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Coalition for 21st Century Medicine Advisor Sheds Light on IVDMIAs and Dx Options


Paul Radensky
McDermott, Will & Emery’s Health Law Department
Name: Paul Radensky
Position:  Partner, McDermott, Will & Emery’s Health Law Department; legal advisor to the Coalition for 21st Century Medicine.
Background: Member,
American College of Physicians; member, Alpha Omega Alpha Honor Medical Society; member, Florida Bar.
Education: Harvard Law School, JD, 1998; University of Pennsylvania, MD, 1979; Princeton University, AB, 1975.

The Coalition for 21st Century Medicine – a newly formed group comprising genomic, proteomic, and molecular diagnostic companies, advocacy groups, and investors – recently testified during an US Food and Drug Administration public hearing regarding regulations for in vitro diagnostic multivariate index assays.
The group was formed last fall, around the time FDA issued a draft guidance to regulate the algorithm-based assays, currently under the purview of CMS’ Clinical Laboratory Improvement Amendments.
The 26-member coalition has asked the FDA to alter its plan to regulate IVDMIAs, arguing that if the guidance is implemented as drafted, “vital medical tests may become unavailable, innovation and improvements could be impeded, the cost of research and development could rise, and insurance coverage for laboratory tests could erode or disappear.”
Paul Radensky, a partner at McDermott, Will & Emery, one of the law firms that advises the coalition, spoke to Pharmacogenomics Reporter this week about the group’s current efforts and future aims regarding regulation of advanced lab-developed diagnostics.
How and why was the coalition formed?
The coalition was formed around Thanksgiving [last year]. The specific trigger that brought the companies together was the release of two guidances: the IVDMIA guidance and a parallel guidance, released on the same day, on analyte specific reagents. ASRs are the building blocks for a lot of the laboratory-developed tests, so the two guidances go hand in hand. The coalition involves companies that are very much interested in advanced diagnostics that either use ASRs in their tests or otherwise might fall under the IVDMIA guidance. As the coalition was more formally formed, it brought in … some venture capital companies, as well as some patient advocacy groups.
The coalition comprises laboratories, medical product manufacturers, venture capital companies, as well as patient advocacy groups, really coalescing around what is the most appropriate way to regulate advanced diagnostics.
Does the coalition have a stance on any issues other than those that impact IVDMIAs and ASRs?
[The IVDMIA and ASR guidances] were the main triggers. But really the coalition is interested in all aspects of regulation that affect advanced diagnostics, which would include reimbursement issues [see PGx Reporter 02-14-07]. There are also a couple of bills on Capitol Hill on IVDMIAs and diagnostics that the coalition is very interested in.
What are the issues on Capitol Hill that the coalition is interested in?
Sen. [Barack] Obama’s office submitted a bill last year, in the former Congress, broadly dealing with the development of genetic tests, looking not only at regulatory issues about the performance of genetic tests, but also about trying to advance the science for there to be some permanent HHS department-wide function supporting fellowships, as well as looking at appropriate regulation for genetic-based laboratory-developed tests. The bill also called for an Institute of Medicine study to look at what’s going on in this area, and to make recommendations about appropriate balance between regulation by FDA and regulation by CMS under the Clinical Laboratory Improvement Amendments. … Sen. Obama is expected to reintroduce the bill this year. I’m not sure what types of changes will be in it but we do expect him to reintroduce it [see PGx Reporter 11-21-06].
In addition, Sen. Edward Kennedy, who is the chair of the [Health, Education, Labor and Pensions] committee, we know [he is also] working on a bill looking more broadly at all laboratory developed tests [see PGx Reporter 11-21-06] and there have been a couple of drafts that were circulated last year, … and we understand that Sen. Kennedy’s office expects to submit something as well in this Congress. Likely all of these things together will be worked out, with the drug and device user fee reauthorization that is expected to go forward this spring and summer.
Do the Kennedy and Obama bills specifically mention IVDMIAs?
The Kennedy bill incorporates IVDMIAs because it incorporates all laboratory-developed tests. The IVDMIA guidance is one slice. The way FDA defined it, it actually can be very broad, and go beyond laboratory-developed tests to anything that would have an algorithm using laboratory results. But if you look at what FDA said to focus on, what really are laboratory-developed tests, IVDMIAs would be a slice of laboratory-developed tests.
Obama’s bill is looking at genetic-based laboratory-developed tests. So, Kennedy’s bill would be the broadest in essentially regulating laboratory-developed tests. Obama’s would be a smaller slice. … But presumably the things that would be IVDMIAs would sit under both of them.
Do these bills give the oversight power over IVDMIAs to FDA?
We don’t know what the finals will look like right now. If we go on the drafts we saw, for Kennedy’s bill or the last bill submitted by Sen. Obama, the Kennedy bill would provide for FDA jurisdiction but under a registry, so laboratory-developed tests wouldn’t necessarily be required to go through premarket submission. A laboratory would submit to the registry what its test is, as well as the performance characteristics, FDA would review and make an assessment whether or not they thought that it was in the statutory term that they have in the draft decision, and then based on FDA’s decision the laboratory would have the opportunity to provide more information. If FDA still hasn’t come to a decision, then [the agency] could require the laboratory to go for premarket review for 510(k) or a PMA, depending on the type of laboratory test. In addition, if there are other lab-developed tests… that are, under statutory terms, of the same type [as an FDA cleared test] … then they would be exempt from FDA clearance.
Sen. Obama’s bill asks us to look at what is going on in this area and to come up with a decision matrix. That decision matrix assesses what would appropriately fall under FDA jurisdiction versus that which would fall under CLIA.
Does the coalition prefer the regulatory suggestions in these bills over FDA oversight of IVDMIAs as it is laid out in the draft guidance?
I think there are things in each one of the proposals that the coalition finds … are consistent with the principles [it] has put together. I don’t know that there is any one that we would say fully meets the principles and the recommendations the coalition has put together. For instance, in the Kennedy bill the concept of a registry is something the coalition has said warrants further consideration. … A number of coalition members have met with Sen. Kennedy’s staff and provided some recommendations. 
With respect to Sen. Obama’s bill a number of members think very positively about the idea of having an Institute of Medicine study, the idea that some group should look at what’s out there and make a determination as to what makes the most sense in terms of regulation. The FDA is looking at regulation based on whether or not the laboratory tests have an algebraic equation in them. Many of the coalition members have questioned whether or not that is really a risk-based concern, as opposed to a technology-based concern. Many new laboratory tests may be unfamiliar to physicians, so there is no reason why an equation would be more or less understood by physicians.
During the FDA’s public meeting on IVDMIAs, there were some who brought up just that point, that perhaps IVDMIAs aren’t necessarily riskier than other home-brew tests. Is that something the coalition also feels?
Yes. In so far as the FDA would regulate IVDMIAs, members of the coalition definitely feel that the type of regulation should be risk based. And that there should also be an exemption for low-volume tests. Otherwise, low-volume tests will not be developed. If you have to go through FDA clearance and post-marketing controls, that has a significant expense and that’s why there aren’t kits that are FDA cleared. Because [these kits] are created generally for rare disorders, companies can’t justify the investment [of going through the FDA approval process]. The coalition definitely feels that a risk-based approach with a low-volume test exemption would make the most sense.
There were some other alternatives proposed at the meeting as well, such as emulating the New York State system (see story in this issue) and incentivizing diagnostic development by giving orphan designation for low-volume tests. How does the coalition feel about these alternatives?
I think that with respect to the low-volume tests, the coalition’s recommendation is for an exemption.
With respect to the New York State model, we don’t have a policy position on that. I think where folks have looked at New York State is to respond to the view that lab-developed tests are being used clinically without any regulation today. And that is certainly not true. There is state level regulation [that] all the laboratories that are licensed in a state are subject to, like hospitals and physicians. Unlike hospitals and physicians, however, laboratories are also subject to federal regulation under CLIA. The ones that perform IVDMIAs, what are called high complexity laboratories under CLIA, many if not most are also accredited under voluntary accreditation organizations. …
Also, a number of states take the position that whether or not laboratories are located in a particular state, if the laboratory reviews specimens in a specific state, they must be licensed in that state. New York is a state that has that requirement. So even if I am a laboratory in California or Florida, if I review specimens from patients in New York State, then I must be a New York-licensed laboratory. New York has a requirement to do a premarket review.
The point … is that there is already regulation. Most of these tests under state law, CLIA, as well as New York, have premarket review. As far as the coalition is concerned, the point would not be to have yet another body doing what New York State is doing. It’s simply reflecting the point that the tests that are out there have undergone some kind of review from New York State. … There are probably about half-a-dozen states out there that require the laboratories to be licensed in that state and in their home state. All laboratories would be licensed in their home state.
What alternatives to FDA oversight for IVDMIAs does the coalition suggest?
There are a couple. First, looking at the regulations that exist and determining whether or not those areas should be enhanced that deal with CLIA. … It is very clearly comprehended under CLIA that laboratories can either use FDA-cleared kits as labels, they can use FDA-cleared kits and modify them, in which case they become high complexity, or they can create them on their own, in which case they are high complexity. What many of us have said is that if there are concerns about regulation of these tests, the most appropriate place to look first is CLIA. Many people have said that CLIA only looks at analytical performance … but actually when you look at the CLIA regulation, if the end result you get is a score from an algorithm, then you have to validate that algorithm. So a key piece the coalition supports is looking first to CLIA.
What some groups have suggested is creating a genetic specialty under CLIA. … Another area is that if FDA is going to proceed, then FDA should proceed under notice and comment rule making. What FDA is proposing to do with the draft guidance is clearly something it has not done before. … This is clearly a new set of rules for laboratories, and guidance documents are not intended to be binding. … By their very nature and by FDA’s Good Guidance Practices, they are intended to be documents that say you may want to do things this way, but you are not required to do things this way. [Yet] there is nothing in the guidance that would suggest what laboratories could do other than going through premarket review and post-market compliance.
The third is that if FDA regulates [IVDMIAs] then FDA should proceed only on a risk basis. … Looking at low-volume tests, those should be exempt. Analytical-performance-only tests should also be at the lowest level of FDA regulation. Those tests that provide some information about clinical meaning that are not a binary result … they should be at the medium level of FDA regulation. And only those tests that yield a binary result … should be at the highest level of regulation.
A fourth area is if FDA comes out with a final proposal in this area, then the agency should allow for a transition period. You heard at the meeting that there is a lot of confusion about what FDA intends with the draft guidance. There is a lot of concern that if FDA chose to release a final guidance, no one knows what that will look like until it comes out. So, it’s not fair to ask laboratories to be in compliance with it the day that it comes out.

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