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C-Path's Toxicogenomics Head Talks About Biomarker Recognition at the FDA

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Name: William Mattes

Position: Critical Path Institute director of toxicology

Background: Gene Logic senior scientific director of toxicogenomics, 2003 — 2006

Pharmacia associate director of the toxicogenomics center of excellence, 1996 — 2003

Education: PhD in Biochemistry, University of Michigan, Ann Arbor, 1980


The Tucson-Ariz.-based Critical Path Institute opened its doors last July with the aim of assisting the FDA's Critical Path Initiative with is goal of helping the pharmaceutical industry "safely accelerate the development of new medications," according to a C-Path statement.

One Critical Path issue that C-Path is leading is the Predictive Safety Testing Consortium, a collaboration of industry, academia, and government for identifying and clinically qualifying safety biomarkers, which kicked off in March [PGx Reporter 03-22-06]. Initial members included Bristol-Meyers Squibb, Johnson & Johnson, Merck, Novartis, and Pfizer.

William Mattes, director of toxicology at the C-Path Institute, is directing the project. Pharmacogenomics Reporter recently spoke to him about the project and biomarker recognition at the FDA.

Can you tell me about the project you'll be overseeing at C-Path?

Of the projects that [C-Path] put together, the one that I direct — the predictive safety testing consortium — was initiated with some folks from the FDA and some folks from industry who wanted to put together a consortium that was different from the usual kinds of industry consortia that had been together.

This particular consortium has the focus of doing … a piece of work that they can take to the FDA, and the FDA says, 'Aha. I can relate to this.' It's focused around qualification of biomarkers — taking something that's in [the] exploratory phase — something that a company says, 'We've done some work in our own shop, and we're pretty convinced this [biomarker] works,' and taking it beyond that to an external kind of cross-validation approach where the outcome is a piece of work that the FDA says, 'We believe that the biomarker that you've identified monitors a particular toxicity (in this case) … [and] we can use it in a particular fashion, either as a diagnostic or maybe even as a prognostic.' And the FDA then goes so far as to write a guidance or a public statement saying, 'This particular test carried out this particular way is satisfactory to us.'

So, it's putting that regulatory FDA stamp on it that is ideally going to make this consortium different.

I'm coming into this with a lot of the forming part of a team — that's pretty much done — we're in the stage of 'storming,' so to speak. And in doing that, people are finding really what they have for biomarkers. People are talking to each other in terms of what they would like to see in terms of the qualification process — [such as] what kind of data are we talking about?

There are many unanswered questions. I just got off a phone call with the committee talking about how we're going to handle the data. It actually starts out by saying, 'What is the data?' Some of our data, but probably not initially, is going to be genomic. Most of it is actually going to be discrete biomarker kinds of endpoints — a protein measured by ELISA or whatever assay in urine or serum, something like that — and the correlation will be with the other in-life parameters that were measured at that time.

There are four working groups focused on four different types of pathologies that are of concern, and are needful of novel biomarkers. Those four working groups are: nephrotoxicity, that is, kidney toxicity; hepatotoxicity; vascular injury; and carcinogenesis.

We have 12 companies that have signed up so far, and there should be an FDA press release coming out in the next couple of weeks noting that we're at that point.

So this should provide a pathway that companies can follow to validate biomarkers and gain the FDA's assent?

Absolutely. And hopefully, our goal is that we start really setting forth a process — a standard pathway — by which other biomarkers are qualified. And you know, maybe it will be through a consortium effort, maybe it will be through another means. But by bringing the FDA into this and having them as part of the conversation, and at the endgame having them say, 'Yes, we've followed this all along, we've looked at your analysis, we've looked at the data — it all meets our standards, and we will both bless the biomarker with a guidance, and we'll bless the process in doing so."

Are there any specific biomarkers you have in mind, or can you give an example?

I'll use as an example one that I don't believe we're pursuing, because it's actually out there in a different venue. Most people are familiar with kidney injury molecule one — Kim1. And I'll use that just as a model, but that's not one that we're pursuing.

The reason that I'm so hesitant to mention them [specifically] is because at this point, not all has been openly released for public discussion.

In fact, another piece of this consortium that is unique is that the intellectual property concept was covered right up front. The member companies sign a legal agreement, and it covers how the intellectual property is handled. Effectively, if they come in with intellectual property, they still own it. But anything that is developed as part of the consortium is shared by the consortium, and the Critical Path Institute has a certain set of rights in terms of helping to develop that intellectual property — the focus is not to restrict the IP, but just to sort of control it so that ultimately it will be available for the public.

And sometimes you need to have those IP issues covered clearly, because … let's say have a diagnostic out there, and you would like to have some company take it on and turn it into a commercial assay, they want to be able to know what the IP is and what the restrictions around it [are]. So, that's one of the rationales for having a real upfront dealing with the IP.

Likewise, it means that there are certain things like, 'Which biomarkers are we pursuing?' that I'm a little hesitant to divulge without checking with the rest of the consortium.

When do you expect this to result in a document or policy?

Well, I'd like to believe that we can have something in at least a year. In the case of the kidney group, they're really quite far along. They're having a meeting at the end of this month. I can envision them starting to define what the workflow would look like, such that perhaps some data collection, some actual experiments, would be carried out in the fall. And if you can consider analysis then taking place in the first quarter of 2007, I'd like to believe that a year from now, we might actually have something the FDA is writing on. …

The consortium, while it has the 12 members, it's certainly bound by antitrust laws not to be exclusive of anyone, so we have a process in place for considering membership. We also have a process in place by which those organizations, companies, whatever, who are vendors or service providers, can become involved to be useful to any particular working group.

I mention that because the natural response of many technology companies is to give me a call and say, 'How can I get onboard?' And my response is usually, 'Well, there are some specific requirements for membership, but the only requirement to be involved in a working group is that the working group sees that the technology is useful to them, and they then bring you into that process for a specific reason.'

What companies are currently involved?

[The FDA's upcoming announcement] will include a couple more that have just signed or are on the cusp of signing. The list includes: Merck and Novartis, who were early members; Pfizer; AstraZeneca; Boehringer Ingelheim; and GlaxoSmithKline.

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