests. A more precise scope will be determined after gathering input from the stakeholder community. In the interim, the working definition of a genetic test for purposes of the GTR is, “a test that involves an analysis of human chromosomes, deoxyribonucleic acid, ribonucleic acid, genes and/or gene products (e.g., enzymes and other types of proteins), which is predominantly used to detect heritable or somatic mutations, genotypes, or phenotypes related to disease and health.”* The definition of genetic test is expected to evolve over time, as laboratory technologies are rapidly increasing and changing, and GTR will continue to engage with the community on this issue.

* From the HHS Secretary’s Advisory Committee on Genetics, Health and Society 2008 Report, U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services.

The other key difference between the GTR announcement and the SACGHS recommendation is the limited scope of the registry.

In its letter to the Secretary of HHS that prefaces the report, the SACGHS task force acknowledged that, while it had been charged with investigating the oversight of genetic tests, it had concluded that “the concerns associated with genetic testing generally do not differ from other complex laboratory tests.”  In reviewing the issue the SACGHS task force rejected the idea that genetic tests were fundamentally different from other complex laboratory tests – including tests for cholesterol levels or HIV-status – and determined that this form of “genetic exceptionalism” could lead to unwarranted distinctions in regulation or policy.  As a result, the SACGHS recommendation declared that “since genetic tests are not different from other laboratory tests for oversight purposes, the registry should include all laboratory tests.”

However, the SACGHS report also recognized that “implementing an expansion of Federal oversight of laboratory tests will require incremental steps and that, in this context, genetic tests should have the highest priority.”  It would appear that the NIH has reached the same conclusion in choosing to focus the GTR solely on genetic tests.

Who Does the GTR Cover (Clinical, Commercial, Research)?

Who can contribute test data to the GTR?

It is expected that all providers of genetic tests will be able to submit information to the GTR on a voluntary basis. Providers of genetic tests may include clinical laboratories, test manufacturers, entities that report and interpret tests performed elsewhere, and laboratories outside the United States.

The scope of the genetic test providers encouraged to submit data to the registry is quite broad, if not quite as explicit as might be hoped.

Clinical laboratories are specifically included, as are “entities that report and interpret tests performed elsewhere.”  Together, these categories appear to cover most of the reputable direct-to-consumer (DTC) genetic test providers, which either operate their own CLIA-certified laboratories (e.g., Pathway Genomics) or contract with CLIA-certified testing labs to conduct the actual testing, with the interpretation of the test supplied by the DTC company (e.g., 23andMe).  Although not mentioned by name, it seems clear that the GTR is intended to serve as a repository for information about DTC genetic tests as well as the numerically more common clinical laboratory genetic tests.

Less clear is the status of genetic tests performed in laboratories that are not CLIA-certified.  For instance, certain genetic research laboratories may be too small to have applied for CLIA certification.  This example is one where the substitution of “can” for “must” in the design of the GTR is significant.  The effectiveness of the registry as a tool for accurately mapping the landscape of genetic test providers will remain limited for as long as the GTR remains voluntary.

Is Collaboration a Sign of Future Regulation?

Is NIH collaborating with other HHS agencies in the development of the GTR?

Yes. NIH is working with the Food and Drug Administration and the Centers for Medicare & Medicaid Services (which enforces regulations based on the Clinical Laboratory Improvement Amendments) to streamline the process of data submission for test providers who may be required to provide similar information to these other HHS agencies.

At this point we begin to drift into the realm of hints and speculation, reading between the lines to see if there are any clues as to how the GTR might develop over the next 12-18 months, and whether this announcement portends any further regulation in the area of genetic testing.

First, it’s not surprising that the NIH is working with the FDA and CMS to develop the GTR and “streamline the process of data submission for test providers.”  Indeed, anything other than close collaboration between those three agencies would be a huge mistake, as each plays a pivotal role in the support and regulation of genetic testing.

The relevant inquiry is not whether the agencies are collaborating, but whether that collaboration is a precursor of a more comprehensive system of regulation for genetic testing.  There’s no answer to that question, but the nature of the information that will be included in the GTR does provide grist for the speculation mill.

What type of information can be submitted to the GTR?

It is anticipated that a wide variety of information will be collected in the GTR. NIH plans to seek input from all interested stakeholders to help identify the desirable data elements. The aim of the Registry is to provide information regarding the breath [sic] of available genetic tests—including what tests are available, indications for testing, and who offers the tests—and quality measures such as analytical validity, clinical validity, and clinical utility.

The focus on quality measures – analytical validity, clinical validity, and clinical utility – is particularly interesting.  The regulatory landscape surrounding genetic tests is neither simple nor uniform (which is why the SACGHS report runs to nearly 300 pages).  It is a patchwork quilt of overlapping federal and state regulations, industry self-regulation and indirect regulation (e.g., demands by payors that genetic tests prove both accurate and useful).

The SACGHS report highlighted the issue and, since then, demands for an expanded, coherent system of federal regulation for genetic testing have not abated.  The numerous contested issues include whether and how to regulate certain classes of genetic tests, particularly the category of laboratory developed tests (LDTs) known as In Vitro Diagnostic Multivariate Index Assays (IVDMIAs) which form the basis of many personal genomics products, and whether clinical utility alone captures the value of personal genomic testing.

Does the GTR presage a future collaboration between some combination of the NIH, the FDA and CMS to create such a system?  There’s no answer to that question today, and it’s clear that the GTR in its current incarnation is not going to serve as the point of regulation for genetic tests.  But by beginning to compile, for now voluntarily, a registry of genetic test providers, as well as significant data concerning the analytical validity, clinical validity and/or clinical utility of such tests, the GTR could well serve as one of the central components of any future regulatory expansion.

[Begin Added in Edit, 3/18] Turna Ray of GenomeWeb’s Pharmacogenomics Reporter has a very nice piece examining today’s GTR announcement. Particularly interesting is her suggestion that “housing the registry at a research organization, such as NIH, may quell industry fears of potential regulatory pushback from participating in the registry.”

As discussed below, participation in the GTR will be critical to its success. I think Ray is correct to point out that NIH has the proper pedigree and research focus (as opposed to the more traditionally regulatory focus of the FDA and CMS) to lead the GTR effort without sparking fears that this is just a first step in the direction of increased regulation. Never mind, of course, that the GTR could well be just that: a precursor to a more comprehensive regulatory framework for genetic testing still to come. [End Added in Edit, 3/18]

How Will the GTR Integrate with Existing Genetic Test Resources?

Why do we need the Genetic Testing Registry (GTR)?

There are currently more than 1,600 genetic tests available for clinical testing—a number that has been growing steadily and continues to rise. However, there is currently no single database that provides detailed information about these tests. The GTR is intended to fill this information gap.

How will the GTR be created, designed, and maintained?

The GTR will be created, designed, and maintained by the National Center for Biotechnology Information with input from the stakeholder community and oversight by NIH steering and scientific groups.

At present, there are a variety of public and private resources that offer some of the same functionality as the GTR is promising.  Most notable is the the GeneTests database, which is operated by the National Center for Biotechnology Information (NCBI) and funded by the NIH.  The GTR’s statement that there are “currently more than 1,600 genetic tests available for clinical testing” is likely drawn directly from the GeneTests database which, as of today, lists 1,667 clinical tests and 257 research tests.

Although helpful, GeneTests is neither fully comprehensive nor particularly use-friendly, particularly for consumers seeking a less technical understanding of their DTC genetic test offerings, which are generally not included in GeneTests.  Like GeneTests, the GTR will be run by the National Library of Medicine and implemented by the NCBI, with Kathy Hudson noting that the GTR will be linked to other NIH library resources to “provide “a rich resource for physicians and patients and resources.”

Will the GTR represent a substantial departure and/or improvement from GeneTests and other existing resources?  Here the devil is truly in the details, and the comment period associated with the development of the GTR will be critical to ensuring that participation, coverage and usability are all substantially improved by the GTR.

What Does the GTR Mean for Personal Genomics?

Who will benefit from the GTR?

NIH expects that the Registry will benefit a large stakeholder community including consumers, patients, health care providers, third-party payers, providers of genetic tests, and researchers.

Will the GTR provide information on how to order a test?

Yes. The information in the Registry will help health care providers and consumers determine what tests are available and provide contact information for test providers. The Registry will also assist in identifying health care professionals who can assist with the testing process and other resources such as referral information for community support groups and disease information.

Ultimately, the value of the GTR will depend on the level of participation.  Will companies – particularly consumer-focused companies – contribute data about their genetic tests, and will customers (healthcare providers and individuals, both patients and consumers) and payors turn to the GTR as a reliable source of information about those tests?

At least one DTC genetic testing company, 23andMe, has already indicated its intention to participate in the GTR.

“We welcome the news of the Genetic Testing Registry,” said 23andMe co-founder Anne Wojcicki in response to the announcement.  “23andMe has always been committed to providing individuals with the information they need to make the most of their own genetic information.  We look forward to working with the NIH on this project.”

How many commercial genetic testing providers will follow in 23andMe’s footsteps remain to be seen, but the high profile effort seems likely to garner substantial buy.  Ultimately, however, the level of participation will depend on how the GTR is implemented by NCBI and others, including how easy it is for providers to submit data and for consumers and third parties to mine that data (and other integrated data sources).

If participation proves to be high, the payoff could be considerable.  In the personal genomics space especially, meaningful self-regulation is important, with both academics and industry largely in consensus that clearer standards for inclusion and more consistent interpretation of genetic tests would be beneficial.  The GTR represents an opportunity to centralize genetic test offerings, particularly the multiplex genetic testing products offered by many personal genomics companies, and encourage side-by-side comparisons.

If most test providers voluntarily submit test data to the GTR the registry will provide a useful form of industry self-regulation, helping to standardize (or at least clarify) test offerings, spurring healthy competition between providers and enabling neutral third parties to objectively grade their various product offerings.  And depending on the data that is submitted – will it be all technical data, or will it include other pertinent test information such as price and/or insurance coverage? – the GTR will empower purchasers of genetic tests to evaluate competing tests on the basis of features that are most relevant to their own personalized needs – as opposed to deciding based on marketing claims or advertising campaigns.

More importantly, as Daniel MacArthur has already pointed out, the GTR could serve as the basis for weeding out less reputable genetic test providers whose products lack adequate laboratory quality controls (analytical validity) or scientific evidence to support their claims (clinical validity and/or clinical utility).  Such companies would presumably elect not to subject themselves to the scrutiny of the GTR, particularly if it possessed an active community of genetic test evaluators..  Depending on the degree to which purchasers of genetic tests come to rely on the GTR, inclusion in the GTR may well become a de facto requirement for any commercial genetic test provider, even if it is not converted into a legal requirement.

Although the voluntary nature of the GTR limits its usefulness as a regulatory tool, it has the potential to prove extremely valuable to personal genomics companies and consumers alike.  As usual, time will tell.