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Is Paucity of Outcomes Data Holding Up PGx Adoption?

Name: Linda Bradley
Position:  Geneticist, National Office of Public Health Genomics, Coordinating Center for Health Promotion, CDC, 2003 to present
Education: PhD, UNC-Chapel Hill, 1984

The Centers for Disease Control and Prevention’s Evaluation of Genomic Applications in Practice and Prevention, or EGAPP, a 13-member independent working group established by the Centers for Disease Control and Prevention in April 2005, is charged with reviewing genetic tests for their outcomes profiles [see sidebar].
The group’s first recommendations, based on a study conducted by HHS’ Agency for Healthcare Research and Quality on genomic tests for ovarian cancer detection and management, are expected to be released March 2007.
AHRQ recently released its report on ovarian cancer detection and management, in which it evaluated tests for single gene products, genetic variations affecting risk of ovarian cancer, gene expression, and proteomics for CA-125 and BRCA1/2. Although AHRQ found no evidence suggesting genomic tests for ovarian cancer have adverse effects beyond those common to other ovarian cancer tests – which primarily include the risks of diagnosis for false-positive results and the risks of delayed or inappropriate treatment of false-negative results – “model simulations suggest that annual screening, even with a highly sensitive test, will not reduce ovarian cancer mortality by more than 50 percent.”
Even frequent screening has a “very low positive predictive value,” even with a highly specific test, AHRQ found. The agency concluded that while “research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.”
This week PGx Reporter caught up with Linda Bradley, a geneticist with CDC’s Office of Public Health Genomics, to learn more about EGAPP and the program’s efforts to provide evidence-based reviews of genetic tests with broad public health applications.
What is the timeline for releasing the EGAPP recommendations?
The first evidence report which was released was detection and management of ovarian cancer and that recommendation is currently in draft form and under review. It is undergoing internal review at the moment and it will need to undergo a peer-review process. [The final recommendations from the group] will probably be fast-tracked through publication, so we’re probably talking February or March, but they may be posted before that.
There will be others [reports] following. We have four evidence reports that are currently in draft stage or further. We’re starting three more [see sidebar]. The [ovarian cancer report] is just the first one.
Who are these recommendations intended for and what impact are they expected to have on the field of genetic testing?
EGAPP is a pilot project which is being supported to investigate and implement this sort of a process and evaluate it with the goal of it being a sustainable program at some point. This is very much the investigative phase of this.
In this first round I would say the immediate recommendations are intended for health care providers. They are going to be written in that way. The four groups we’re targeting are health care providers, payors and purchasers of healthcare, policy makers, and consumers.
When you get down to the consumer level that means that some of these more technical evidence reports and recommendations will probably need to be translated into informational messages that are more accessible to consumers. That is something that the project will be working on as well. But our primary goals are to get the evidence reports done by evidence-based practice centers … and have the working group review the evidence and develop the recommendations.
Can you provide more details on the working group’s efforts to present this data in a consumer-friendly manner?
The goal is to take this information once it’s published and translate it into informational messages that can be used by public health workers, by health care providers, by the public on websites.
Would EGAPP issue its own publications for consumers to present their findings?
That’s still under discussion. The CDC supports two Centers for Genomics in Public Health: One at the University of Michigan and one at the University of Washington. These two centers have been working with us to actually think about exactly these questions and how this can be done and what are the most appropriate formats to use for those kinds of informational messages and how do we disseminate them appropriately. The University of Michigan has actually put together a group called the Stakeholder Advisory Group for EGAPP, and they’re talking about just these issues. They’ve just begun their work. The translation phase is obviously the second phase. The first phase is to get the information collected, to review it and then work on translating it.
What role will the EGAPP recommendations play in guiding regulatory policy for genetic testing?
That’s a good question and one that we’d like to know the answer to as well. That’s really the reason this was done as a pilot project because we felt it was really important to not only to test the process itself in terms of the scientific work that we’re doing for the evidence reviews and then to evaluate the evidence and make recommendations, but also to evaluate the value of both the process and the information that’s developed to different stakeholder groups. Part of this pilot project is an evaluation that we’ll probably start in the spring, where we will be surveying health care providers, policymakers, health care payors and consumers … on the value of the information.
What we’re trying to assess is what impact does it have. The evaluation itself will take a year. That information will be used to think about how to build a sustainable process and what should it look like and what we have learned from this.
Can you provide an overview of the platforms and applications that were chosen so far? How and why did EGAPP settle on these tests out of all the available genetic tests out there?
One of the things that the EGAPP working group – which is an independent panel that’s supported by CDC but is composed of all non-federal folks – have really tried to do is pick types of tests, not necessarily focus in on a specific developer like [Roche’s] AmpliChip. AmpliChip is obviously the one that’s so well known, so it often gets mentioned. But they are looking at categories of tests.
You also have to have a clinical scenario in which the test will be used. So, one of the first reviews they are working on is CYP450 testing in individuals with depression who are treated with … SSRIs. They are looking at a number of different tests that do that, of which AmpliChip is one.
The more common misconception that people say to me all the time is, ‘My goodness, there are thousands of tests out there. How do you pick them?’ I think the first thing to understand is that right now there are a little over 1,000 gene-based tests that are available for clinical testing. But the vast majority of those are used for diagnosis or family testing with rare single-gene disorders. While this evidence-based process applies to those kinds of tests, you would obviously have to use different standards, otherwise you would limit access to the tests. …
What EGAPP is focused on right now is the smaller number of tests that have a broader population application. So carrier testing for cystic fibrosis is a good example, but not one we’re doing. It’s a test that has broad application in the public because it’s offered to all pregnant women. Predictive testing for certain inherited risk for common disorders [is something we will investigate, including] … markers for heart disease or diabetes, [or] pharmacogenomics testing for variation and drug response.
Right now we’re focusing on these smaller group of tests that are entering the marketplace fairly quickly that have these broader population applications. … In order to accomplish that EGAPP is selecting topics to create a portfolio that will test the methods in the process.
How is the EGAPP panel evaluating the efficacy and clinical utility of these genetic tests?
The panel is basing their investigations on two things: First, they are using the recommended evaluation component from the original task force on genetic testing that put out their report in 1997, and second, the Secretary's
Advisory Committee on Genetic Testing, which said you should understand and have information on analytic validity, how well the tests themselves perform, the clinical validity of the test … and the clinical utility of the test. …
We started the process using the Agency for Healthcare Research and Quality. They support a group of evidence-based practice centers. These centers have experience doing evidence reviews using standardized methodology. [M]ost of the reviews that we’re doing will be done in one of the AHRQ practice centers. We are doing a couple of reviews using other approaches to test those other approaches and we’re mainly focusing those on new tests where there is very limited literature and you’re really looking for a shorter turnaround kind of answer.
Based on EGAPP’s preliminary findings, what advice would [you] give developers of genetic tests to ensure adoption by physicians?

What’s needed for these tests to move into the marketplace in an appropriate manner is data that supports their validity and utility. That’s what we’re trying to show: is that data available? … We’re trying to figure out what we know and what we don’t know. And what we don’t know [creates] gaps in knowledge. So what … we need to do to resolve those gaps in knowledge [is collect] appropriate data. … The point is that in order to get these things to the marketplace quickly that information really needs to be there.

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