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FDA s Felix Frueh On the Agency s Current Thinking on Proteomic Biomarker Data

Felix Frueh
Associate director
US Food and Drug Adminstration's Center for Drug Evaluation and Research

At A Glance

Name: Felix Frueh

Position: Associate director of the US Food and Drug Adminstration's Center for Drug Evaluation and Research, and head of the FDA's Interdisciplinary Pharmacogenomics Research Group.

Background: Founder and managing partner, Stepoutside Consulting, 2002-2004.

Pharmacogenetics research director, Transgenomic, 2001-2002.

Assistant director, Protogene Laboratories, 1999-2000.

PhD in biochemistry from the University of Basel, Switzerland, 1995.

MS in biology from the University of Basel, Switzerland, 1991.

Though they are still significantly behind genomic biomarkers, proteomic biomarkers appear to be gaining steam as components in molecular diagnostic and pharmacogenomics applications.

Last month, Correlogic, which uses bioinformatics to identify protein patterns in mass spectra, obtained an undisclosed equity investment from Quest Diagnostics, which happens to be a long-term development collaborator. And last week, Ciphergen said it is in discussions with Quest to develop its own proteomics-based diagnostic.

Despite these gains, proteomic biomarkers remain a poor relation within pharmacogenomics in part because the US Food and Drug Administration's thinking on the topic is still evolving. And as genomic biomarkers have shown, industry waits for the agency to help guide it before committing R&D dollars.

ProteoMonitor's sister publication, Pharmacogenomics Reporter, this week caught up with Felix Frueh, associate director of CDER and head of the FDA's Interdisciplinary Pharmacogenomics Research Group, to talk about the agency's current position on proteomic biomarkers and the role they can play as pharmacogenomics tools.

What is the FDA's current thinking on the use of protein biomarkers or protein biomarker technologies as either stand-alone diagnostics, components of the drug-discovery process, or even as potential companions to new or existing therapeutics?

I think it's not going to be different from any [genomic] diagnostic that has been approved or that is in approval, or can be approved. The nature of the biomarker is different, but the fact is we're not approving or disapproving based on what the biomarker is — as a protein or a gene, or blood pressure. We are basing our decision on the usefulness of the biomarker, regardless of its nature. … Its analytical performance and clinical performance and clinical usefulness.

It just seems that, as you said, the field is heating up rapidly, and developments can be seen very quickly. Perhaps also from a regulatory perspective, we are going to see submissions in that area.

There's been some talk in industry … that protein biomarker technologies play second fiddle to DNA biomarkers specifically at the FDA. Is that a fair criticism, or would say that this is the case because there's been more research in DNA biomarkers than protein biomarkers?

There certainly have been more research for genomic biomarkers than proteomic biomarkers. However, it's kind of a funny thing: We call it proteomic. A few years ago it was called biochemistry. The difference, really, is that we've been looking at single data points — you're looking at one marker in serum, and you measure that antibody in an ELISA test. Well, now you're calling it proteomics because you're doing it in very high-throughput mode or because you're looking at four or five different markers at the same time. … What we really need to put our focus on is really the technology and the usefulness of these combined proteomic biomarkers as we know them today.

As far as genetics and SNPs go, they are very straightforward to measure — the variability among the tests isn't really all that great. You either detect it or not. Proteomics, as we have seen with several different tests — in vitro hybridization, immunohistochemistry — is not as straightforward. …

I think, technology-wise, proteomics is earlier-stage than genomics and genetics in terms of developing tests that are being used on a routine basis in diagnostic labs.

Do technologies exist today that can reach the FDA's threshold for clearance? For example, two companies, Correlogic and Ciphergen, have commanded headlines because of their success in getting the attention of diagnostic giants Quest and LabCorp.

Again, I think there's no difference between them and Affymetrix, or any of the genomic counterparts. It depends how solid the assay is, and we will be looking at each assay with fresh eyes to make sure that the clinical and analytic performance are up to the standards we expect these tests to be. So, I couldn't tell you if a particular assay or company is ahead of others. We know the usual suspects.

Has the FDA been receiving data submissions from protein biomarker companies, compared to genomic biomarkers?

What we have seen coming in pre-Investigational Device Exemptions stage at the Center for Devices and Radiological Health is predominantly genomics. But we're starting to see proteomics as well. I wouldn't know the ratio, but it's twice genomics to proteomics at this time. I'm talking the new kind of proteomics, like mass-spec tests, not ELISA tests.

Conspicuously absent in the recently released pharmacogenomics guidance [see PGx Reporter 3/24/05] was any mention of protein biomarkers. Is the FDA right now considering a draft guidance for proteomic biomarkers, or has the agency not attained enough data to have a formal thinking on the matter?

There is a simple reason for that: We do believe that genomics in that sense as a science is more advanced than proteomics. Also, writing such a guidance — it's not [easily] done. We need the appropriate resources to review them once we solicit them. To do that, you need to create one, an infrastructure, and, two, identify personnel and expertise that actually can do the work. So, what we assessed at the time the genomics guidance was written was that, most likely, the biggest boost in the — 'omics' field was coming from genomics. That's where we put the emphasis on. However, if you read the guidance, and if you were to exchange the word 'pharmacogenomics' with 'proteomics,' a lot of what's written in the guidance holds true. In other words, the decision trees and the validity of biomarkers that now would be proteomic rather than genomics biomarkers would hold up. There is no reason why there shouldn't be any difference. Take that further to the [FDA's Voluntary Genomic Data Submission guidance, which is a part of the pharmacogenomics guidance document], I don't see a reason why voluntary submissions for proteomic could or should be any different than they are for genomics.

In other words — and we've been talking about this — you could imagine some kind of process where you exchange 'G' with 'X,' so it would not be a VGDS but rather VXDS, and that 'X' could stand for … 'Exploratory.' What we have created with the pathway for voluntary genomic submission is a pathway not necessarily only for genomic data, but for all exploratory early-stage research-type data. However, we encourage at this moment the submission of genomic data because we believe that this is the one field that is most ready for regulatory implications and we want to see and learn what the industry is learning.

You've also been receiving proteomic biomarker data within the VGDS pathway?

No, we have not. We have been contacted several times for requests about whether or not we accept them. What we've gotten so far really wasn't at the stage that we thought would warrant a submission at this point. But we definitely are open-minded. Let's put it this way: The process would be the same.

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