Public Meeting on In Vitro Diagnostic Multivariate Index Assays (IVDMIA) Transcript

UNITED STATES OF AMERICA
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FOOD AND DRUG ADMINISTRATION
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PUBLIC MEETING:
IN VITRO DIAGNOSTIC MULTIVARIATE
INDEX ASSAYS (IVDMIA)
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Thursday, February 8, 2007
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FDA PANEL PRESENT:
LARRY KESSLER, Sc.D.Moderator
ALBERTO GUTIERREZ, Ph.D.
STEVE GUTMAN, M.D.
LINDA KAHAN
DANIEL SCHULTZ, M.D.
JAMES WOODS

C O N T E N T S
PAGE
Welcome and Introduction, Dr. Steven Gutman 3
Overview and Scope of IVDMIA Guidance
Document, Dr. Courtney Harper 4
Public Presentations:
Dr. Paul Redensky 13
Dr. Thomas Grogan 21
Steven McPhail 25
Mary Steele Williams 29
Richard Samp 35
Thomas Tsakeris 44
Dr. William Clark 54
Dr. Carolyn Compton 57
Dr. Carolyn Popper 67
Alan Mertz 71
Michael Goldberg 79
Dr. Arthur Beaudet 85
Michael Ostrolenk 92
Mara Aspinall 98
Gail Javitt 105
Dr. Craig Shimasaki 114
Helen Schiff 123
David Levison 128
Sharon Terry 136
Stuart Hogarth 140
Jonathan Cohen 151
Sherry Salway Black 162
Robert Erwin 167
Elda Railey 175
Carol Berry 180
Elissa Passiment 185
Dr. Colette Saccomanno 191
Carolina Hinestrosa 199
Guido Brink 205
Dr. Judith Wilber 208
Carolyn Jones 216

Closing Remarks:

Dr. Daniel Schultz 226
Dr. Steve Gutman 230
Dr. Larry Kessler 232

P R O C E E D I N G S (8:02 a.m.)

DR. KESSLER: Good morning. It's 8:00 a.m., and we're going to start.

My name is Larry Kessler. I'm the Director of the Office of Science and Engineering Laboratories, and I'm moderating today's meeting.

I'm going to turn the podium over to Dr. Steven Gutman, Director of the Office of in Vitro Diagnostics, followed by Dr. Courtney Harper to make a presentation. then I'll provide the rules of the road for the day after those presentations.

Dr. Gutman.

DR. GUTMAN: Good morning. I would like to welcome you to the open meeting on the in vitro diagnostic multivariate index assay guidance.

FDA has a dual mission to protect public health through its regulatory programs while promoting public health by assuring timely access to cutting edge, new products. There's an inherent tension in this dual mission, which I think comes clearly into play as we consider issues related to today's topic.

Because of the complexity of the issues involved, FDA has extended the public comment period for the IVDMIA guidance for 90 days, until March 5th, and has arranged this opportunity for public discussion. FDA is clearly here to listen and to try to understand the concerns, issues, and ideas of all of our key stakeholders.

I want to thank the members of the FDA panel who will include throughout the course of the day Dan Schultz, our Center Director; Linda Kahan, our Center Deputy Director; Alberto Gutierrez, Deputy Office Director; and James Woods, Deputy Office Director, as well sa me.

I want to thank Dr. Altaie for coordinating this event, and Dr. Kessler for moderating, and of course, I want to thank you for coming to Washington and participating and being here.

Last and most important, I want to set a good example by concluding my remarks within the requisite five minutes so that you will all do the same.

Thanks.

DR. HARPER: Good morning. My name is Courtney Harper, and I am going to give a brief summary today on our guidance document entitled "In Vitro Diagnostic Multivariate Index Assays."

I'd like to give a little bit of background information to start off this day in which we're going to receive public comment on this document. We believe that there is a lot of confusion about the regulation of diagnostic tests that are developed by and used in a single laboratory. We believe that this confusion actually is derived in part from our approach to the regulation of laboratory develop tests that use analyte specific reagents and other commercially available FDA regulated components in these tests.

FDA actually stated in the preamble of the final ASR rule that clinical laboratories that develop in-house tests are acting as manufacturers of medical devices and are subject to FDA jurisdiction under the act.

When these laboratories who develop in-house tests actually use ASRs, there's often some confusion in that the ASR regulations themselves do not actually extend to the tests that are made from them. That is that laboratory developed diagnostic tests that use, for example, Class 1 exempt ASRs, another sort of Class 1 exempt FDA regulated products, such as general purpose reagents, the test themselves are not by extension necessarily Class 1 exempt tests, but as you all know, historically, FDA has generally exercised enforcement discretion in the regulation of laboratory developed tests.

However, we have noticed a growing category of tests that include elements that are not standard primary ingredients of laboratory developed tests, and we believe that these differences, such as complex, statistically driven data derived algorithms actually raise new safety and efficacy concerns.

Therefore, these types of tests, which we call IVDMIAs, we are basically stating that these do not fall within the scope of laboratory developed tests over which we have generally exercised enforcement discretion.

To communicate this policy and to actually define this class of tests, we created a new guidance document that was released in draft form in September of 2006 called "In Vitro Diagnostic Multivariate Index Assays." This document was intended to define a very narrow niche of devices, and these devices may be commercially distributed for use in laboratories across the United States or they may be developed in a single laboratory for use within that laboratory, and we believe that this narrow niche of laboratory developed and commercially distributed tests should be subject to active FDA regulation rather than enforcement discretion.

The guidance document contains three criteria that define IVDMIAs, and here I have abbreviated them. Basically an IVDMIA is a test that is developed using clinical data. Often these types of tests are developed from what's called a test set, a training set and a test set.

Basically they use a clinical data set and they use that data to derive an algorithm that basically can be used to discriminate between, for instance, two clinical parameters.

Then in unknown patient data, the test will employ the algorithm to integrate data from tests and/or demographic data to calculate a patient's specific result. This result is often called a classification, a score, a pattern, an index or something similar to that.

And this result cannot be interpreted by clinicians using their prior knowledge of medicine without information from the test developer about the performance of the assay.

Some potential examples of tests that might be IVDMIAs might be a microarray that predicts colon cancer recurrence based on an RNA expression pattern or perhaps an assay that integrates quantitative results from immunoassays to obtain a score that predicts a person's risk of developing Alzheimer's disease, or even a test that integrates demographic data, such as age, gender, et cetera, and the genotype of several genes to diagnose cardiovascular disease.

But we realize that after the publication of the guidance a lot of the questions that we have been hearing have been related to the clarification of this definition. So we'd like to point out that a device may actually use an algorithm and not be an IVDMIA. That's one common misconception.

Devices may also use software and not be IVDMIAs, and devices may be multivariate, measure multiple parameters at one time and not be an IVDMIA. For instance, some devices that are common laboratory developed tests that are not IVDMIAs would be things such as standard creatinine clearance determination or perhaps using the measurements of total cholesterol, HGL cholesterol, triglycerides, and a calculation to determine LDL concentration, or even assays that measure, for example, 25 snips in the CFTR gene to determine a patient's genotype. These things would all not be IVDMIAs.

But since there is a lot of confusion out there and the guidance comment period is still open, we would really love to see a comment from the public to help us clarify this definition. Give us concrete suggestions on how to make the definition of IVDMIAs clearer so that industry has clear guidance going forward.

The regulation of an IVDMIA will be just like the regulation of all other medical devices in that it will be regulated by the risk of its intended use. Therefore, there's actually opportunity for an IVDMIA to be any of the three classes, Class 1, Class 2 or Class 3.

And we believe that for good IVDMIAs, FDA regulation will not be a significant barrier to innovation in this area. FDA regulation will provide an independent assessment of the data and the labeling claims, but we're also grounded by a least burdensome mandate and that we ask questions about the science that are the least burdensome way to answer safety and effectiveness questions.

But all in all, we believe that good science is good science, and if tests such as IVDMIAs are being used on patients, we believe that the data probably already exists to show that they're safe and effective, and so we encourage companies to come and talk to us about that.

In fact, this week we actually cleared the first IVDMIA by de novo. This is the Agendia MammaPrint Test, and it is intended to predict the likelihood of breast cancer recurrence. This particular test is a laboratory developed test intended to be used at a single laboratory site.

This was very efficiently reviewed by FDA in that the total time of FDA's portion of the review actually took a total of less than 30 days, including classification.

This particular test was classified de novo and a Class 2, and it as such can actually now be used as a predicate device for IVDMIAs who had a similar intended use.

We intend to publish the special control guidance document for this new regulations fairly soon, and this guidance document will contain valuable information describing the type of information that should be submitted for these types of assays.

With that I'm going to close this introduction, and I'm going to remind everyone that this draft guidance document is open for comment until March 5th, and now we welcome your comments today.

Thank you.

DR. KESSLER: Thank you, Dr. Harper.

There is no truth to the rumor that Dr. Gutman personally cleared the IVDMIA this week just so he could be on TV.

I'm going to provide just a few logistics comments, and then we are going to being with the first speaker. I'll moderate today, and I'll be ably assisted by Dr. Susan Altaie, who is standing over there at the podium right now.

We have 31 speakers today, and we want to hear all of them in their entirety. We're going to insist that they take no longer than ten minutes, and to do so there's a little timer up there by the podium. It will start off green. At seven minutes it goes yellow. At nine minutes Dr. Altaie will hand the speaker a one-minute warning. At ten minutes it will go red, and at about ten and a half minutes I'll stand up, and at ten minutes and 45 seconds I'll walk over to the podium and push the button so that the speaker is turned off.

(Laughter.)

DR. KESSLER: Actually I'll do that.

(Laughter.)

DR. KESSLER: There are two reasons for that, and the biggest reason is to be fair and courteous to the other speakers. Thirty-one people have asked to speak and they have a right to be heard today, but just as important, if we stay on time, there will be a few minutes for open discussion by the rest of the audience who is here, and we would like to preserve some of that time for the open discussion. So that's very important.

If I leave the podium for a little while, Dr. Altaie will take over the moderating duties.

Okay. We're going to conclude promptly at 5:00 p.m. I'm hoping we'll have some closing remarks at the time. If we go over, we won't. We'll just walk out at five o'clock. Dr. Gutman unfortunately has to leave a little bit before then. So if we are a little bit earlier, that would be great as well.

I ask that you either turn off your cell phones or put them on vibrate so that they're not ringing while we are having -- ah, if you want, the agenda is outside at the desk where Anne Maria and Shirley Meeks are sitting.

Finally, just a comment from me, why we're here. As you heard from Dr. Gutman, we're here to listen. We're here not to have an active interchange today. That's not what the purpose of this meeting is. We're here to hear and listen to your comments.

And so I'll start off in a slightly unusual fashion with a brief passage from the Bible. It's from Isaiah 1:18. "Come now and let us reason together." And the whole phrase is, "'Come now and let us reason together,' sayeth the Lord. 'Though your sins be as scarlet, they shall be as white as snow. Though they be red like crimson, they shall be as wool.'"

There's a metaphor in there somewhere. I'm just not exactly sure where it is. Maybe you'll help me today.

We're a few minutes ahead of schedule, which is terrific, and I'm going to ask our first speaker, Paul Redensky of McDermott, Will & Emery to stand up and talk, and I will not od any fanfare with the introductions. Just a name and where they're coming from.

Thank you, Paul.

DR. REDENSKY: Good morning. My name is Paul Redensky. I'm an internist by training and a health law attorney with McDermott, Will & Emery, residing in their Miami office where it's much warmer.

and McDermott, Will & Emery represents a number of clinical laboratories who may be affected by the policies announced in the draft guidance if implemented, but this presentation is not intended to represent the policies or opinions of either our clients or the firm.

The draft guidance on in vitro diagnostic multivariate index assays raises a large number of issues. Included among them are questions about FDA's legal authority to regulate in this area, what is the most appropriate regulatory framework for laboratory developed tests, and what is the least burdensome pathway to approach that.

But those are not the topics that I'm going to discuss during the presentation today. What I'm going to focus on are what are the questions that laboratories really need to have answered if they are going to be required to comply with the policies announced in the draft guidance, and those include concerns about the definition of an IVDMIA. As Courtney outlined, there is a lot of confusion.

Second, identifying what elements are a medical device within the laboratory service.

Three, what are the pathways for premarket review and how we would understand what are likely pathways.

Four, the compliance with FDA quality system requirements and how that dovetails with CLIA. In particular, there are certain conflicts existing in the regulations between the two regulatory frameworks.

And then lastly, with respect to whenever a policy is finalized, what the time lines will be for coming into compliance.

First, with respect to the definition of an IVDMIA, laboratories considering the development of a novel assay have to have a clear and predictable set of rules to know whether or not a particular test will or will not be subject to FDA regulation. It is not a question of good science. Good science is there, as was in Courtney's slide, whether you go through a CLIA pathway or an FDA pathway.

But those who fund research on new tests will not find it acceptable to find out midway that FDA has issued a new guidance document or an expanded guidance document that will bring new tests under regulation.

So what is subject to FDA regulation and what is not subject to FDA regulation must be clear, and any changes in that have to have a fair amount of explanation as to why and timeliness in any change.

Second, and a key point is identifying what is the medical device within the laboratory service. If you're going to prepare a premarket application, if you're going to put down policies and procedures to comply with quality systems requirements, you have to be able to start by saying what is the device.

That is clear with an IVD that's a kit. You have something that's going out in interstate commerce. It is not at all clear with a laboratory developed test.

The proposed guidance mentions test system and says in a footnote that that term does not mean the same thing that those same two words mean in the CLIA regulations. That's very good to understand, but what does it mean and how does it differ from what CLIA is saying? It begs the question to simply say it's different.

Three, what are the pathways for premarket review? FDA regulation of medical devices is risk based, as everyone knows. The draft guidance indicates that IVDMIAs are likely to be classified as Class 2 or Class 3 and talks about prognostic claims most likely being Class 2 and predictive claims being Class 3.

One of the difficulties is that it's not clear what is the difference between a prognostic claim and a predictive claim. Generally, you will have a claim that is talking about the likelihood of some outcome, survival, disease free survival, cancer recurrence, a cardiac event. That's going to be on some therapy.

Is that a prognostic claim or is that a predictive claim with respect to the particular therapy? These things are key because if something is going to require a PMA versus a 510(k), those are important decisions that are there in developing the initial thoughts about the service and also for the funders to know what the time line is likely to be and what the amount of capital is likely to be required.

Four, compliance with the QSRs. CLIA has substantial quality system requirements that the laboratories already must comply with. In addition, there are state law requirements that are imposed as well, and for laboratories that accept specimens throughout the United States, New York State requires that laboratories be regulated by New York State and has proof up requirements prior to using tests in clinical practice.

How those dovetail to requirements under the quality system requirements is something that needs to be explained with particularity. It is not something where it is sufficient to say we're not going to go after folks the day that we begin enforcement.

Laboratories need to understand what they have to do, and again, this dovetails to what the definition is of what is the product, what is the device that the quality system requirements were looking at having processes in place so that you can be assured that the device is as it was intended to be and how that differs from laboratory quality control, which is really focused on accuracy, reliability of a process, not a widget.

The fifth is conflicts between FDA and CLIA requirements. FDA limits what manufacturers can say promotionally to those things that are four square within labeling. The new publication comes out that is not four square within labeling, and you can only send that out in response to an unsolicited request.

CLIA, by contrast, puts an affirmative obligation on laboratories to update information so that the treating physicians can interpret the laboratory test. So if a new publication comes out, CLIA would require that you include that information proactively to help doctors understand your test report.

These two systems are in conflict, or at least I wouldn't know how to tell someone how to comply with the two systems without further policy instruction on that.

Sixth, a transition. These are new requirements for the laboratories. Make no mistake about that. This is a substantial new regulatory burden with laboratories. They have to propose policies go forward as drafted. A laboratory is going to have to look through its portfolio and determine what is an IVDMIA, what are the elements within the IVDMIA that are a medical device, what premarket pathway they're going to have to go through, how they can set up quality system requirements to meet FDA. All of these things need to be addressed.

It will take time. There's a lot of questions inherent in the draft guidance. Those questions need to be answered so that everyone knows what the rules will be, and folks need to have time after a final policy document comes out in order to be able to come into compliance. It cannot happen the day that the final policy comes out because no one knows what FDA is thinking.

I'm not saying that in a negative way. Everyone is learning and trying to understand this space. We would recommend a period of at least two years for coming into compliance for those products that would be Class 2 and four years for those that would require a PMA.

That's not to say that there's no enforcement mechanisms that are out there. If FDA is concerned today about any laboratory test, CLIA can shut a laboratory down tomorrow or tell them that they have to cease and desist performing a particular test, and the Federal Trade Commission can challenge promotional claims that are deceptive.

So there are tools today that can be in place if there are concerns from a public health perspective until a final regulatory policy is set forth and time to come into compliance is completed.

Lastly, FDA has not really articulated what are the public health concerns it has about IVDMIAs, why putting something together in an equation is something that concerns the agency other than suggesting that it's new.

There has been some discussion about these are black boxes, but many of these are things that have been published. The algorithms have been published. They've been independently validated, and we don't see that that is sufficient.

We would urge the FDA to explain the findings that have led it to lead to regulation here, that the agency provide formal notice and comment rulemaking, not on every detail, but on the fundamental issues of why it's extending regulation, what the types of services that it plans to regulate, and at least top line on the key issues that I raised in the presentation.

Thank you very much, and we definitely appreciate the opportunity to speak here this morning.

DR. KESSLER: Thank you, Dr. Redensky. We appreciate it.

Dr. Thomas Grogan from Ventana Medical Systems. He has some slides for us as well.

DR. GROGAN: My presentation emphasizes the medical practitioner's perspective. My objectives are to demonstrate the medical utility of multivariate analyses and multiplexing and to suggest the kind of draft guidance would impede medical practice.

My career has been in patient care and in cancer biomarker development, as shown.

Next.

I will use two medical examples to make my points.

Next.

EGFR and HOA.

Next.

EGFR is a trans-membrane molecule often associated with cancer and, importantly, the object of targeted anti-EGFR therapy. There exists today a PMA approved single analyte diagnostic. The use of this assay is limited by the observation that EGFR negative tumors may respond to anti-EGFR therapy.

This leads to the NCCN to discount EGFR testing. This lack of single analyte EGFR testing effectiveness is not surprising, given our deeper knowledge of EGFR molecular biology shown here.

To decipher this complexity, we have used multiplexing with QDots directed at EGFR related molecules. These non-bleaching fluorescent QDots allow ready quantitation and give us ratiometric mathematical findings. The draft guidance suggests this type of mathematical result may not be decipherable by a medical practitioner, but I contend that if ratiometric results are put in the context of systems biology as shown here, then the medical meaning is readily interpretable. It is medically relevant to discern that an anti-EGFR therapy has decreased downstream signaling and affected proliferation and apoptosis.

The second example is HLA expression in lymphoma. Here I cite my ongoing six-year experience as an investigator on the NCI DNA array project where 13,000 ESTs were reduced to five prognostic signatures. One of these signatures shown here calls out the medical relevance or high risk of low tumor HLA expression. As shown in the left, there is a surprising mathematical relationship between HLA and the risk of death. As the HLA level drops, arithmetically the risk rises logarithmically.

This emphasizes the importance of analyte quantitation. To extend our knowledge of the HLA risk equation, we again went to QDots to multiplex the HLA associated molecules. This illustrates the complexity of HLA transcription which necessitates multiplexing.

Utilizing multiplexing, we discovered as shown that the change of the HLA family members is coordinate. Hence, the description as a signature. Again, I contend that the multiplex signature is medically more useful than the single analyte.

To further illustrate my point that signatures trump single analytes, in the next slide I'll show you text in which every word is misspelled, but you will discern the meaning by context and by signature.

Could you go back to that one? Just make sure you can read every word.

Notice the word "total mess."

Okay. Lastly, the patient's perspective. This patient report indicates the current state of anatomic pathology. Our reports now go well beyond the diagnosis found on the top line to include items found in the middle on prognosis and targets of therapy.

In 2007, the patients asked for much more than a diagnosis. On the left are the dozen questions they want the answer to.

Next.

By demand, we are going beyond diagnosis to treatment questions and beyond single analytes to multiplexing.

To conclude, from the lab director's perspective, we need as soon as possible the next generation of tests, and we need to get there probably by successive approximation.

From the patient's perspective, we need now to have their questions answered as soon as possible. So my recommendations are that we not apply single analyte logic to multiplexing. We allow new assays informed by research. We let the practitioners sort it out. We don't impede the practice of medicine. We keep the current status for IVDMIAs and ASRs until we find a flexible regulatory alternative.

Thank you.

DR. KESSLER: Thank you, Dr. Grogan.

The next speaker is Steven McPhail from Expression Analysis.

MR. McPHAIL: Thank you.

My name is Steve McPhail from Expression Analysis, a genomic service provider in Durham, North Carolina.

What I'd like to cover this morning are the current state of genetic testing, draft guidance issues as I see them, and potential unintended consequences, a possible alternative approach, and I'd like to close with what I consider to be some of the challenges to widespread genetic testing.

The application of genetic testing to date has typically been associated with rare genetic disorders, but is currently moving into certain therapeutic areas where disease etiology is not well understood, and these are all complex diseases.

So the majority of diagnostics coming out of this disease I contend will use multiple analytes. There are over 1,000 genetic tests today offered by reference laboratories. There are a few FDA cleared and approved tests, and many, many laboratory developed tests.

Issues with genetic testing today are perceived lack of oversight. Now, it depends on who you talk to. If you talk to a CLIA laboratory, they'll tell you that there's plenty of oversight. There's oversight from a federal level. There's oversight from a state level, and from voluntary organizations, such as the College of American Pathologists.

However, there is a lack of transparency associated with this testing. Does a patient and a physician really know what they're getting?

There's also a lack of consistency associated with this testing. If I were to order a cystic fibrosis test in California and order the same test in Texas, would I necessarily be getting the same results? Not necessarily, depending upon the number of variants that are actually tested.

There is also an issue with validation standards. As we're aware, CLIA laboratories are required to form analytic validation of assays that they provide, which include performance measures of sensitivity, specificity, accuracy, and reproducibility versus clinical validation that may be required in a PMA format by the Food and Drug Administration.

There's also potential problems with data interpretation and, therefore, I do believe that some level of enhanced regulation is necessary to insure high quality genetic testing.

But I would make suggestions for improvements in future guidance. These suggestions include an increase in the specificity of the guidance, and I think we've heard that already this morning. The way that I read the guidance, I believe that many, many genetic tests could fall under IVDMIA regulations.

Also, it's very important to reconcile, I believe, the laboratory quality systems versus the FDA quality system. If we force laboratories to move into the FDA quality system requirements, that is a significant cost and regulatory burden for laboratories and cannot be implemented overnight.

I think we also need to address a path for test improvements. Genomic information is coming at us very quickly. If new variants are found, for instance, for cystic fibrosis, we should be able to implement those quickly without having to go through potentially another PMA submission again.

We also need to define a mechanism to assess risk versus technology, and when I look at the IVDMIA guidance, what I see is a technology driven guidance more so than a risk driven guidance.

So some potential unintended consequences of the guidance, I believe, are reduced patient access potentially, potential interference in physician practice of medicine, a potential barrier to innovation.

When we look at many of the companies that are developing these tests, they are small companies, small laboratories. They need access to capital to be able to innovate, and this may have potential negative unintended consequences on their access to capital.

So here's a potential alternative to the guidance, and that is a laboratory developed test registry. I believe that the laboratory developed test registry could include analytical performance characteristics, clinical performance characteristics, both in terms of papers that have been published, as well as laboratory experience. It could include information on adverse events, volume, controls, et cetera.

I believe that this type of a registry would provide a path to additional regulation where necessary. It would allow for regulation based on risk versus technology, and it would provide transparency for regulatory agencies, patients and physicians.

I think I'd like to close with this. I know that the FDA is certainly very excited about personalized medicine and the use of pharmacogenomics in personalized medicine. There are a lot of challenges associated with bringing this technology to use, to widespread market use. I've listed just some of them here, and I think that it's prudent for the agency and for the legislature to focus on how do we reward innovation associated with these types of companies that are struggling to bring this testing to market.

Thank you very much.

DR. KESSLER: Thank you, Mr. McPhail.

Mary Steele Williams from the Association for Molecular Pathology is next.

MS. WILLIAMS: Good morning. My name is Mary Williams. Thank you for the opportunity to speak with you today.

AMP is an international, not for profit, educational society representing over 1,400 physicians, doctoral scientists and medical technologists who perform molecular diagnostic testing. For the last several years, AMP has provided national leadership to advance safe and effective practice and education for molecular diagnostic testing in the health care industry.

AMP is dedicated to the advancement, practice and science of clinical molecular laboratory medicine and translational research based on the applications of genomics and proteomics. Our goal is to represent all members, regardless of the setting in which they practice, because they are united in the end intent to provide high quality, relevant information for the purpose of directing individual and patient community health management.

We acknowledge, however, that different perspectives may emerge from those widely diverse settings. In those instances our primarily responsibility is to comment from the standpoint of molecular testing laboratories and the patients they serve.

Next.

AMP supports the development of tests and test systems for in vitro diagnostic use and encourages industry to pursue FDA clearance and approval where current regulations require. We would like to comment on the recently issued draft guidance, "In Vitro Diagnostic Multivariate Index Assays," or IVDMIA.

The FDA defines IVDMIAs as test systems that employ data derived in part from one or more in vitro assays and an algorithm that usually, but not necessarily, runs on software to generate a result that diagnoses a disease or condition or is used in the cure, mitigation, treatment, or prevention of disease.

In this guidance, FDA asserts that IVDMIAs are not within the ordinary expertise and ability of laboratories and, therefore, raise safety and effectiveness concerns. The FDA then advises that these test systems meet pre and post market review requirements for Class 2 and 3 devices.

AMP questions the agency's interest in regulating medical algorithms, particularly those that are disclosed by the manufacturer and are transparent to both the laboratory and the clinician.

The use of an interpretive algorithm is routine in medical practice and should not in and of itself raise specific concerns with FDA. Algorithms using patient information, such as tumor size, extent of malignancy and node involvement, have long been used to determine the recurrence risk and to classified certain cancer. Many laboratory tests cannot be properly interpreted unless patient data is collected.

One example is interpreting a glucose reading without knowing when the patient last ate. Many algorithms are published with peer review and are available for professional scrutiny.

Next.

As our members routinely design and perform many molecular tests in oncology, hematology, human genetics and infectious disease, we are particularly concerned about the broad language in the document. We feel it could severely reduce the availability of certain laboratory developed testing services and compromise the quality of molecular test development by laboratories under CLIA, many of which have become the diagnostic or prognostic standard of care.

Reduced availability of testing services would limit a health care provider's ability to manage patient care and ultimately limit patient access to new or improved molecular tests.

For example, broad interpretation could classify maternal serum screening or Bayesian analysis for cystic fibrosis carrier screening, both of which use well defined risk calculations as IVDMIAs. Laboratories offering these tests would not likely be in a position to meet FDA requirements as manufacturers.

The FDA identifies IVDMIAs not as laboratory developed tests, but as test systems that combine data derived from the laboratory assay with an algorithm or calculation to reach a patient specific result.

This definition is not found in the federal Food, Drug, and Cosmetic Act, nor in any regulation from the FDA, and was not developed through notice and comment rulemaking. With this proposed definition, the laboratory is the manufacturer of a test system and is subject to FDA regulation as a medical device. We are unaware of such a definition in any FDA regulation.

This area of laboratory operation currently is regulated by the Centers for Medicare and Medicaid services under the clinical laboratory improvement amendments of 1988.

AMP respectfully requests that FDA provide the scientific rationale for their new concerns over the safety and effectiveness of laboratory developed tests, as well as the justification for their jurisdiction over medical testing algorithms.

Next.

FDA convene a classification panel, for example, as was done in the reclassification of immunohistochemistry tests, so that criteria for determining which tests will be subject to FDA regulation will be transparent to laboratories developing such tests.

Next.

FDA clearly and specifically defined the scope of IVDMIAs that it intends to regulate.

Next.

FDA insure that any new guidance does not insert FDA into the purview of CMS regulation of laboratories under CLIA.

FDA apply restrictions requiring PMA or 510(k) clearance of an IVDMIA only when the interpretive algorithm remains undisclosed by the manufacturer.

FDA clarify the scope of its regulations that renders laboratories responsible for meeting criteria as medical device manufacturers, that is, premarket review only or all general controls, registration and listing, quality systems, labeling, medical device reporting.

Thank you for the opportunity to comment on this important document. AMP will provide a formal, written comment to the docket and remains available to work with FDA to develop clear, reasonable guidelines consistent with FDA's mission to promote and protect public health in the development of molecular pathology tests, balancing safety concerns with access and availability of exciting new medical breakthroughs.

DR. KESSLER: Thank you very much.

We will now hear from Richard Samp from the Washington Legal Foundation.

MR. SAMP: Good morning. My name is Richard Samp. I am Chief Counsel of the Washington Legal Foundation, a public interest law firm and policy center located here in Washington.

WLF devotes a substantial portion of its resources to improving health care delivery in this country. We believe that that goal can be best achieved if government regulators devote their energy to addressing proven hazards to public health while at the same time allowing medical professionals the freedom and flexibility to arrive at innovative solutions to our ever changing health care needs.

WLF has no direct financial stake in the issues being addressed at today's public meeting. We have no connection with any of the laboratories whose tests FDA is proposing to regulate. If FDA has received financial support from any laboratory, it is negligible.

I am testifying today because I am convinced that any FDA effort to impose significant regulation on laboratory developed test will be a setback for public health. My background is as a lawyer, not a medical professional. So I can speak with somewhat more confidence when I tell you my other reason for testifying today.

I am convinced that FDA's proposed regulatory effort is contrary to law.

For those reasons, WLF filed the citizen petition with FDA on September 28th, 2006. The citizen petition requests that FDA determine that it will not attempt to regulate as medical devices any assays developed by clinical laboratory strictly for their in-house use.

The petition was prepared independently of FDA's September 7th, 2006 draft guidance and raises several legal issues not addressed in the draft guidance. The citizen petition docket is open, and we encourage those with any interest in the issues addressed today to file comments in that docket.

Because I do not claim expertise as a medical professional, I've only briefly described why I view laboratory developed test, or LDTs, as so important, and why FDA's proposed regulation could significantly hinder effective development and use of LDTs.

Well, over 1,000 different tests are being used every day by clinicians to better inform diagnostic and therapeutic decisions. When new infectious agents first appear and a new diagnostic test is urgently needed for patient care, it is generally an LDT, not an FDA approved or cleared device that first meets that medical need.

For patients with cancer, LDTs have entered wide clinical use in helping to manage their care. Moreover, while inaccurate tests have the potential to cause health care problems, there is no evidence to suggest that currently available LDTs are inaccurate and clinical labs are already subject to regulation by CMS under CLIA.

If the system is not broken, it is difficult to understand why FDA feels such a compelling need to try to fix it.

Moreover, it is plain to anyone with an understanding of clinical labs that requiring them to go through FDA's premarket review process and comply with FDA's device regulatory rules would have a crippling effect on their ability to continue to provide access to LDTs. Laboratories are not operated as medical device manufacturers. Although they must comply with CLIA, they do not maintain the procedures and documents for compliance with FDA's quality system regulation, its QSR.

Nonetheless, FDA is now asserting that labs are subject both to the QSR and to the adverse event reporting regulation. Labs are being told that they will have to figure out for themselves how procedures developed for device manufacturers would apply to them. Yet I don't know anyone who knows how one would go about retrospectively developing design history files as required by the QSR.

Food and drug law attorneys are unanimous in concluding that these and other medical device regulations will preclude at least some tests from being offered at all. Labs constantly innovate and improve their tests. The need to comply with FDA regs. would prevent many of these changes from being made and severely inhibit the flexibility of laboratories and their ability to meet clinicians' needs, e.g., identifying rapidly changing pathogens, such as SARS or HIV.

Moreover, if, as is likely, FDA regulation requires many existing tests to be labeled investigational, patients' ability to obtain reimbursement for these often expensive tests will be thrown into doubt. Many insurers balk at paying for procedures deemed investigational.

I recognize that FDA may be reluctant to heed medical advice from the Washington Legal Foundation, but I ask you to heed our legal advice. The regulation of LDTs proposed by the draft guidance is contrary to law. I have three grounds for that conclusion, all spelled out in more detail in our citizen petition.

First, Congress has spoken, and it has allocated the requisite regulatory authority to CMS under CLIA, not to the FDA under the Medical Device Amendments of 1976.

Second, the Secretary of HHS confirmed in 1992-93 that the regulatory authority lies with CMS.

Third, even if FDA does possess authority to begin to regulate LDTs as medical devices, it is going about doing so in a manner that violates the Administrative Procedure Act, the APA. The only congressional legislation directed specifically at laboratories is CLIA, a 1988 statute whose enforcement responsibilities have been assigned to CMS.

CLIA establishes quality standards for virtually all clinical laboratory testing. Clinical labs that offer LDTs fit to a tee the type of facility that Congress said would be regulated under CLIA, and I quote: "a facility for the biological, microbiological, pathological or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of or the assessment of the health of human beings."

In contrast, the 1976 medical device amendments under which FDA claims regulatory authority does not have anything at all to say about laboratories or lab testing, nor is there anything in the MDA's legislative history to suggest that Congress intended to grant FDA authority to regulate labs, nor is there any evidence that in the years immediately following adoption of the MDA, FDA understood the law as granting such authority.

It was not until the 1990s that FDA first began to suggest that it might possess regulatory authorities over labs offering LDTs, and it is only in the past year that FDA has sought to exercise that alleged authority.

Under these circumstances, it is simply not credible to suggest that Congress did, indeed, intend in 1976 to grant FDA its newly discovered regulatory authority. It is theoretically possible, of course, that Congress in adopting the MDA and CLIA intended to create parallel regulatory schemes each with independent authority over lab testing.

But such an intent is highly improbable when one considers that the MDA said nothing about lab tests, while 12 years later CLIA specifically mandated regulation of lab tests without once suggesting that a preexisting statute provided for a more elaborate set of regulations.

In the absence of authority from Congress, FDA's recent attempts to regulate lab tests are improper and should cease.

Second, even if the regulatory language were deemed ambiguous, subsequent action by the Secretary of HHS removes any doubt that FDA lacks authority to act. It is the Secretary, not any of his subordinate agencies, that possesses the authority through lawful rule making to decide where the authority to regulate clinical labs should lie.

The Secretary made that decision in 1992-93 when he approved comprehensive CLIA regulations that assigned regulatory authority to CMS. In February 1992, final regulations took effect that set forth, and I quote, all requirements applicable to clinical laboratories engaged in testing and interstate commerce.

The final regulation adopted in January 1993 established, and again I quote, uniform requirements to insure the quality of lab services. CLIA regulations underwent extensive revision in 2003, and again there was no acknowledgement of any FDA rule in regulating LDTs.

The Secretary's approval of those regulations is wholly inconsistent with FDA's argument that it possesses the authority to impose a regulatory regime that would void huge parts of the existing CLIA rules.

Third, even if FDA really did possess the regulatory authority it now asserts, it is attempting to assert that authority in a manner that violates the APA. Although FDA has quietly said for about a decade that it possesses regulatory authority, it never attempted to exercise that authority until the past year. It is not the character of LDTs that has changed. It is FDA policy that has changed.

Before a federal agency may change policies in a manner that materially changes established benefits and burdens, it must comply with formal APA notice and comment procedures.

Let me skip ahead and finally say a few brief words about First Amendment concerns that I have with FDA's assertion of regulatory authority. When a lab professional provides a physician with test results, he or she is communicating medical information that FDA has no reason to believe is untruthful.

Even if FDA asserts that such communication should be deemed commercial speech, it is still entitled to a substantial degree of First Amendment protection. Before FDA gets into the business of regulating such speech, it ought to think long and hard about whether its regulatory objectives are sufficiently compelling to justify government impairment of free speech rights in this manner.

Thank you for the opportunity to share my views with you today.

DR. KESSLER: Thank you.

Next we'll hear from Thomas Tsakeris, Coalition for 21st Century Medicine.

MR. TSAKERIS: Good morning. My name is Tom Tsakeris, and I'm speaking today on behalf of the Coalition for 21st Century Medicine.

I am not being compensated by the coalition or by any of its member companies.

Many of my comments this morning are in parallel to many of the earlier speakers. However, I think given the impact that the IVDMIA guidance document has on the practice of laboratory medicine, I think whatever points have been made previously about any adverse unintended consequences are certainly worth repeating.

The coalition represents innovative diagnostic companies, clinical laboratories, researchers, physicians, venture capitalists, and patient advocacy groups who believe in a common mission to develop and offer specialized diagnostic testing to improve the quality of health care for patients. Innovation in quality patient care are the key objectives for the 21st century medicine.

The timely development and availability of high quality, innovative diagnostic tests and services meet today's needs for personalized medicine and, therefore, public health.

The Coalition is concerned that in its current form, the draft guidance document will have adverse unintended consequences. In my discussion today, I will identify some of these unintended consequences and stress the need to obtain better clarity from FDA on the scope of its intent to regulate these types of tests and also to present alternatives to the draft guidance.

The coalition has identifies several serious adverse consequences.

Number one, active FDA regulation of IVDMIAs will impede the innovation of new tests and services, while precluding improvements from being made to existing tests and service.

Two, implementation of the guidance will impose undue regulatory burden on clinical labs by adding new regulatory requirements that conflict with existing CLIA requirements.

And, three, implementing the guidance will preclude tests and services from being reimbursed by health plans, thereby creating disincentives for future research investment in new diagnostic technologies.

I will elaborate on these points.

In its current form, the draft guidance will significantly affect ability and incentives for clinical labs to develop new diagnostic tests and services that build on current medical knowledge. Innovation and diagnostic testing traditionally has been a key attribute of clinical labs.

The draft guidance extends the scope of FDA regulation to certain clinical laboratory tests referred to by FDA as IVDMIAs on the premise that IVDMIA test results -- and I'm quoting directly from the guidance -- cannot be interpreted by well trained health care practitioner using prior knowledge of medicine without information from the test developer regarding its clinical performance and effectiveness.

On the contrary, the coalition believes FDA should be clear that the primary incentive for clinical labs to develop technologically new diagnostic testing capability derives from the demand from physicians and other health care providers to obtain new innovative testing services commensurate with their advancing knowledge of the potential usefulness of such testing to laboratory medicine and not vice versa.

In short, the coalition believes that the clinical labs which offer new tests, IVDMIAs or otherwise, are typically serving informed physicians who are sufficient knowledgeable about a given test technology and its potential clinical utility to seek its availability.

The coalition believes that subjecting clinical labs to added burden of complying with FDA regulatory requirements will result in physicians and patients experiencing either unnecessary delay or doing without access to important tests in rapidly advancing fields, such as genetics, oncology, and infectious disease.

As written, the draft guidance introduces additional unnecessary regulatory burdens on an already highly regulated clinical laboratories. Clinical labs are currently regulated by CMS under CLIA. This has been mentioned before. I won't go through all of the requirements that laboratories are subject to. You're well familiar with all of them.

However, under the draft guidance, laboratory tests and services that are already subject to CLIA's quality standards would now also be subject to FDA's QSR requirements which are tailored for traditional medical device manufacturing operations.

For laboratories to develop systems that comply with FDA's QSR requirements while continuing to comply with CLIA could take years, would be prohibitively costly, and will likely drive up health care costs.

In short, what would result for both existing and prospective clinical labs is, at best an untenable business model.

If the draft guidance is implemented immediately, existing products regulated as IVDMIAs will become illegal unless they obtain FDA clearance or approval. Labs will not be able to complete the review process for a long period of time.

Offering tests that are deemed illegal raises serious risks to labor licensure and accreditation and exposes labs to unnecessary liability risks.

Of even greater concern, labs may also be prevented from being reimbursed by federal, state, and private insurance coverage. The lack of coverage, along with other increased regulatory obligations will hinder the ability of labs to maintain current operations, as well as attract adequate financial capital to support research and development of new tests and technologies.

The coalition is also concerned by the ambiguities that exist under the current draft guidance. As has been mentioned previously, the definition of the IVDMIA itself is ambiguous and introduces new terms that are not included in FDA's existing regulations. We heard from Dr. Harper. You're asking yourselves for clarification on what the definition should be. Interesting.

This ambiguity creates uncertainty as to which tests are IVDMIAs subject to regulation by FDA. As written, the definition could be interpreted to include a broad array of testing, including standard medical treatment algorithms.

The coalition has identified scores of algorithms that are not in use and many more are being published each month. FDA could be faced with regulating hundreds of IVDMIAs. This will require a tremendous amount of agency resources, diverting personnel from reviewing new marketing applications for manufacturers of assays.

The draft guidance sets forth a major change in laboratory regulation and establishes a new regulatory regime. Yet remarkably the document is only five pages long. In those five pages, there is very little detail about the proposed new regulatory path or any mention of FDA enforcement policy.

In short, labs need far more clarity than has been provided by the draft guidance.

We believe FDA should adopt alternative paths. The coalition has developed several possible alternatives to the IVDMIA guidance. For purpose of this meeting, we'll focus on four important alternatives.

First, FDA should not pursue regulation of IVDMIAs by way of the draft guidance route. Rather, the agency should propose new regulations that are detailed, clear, predictable and establish the least burdensome regulatory controls in light of the actual risks and benefits of IVDMIA testing.

FDA's exercise of authority over laboratory developed tests represents a substantial change in the regulation of labs and needs to be implemented through new regulations, not a guidance document. This will insure the maximum public participation and scrutiny.

Given the precedent that is being set, rulemaking is imperative.

Second, FDA should base any level of regulation of IVDMIAs on risk. The level of risk is higher for IVDMIAs that are predictive and that result in a binary therapy recommendation to treat or not to treat based solely on the IVDMIA outcome. Other IVDMIAs, whether predictive or prognostic, advisory or adjunctive, that do not give binary therapy recommendations are lower risk. These types of IVDMIAs should not be held to the same regulatory standards.

A risk based approach would lead to a more appropriate allocation of regulatory effort by both labs and FDA.

Third, there needs to be a transition period to assure labs with IVDMIAs to adjust from the current CLIA regulatory path to a CLIA plus FDA regulatory path. The lack of a transition period could severely disrupt the availability of tests. If FDA imposed the device requirements on labs without any transition period, it could halt the use of development of tests, as well as improvements to existing tests.

If based on risk an IVDMIA is subject to FDA regulation, a lab should have between two and four years to submit an application to FDA. During the transition period, FDA should not require labs labeled with IVDMIAs as investigational and IDE should not be required.

Note that in 1998 FDA released its draft compliance policy guidance titled "Commercialization of IBDs labeled for research use only and investigational use only," which permitted a transition period for subject IBD companies to come into compliance with the agency's premarket submission requirements. A similar transition period should also be applicable to IVDMIAs.

Fourth, FDA could institute a disclosure program. This registry could provide reliable information about the strengths and particular limitations of IVDMIAs and allow FDA to understand the scope of these tests. The information available through the registry could help FDA create a more specific definition of IVDMIA and could help show how these tests should be regulated. This would facilitate FDA's regulatory approach.

In conclusion, we believe that the draft guidance, if implemented in its current form, important medical tests may become unavailable, be frozen at their current technological state, become more expensive, or potentially lose insurance coverage. None of these outcomes benefit patients.

Labs have been a significant source of innovation for decades. Laboratory developed tests, including tests and services that would be considered IVDMIAs under the guidance, are an essential part of public health and are the future of personalized medicine.

To preserve the future, FDA should go through formal rulemaking procedures and carefully consider the alternatives we have presented.

Again, on behalf of the Coalition for 21st Century Medicine, I thank you.

DR. KESSLER: Thank you.

Before we hear from our next speaker, a brief logistics comment. I want to thank all of the speakers for not only their thoughtful and articulate comments this morning, but for staying on time. After the next two speakers, we'll have approximately a half an hour to open up the mics to the floor. So I'm giving you a chance to think about the comments and questions you have.

We will concentrate on your comments on the previous speakers or other comments we want to make. We're not going to be handling questions from the front of the room here, but the mics will be open for quite a little while. If we get a chance, we may even advance a couple of the speakers from after the break into the morning session so that we can advance the whole day.

Next we're going to hear from Dr. William Clark from the American Association of Clinical Chemistry.

Dr. Clark.

DR. CLARK: Good morning. My name is Bill Clark, and I'm a clinical laboratory director at Johns Hopkins Hospital in Baltimore.

Today I'm speaking on behalf of the American Association for Clinical Chemistry.

AACC is the principal association of professional laboratory scientists whose membership includes M.D.s, Ph.D.s, and medical technologists. Our members develop and use chemical concepts, procedures, techniques, and instrumentation in health related investigations and work in hospitals, independent laboratories, and the diagnostics industry worldwide.

AACC would like to thank the agency for holding this public forum. We believe this meeting gives the agency an opportunity to clear up much of the confusion surrounding the IVDMIA draft guidance while also giving the public and other stakeholders an opportunity to express their views on this important document.

Although AACC is still finalizing its comments on the draft guidance, we generally supported the agency's goal, which is to insure that IVDMIAs provide accurate, verifiable test results.

Further, we agree with the FDA's decision to leave primary oversight of traditional laboratory methods, develop tests with CMS utilizing the CLIA ADA standards.

AACC is concerned, however, that the agency may be moving forward too quickly in this area without fully examining the unintended consequences that could arise from this policy. AACC suggests that the FDA consider and address the following questions before fully implementing its IVDMIA policies, such as:

What impact will this policy have on incremental advances to existing technologies as well as the development of first of a kind assays?

Also, will tests no longer be offered as a result of this policy? If so, which of these tests?

And will the loss of these tests hinder the delivery of patient care?

Will the agency allow laboratories to continue utilizing existing unapproved algorithms until it or similarly approved algorithms are approved by the FDA?

How will the FDA inspect laboratories under the promised QSR guidance?

Also, we are requesting that the agency clarify whether IVDMIAs can serve as a predicate device, particularly if the IVDMIA is not available for clinical comparison or precision comparison studies. Typically devices approved or cleared under the PMA or 510(k) processes serve as predicate for future submissions to the FDA.

In this instance, however, a manufacturer laboratory would not have access to the reagents since they are not in commercial distribution, although I think this was partially addressed through the comments in the introduction.

Finally, AACC recommends that the agency include examples of tests which employ algorithms but would not be subject to this guidance. For example, we expect that a test employing simple calculations to result, such as creatinine clearance addressed in the introduction, would not be considered an IVDMIA, nor would an assay utilizing publicly available algorithms or clinical guidelines, such as prenatal screening for open neural tube defects.

AACC believes these and other examples would more clearly demarcate the limits of the document. AACC welcomes the opportunity to comment here today and will provide more detailed comments to the agency by the March 5th deadline.

Thank you.

DR. KESSLER: Thank you, Dr. Clark.

We're next to hear from Dr. Carolyn Compton of the National Cancer Institute.

DR. COMPTON: Thank you.

I appreciate the chance to speak to you today because I'm bringing a new focus to the table, one that is not directed toward the test itself but toward the thing being tested.

I'm here from the National Cancer Institute, which as you know represents a vast scientific enterprise that's dedicated to the development, validation, and application of new methods of diagnosing, treating, and preventing cancer for the American public and cancer patients, and it has been the perspective of this agency that the new methods, the new technological platforms that are being developed to focus on analysis of human specimens that raise the bar for specificity, sensitivity, and complexity, especially multiplexing tests, raise the bar for the quality of the thing being tested, the human specimen.

And, in fact, the institute has focused on this problem in such a critical way that a year and a half ago it created the office which I now direct, the Office of Biorepositories and Biospecimen Research, which is focused on optimizing and standardizing the quality of human specimens for the research that will drive personalized cancer medicine, and certainly IVDMIAs fall into the category of personalized medicine very centrally and to remove the current and future barriers to cancer research represented by the limitation in quality of human specimens; that human specimens are not regulated in any way right now, and in fact, very little guidance exists as to how to standardize or optimize the quality of human specimens as they are used in analytic testing across the medical enterprise.

Our office, the OBBR, has in the last year and a half taken direct steps toward providing guidance for our research enterprise, and hopefully this will translate into clinical medicine very shortly, by providing the first of its kind, first generation guidelines for NCI supported biorepositories that represent the state of the science, best practices for the handling of human specimens for molecular analysis.

And we have many other initiatives in place that are focused toward developing second generation guidelines that will be largely, if not entirely data driven because the state of the art at it exists today is mostly empirical and based on expertise and experience, but not objective scientific data as to the effects of handling, processing and storing variables of human specimens on molecular profiles, and therefore, guidance on how to optimize the handling of these specimens for consistency in testing results does not exist.

Next slide.

Our view of biospecimens is a dynamic one. We view the biospecimen as a viable entity that, in fact, has two phases as it enters clinical analysis. One is the preacquisition phase, before it becomes a specimen and comes out of or off of the patient. It is subjected to iatrogenic variables that can dramatically change its biomolecular profiles, and after it is removed and sent to the pathologist or into the testing process, additional variables can also change these specimens biomolecular profiles because it is, in fact, still viable until it is suspended in biologic animation by fixation or freezing.

Next slide.

These are only a few of the pre and post acquisition variables that we know can dramatically change singular molecular profiles and certainly complexes or fingerprints of molecular profiles in specimens of a different type, and each one of these variables can have differing effects on different types of specimens and even from the same specimen type, such as a cancer specimen, from different sites in the body.

So we expect this to be a very complex issue and one in which we have undertaken a serious scientific effort to sort out.

Next slide.

One of the most critical issues has just come forward recently when it was pointed out that a diagnostic test, which in fact I am a pathologist so I can speak for this very strong. This is the first diagnostic test in pathology that determines whether or not a patient will be treated with a specific therapy irrespective of any clinical input.

HER2 new testing, as you know, is performed on breast cancer tissue, and it is performed by an immunohistochemical test that if it is shown to be positive and the cut points for that were determined, of course, by validation tests, that the patient will receive herceptin therapy, and positive results trigger a therapeutic burden for the medical system of $60,000 per patient per year, and false positive results can carry a risk of cardiotoxicity.

So this is a very critical test which it was learned several years after this therapy had been on the market and had been actively being used in the clinic for patients, was discovered that there was, in fact, no strictly standardized testing method for the biospecimen.

ASPA went to the College of American Pathologists, and just recently a standardized guidance was published. However, even in the process of writing this guidance it became clear to the College of American Pathologists that there were unanswered questions about handling of the specimen, and this brings up a general issue about the way the FDA approaches its diagnostic testing guidances and its regulations.

There's very specific guidance typically about how to do the test. Yet even if your test is validated, standardized, and perfect in its execution, you can build in the variation up front in the biospecimen if the handling processing of the specimen itself is not standardized.

So standardization of the analyte is at least as important as the standardization of the analysis, again, as pointed out by HER2 testing, and it was documented by Asbill and Capp that as much as 20 percent of the diagnostic tests performed on breast biopsies were, in fact, inaccurate based on handling variables, such as type of fixation, length of fixation, temperatures in imbedding machines, and other types of variables.

Next slide.

So with the emergence on the horizon of other diagnostic multiplex tests, this problem becomes even more significant, and on the horizon we certainly have, as was mentioned by previous speakers, EGFR testing, Oncotype Dx testing, which is now in clinical trials, Lymphochip tests, and in fact, some of these multiplex tests, such as Oncotype Dx, are performed on specimens that are handled for clinical purposes and borrowed from the clinical enterprise with no specific guidance up front as to how to handle the specimen specifically to acquire reproducible results from the tests.

So, in fact, on matter how clever, how standardized, how perfected your test, or even how highly diagnostic or prognostic, under the correct conditions these tests are still subject to the rules of all good science, which is garbage in, garbage out.

Next slide.

So I don't come here to suggest that biospecimens are something that the FDA can or should regulate. I'm only bringing this issue to your attention as a problem that affects multiple stakeholders, may, in fact, affect multiple government agencies, but for which there is no answer at the moment as to where and how to develop standards for specimen handling, how to draw the development and implementation of biospecimen quality standards, or how to provide the reimbursement that will be necessary to make certain that the pathologists who are the people that handle these specimens for the most part or if the handling of the specimen for a given test happens up stream are reimbursed for the extra time and expert input that they will have to provide in order to standardize this critical variable for testing.

Thank you.

DR. KESSLER: Thank you, Dr. Compton. We're glad to have our NCI colleagues here and have your program presented. We appreciate it.

We're doing great on time. I want to thank all of the speakers of the morning so far, and leave the microphones open. We'll try to recognize you in some order if you stand up, and please feel free to comment, particularly about the morning's presentations.

And, please, for the record, state your name and your affiliation. And you can use the mics in the center if you prefer.

MS. CHARACHE: My name is Patricia Charache, and I'm representing the American Society for Microbiology.

And I'd like to first agree with my colleagues, including my co-member of Johns Hopkins University from AACC, that there's a need, and all other speakers, there's a need to clarify the definitions so that we know more clearly exactly what's meant by the different categories.

We are concerned about the needs to address patient safety with these tests, and I would point out that although CLIA is responsible for laboratory processes, thus far CLIA and its deemed agents that review laboratories through CMS have emphasized analytical validation of tests rather than clinical validation as they review development of new tests.

The FDA, and I'm familiar from advisory panels particularly in microbiology, does address the clinical validation area.

The point that Dr. Tsakeris pointed out that there is a major increase by clinicians for the use of these molecular tests is certainly supported and our own experience at Johns Hopkins, and this pressure comes primarily from two sources. One is the literature, but the other is a new tendency that we've seen very heavily in our home institution, which is direct to clinician marketing by laboratories that offer this type of complex test.

This direct to clinician marketing in our institution has covered diverse diseases, such as the ability to diagnose inflammatory bowel disease, some endocrinopathies, to cancer management and to the diagnosis of genetic disorders.

And all of this has bypassed the expertise of anyone who can objectively look at the quality of the information being provided. We've had to interrupt when we've learned about these processes direct sending of specimens to at least four such laboratories that had not done clinical validation.

So that we do feel that there's a need to look closely at this type of test, which has very major impact upon patient management, particularly if the quality of the test or, as the NCI just pointed out, the way in which the test was validated, have not been addressed.

So we think that the underpinnings of the desire to improve quality of these complex tests and our knowledge that the clinicians despite their skill and their excellent knowledge of clinical diseases are not equipped to know whether the test is one in which they should be managing their patients presents a need to look further into how to achieve those goals.

Thank you.

DR. KESSLER: Thank you very much.

Are there other comments from the floor, questions, clarifications, funny jokes?

(Laughter.)

DR. KESSLER: Well, we're not yet ready for a break. So I'm hoping that a couple of the speakers for the next session of the morning are prepared and we'll begin with a few of those presentations. We'll break a little bit early and that will advance the schedule today.

So I'd like to call up Carolyn Popper if she's here from Exagen Diagnostics.

Well, it's not true that if you snooze you lose. We'll come back to Carolyn. Perhaps Alan Mertz is here from the American Clinical Laboratory Association -- oh, wait, wait. Carolyn, is that you? No, no, no. Come on. Thank you.

So we are going to begin with Dr. Carolyn Popper from Exagen Diagnostics, correct?

DR. POPPER: Correct.

DR. KESSLER: Okay.

DR. POPPER: And I'm not going to tell a joke.

DR. KESSLER: You just did.

DR. POPPER: Good morning. I'm Carolyn Popper, and I'm a physician and a senior regulatory advisor to Exagen Diagnostics.

I very much appreciate the opportunity on behalf of Exagen to comment on the draft guidance. In sum, we at Exagen appreciate the FDA's efforts to protect public health by a reasonable regulatory oversight, and we particularly are glad to have this opportunity to offer our thoughts and perspective on many of the issues raised both in the document and in the comments here today.

Exagen was founded in 2002 in Albuquerque, New Mexico, and it discovers, designs, validates, manufactures, and commercializes small sets of genomic markers to provide prognostic and diagnostic kits for commercial laboratory testing and for use in clinical trials by drug developers.

Exagen is currently developing a number of products that fall under the food drug and cosmetic act and FDA regulations. During the past year, we have been working closely with the Office of in Vitro Diagnostics as we are pursuing regulatory review for the first of several products in the coming months. We understand that new technologies giving rise to new, more complex marker sets challenges conventional diagnostic regulatory paradigms and believe that reasonable oversight to protect public health is entirely appropriate.

Like the FDA, we feel that an IVDMIA that utilizes data from an IVD assay which is then manipulated by an algorithm to produce a final result in tended to help diagnose, mitigate, treat, or prevent disease is, indeed, a medical device and should, therefore, be regulated by the FDA.

We hope though that as the FDA seeks a regulatory framework for IVDMIAs that the agency takes what it describes as the least burdensome approach, thereby facilitating regulatory oversight while not impeding commercialization of new technologies.

In that regard we congratulate Agendia at having achieved FDA clearance.

It is also important to note, in our opinion, as have others here this morning, that not all IVDMIAs are equal. The agency should take into consideration the intended use of new IVDMIA products and recognize that they vary quite considerably. As such, a whole variety of new regulatory approaches may be warranted based upon the risk to the patient and the benefit of the test.

We agree with the statement in the draft guidance that most IVDMIAs will be either Class 2 or Class 3. As for example, any device intended as an indicator of the patient's risk of cancer recurrence would be a Class 2. The IVDMIA which provides another data point to the physician without specifically dictating treatment is not relied upon by the physician as the sole decision point in the diagnosis or selection of therapeutic options.

Exagen does request clarification of an item on page 3 of the guidance. On page 3 in the guidance document under the section about definition and regulation of status of IVDMIAs, there's a sentence which reads, "Even if a laboratory or other IVDMIA manufacturer. . . . " This sentence we find to be ambiguous, and we recommend that the FDA clarifies its position.

I believe other speakers before me have raised this position, too. It is clear that the IVDMIA applies to laboratories. However, Exagen does not believe that manufacturers seeking premarket review under the act for interstate commerce fall under this guidance.

Clearly, this is a very exciting time for science and medicine and for patients, with a promise of many new discoveries and IVDMIA products on the horizon from many companies and innovators. Given that laboratories and IVDMIA manufacturers are in the early stages of discovery and development and validation of these IVDMIA products, it is important that the FDA guidance and regulations support the degree of innovation that we have seen in the industry in recent years.

We look forward to continued discussion here this morning and in the weeks ahead, and look forward further to the opportunity to offer our thoughts as the FDA refines its position in the coming months.

Thank you.

DR. KESSLER: Thank you very much.

We'll turn now to Alan Mertz from the American Clinical Laboratory Association.

MR. MERTZ: Good morning. I'm Alan Mertz, president of the American Clinical Laboratory Association, and we're an association that represents local, regional, national, hospital and independent clinical laboratories, and we thank the FDA for this public meeting this morning.

This is important because many of ACLA members perform laboratory developed tests that could be very much affected by the FDA's draft guidance on IVDMIAs.

Next slide.

ACLA strongly supports the goal of the draft guidance, namely, to dispel the existing confusion and lack of clarity regarding FDA's regulatory approach towards certain laboratory developed tests.

Although the concerns identified by FDA in its draft guidance are clear, the guidance falls short of achieving the goal. We would like to work with FDA toward resolving these concerns in a manner that promotes the promise of personalized medicine and encourages the continued investment in these rapidly advancing areas of laboratory medicine.

Next slide, please.

We focus on three key recommendations this morning. First, ACLA recommends that FDA issue a proposed rule to address this important subject matter through the formal notice and comment rulemaking process rather than through subregulatory guidance.

Second, we recommend that FDA consider proposals to narrow and clarify its definition of IVDMIAs to avoid confusion and unintended consequences.

Third, we recommend that FDA work with CMS through HHS to address its concerns through enforcement and better enforcement of the regulations promulgated under the Clinical Laboratory Improvement Amendments, CLIA.

Next slide.

The procedural recommendation in favor of notice and comment rulemaking is important. Since the draft guidance announces the laboratory developed tests deemed IVDMIA are Class 2 or Class 3 devices requiring FDA premarket clearance or approval, it represents a significant change from the agency's historical practice regarding laboratory developed tests and has a present binding effect.

Rather than merely stating the agency's current thinking on the topic without creating or conferring any rights or binding FDA or the public, the draft guidance operates as a substantive rule. As such, its subject matter should be vetted through the formal, on-the-record notice and comment rulemaking procedures of the APA.

Similarly, while FDA declined to classify laboratory developed tests as Class 2 or Class 3 medical devices in the ASR rule, on the policy grounds, laboratory developed tests have contributed to enhanced standards of medical care in many circumstances, and the significant regulatory changes in this area could have negative effects on the public health.

The draft guidance seeks to regulate certain laboratory developed tests on the ground that the public health requires it. Since the FDA's advisory opinion in the ASR rule was published in the Federal Register as part of a formal notice and comment rulemaking, the modification of that policy which the draft guidance represents must be treated in the same manner procedurally.

The best substantive result for all stakeholders is most likely to be achieved only when all stakeholders are afforded the full procedural protections of notice and comment rulemaking.

Next slide, please.

While FDA has noted that IVDMIAs are intended to describe a narrow niche of devices, the draft guidance defines IVDMIAs so broadly and so vaguely that the scope of the draft guidance's application could easily be interpreted to extend far beyond its intended reach.

Specifically, the draft guidance defines IVDMIAs as, quote, test systems that employ data derived in part from one or more in vitro assays and an algorithm that usually, but not necessarily, runs on software to generate a result that diagnoses a disease or condition or is used in the cure, mitigation, treatment, or provision of disease, end quote.

It further describes three interlocking criteria of IVDMIAs, use of clinical data, an algorithm, and a result that cannot be interpreted by a health care provider without the help of the test developer.

As written, the draft guidance could be interpreted to apply to many well established tests that are already the part of the standard of care. Upon citing examples of such tests to FDA, ACLA was informed by FDA that it was not their intent to include such well established tests within the scope of the draft guidance, and FDA requested our assistance in clarifying and narrowing the definition to conform to its intended application.

Next slide, please.

While the following recommendations for clarifying and narrowing the definition of IVDMIA should not be construed as an endorsement by ACLA of FDA regulation of any lab developed test nor an acknowledgement that FDA has the authority to regulate these tests, and while ACLA and its members reserve the right to offer modifications at a future date, we offer the following recommendations in a good faith effort to make progress toward achieving our shared goals.

FDA should consider the following link factors in formulating a definition.

One, a new single source test system.

Two, use as patient and/or clinical data derived from one or more in vitro diagnostic assays together with a proprietary non-published algorithm.

Three, generate a patient specific binary result that is intended definitively to diagnose a condition or to direct behavior for the cure, mitigation, treatment or prevention of disease.

And, four, present significant safety and effectiveness risk not present in test systems which have become part of the standard of care.

Next slide.

Moreover, certain factors, if present, would indicate the FDA regulation is not warranted. Specifically, test systems which meet one or more of the following criteria should not be deemed IVDMIAs: low risk consequences of invalid or inaccurate test results; independent verification by one or more laboratories; support of clinical relevance in peer reviewed literature, transparent algorithms, interpretation support for clinicians, support in clinical guidelines, established use, CPT code assignment, and payer recognition.

We'll provide further elaboration of these points in our formal written comments on the draft guidance.

next slide.

Nevertheless, ACLA firmly believes that FDA should also consider working with CMS and through HHS to enhance this CLIA regulations and provide means for the systematic and rigorous enforcement. This approach has the potential to address the concerns that prompted FDA ot issue the draft uigdance in the contest of the regulatory framework specifically designed for clinical laboratories and the services they provide, CLIA, and could avoid the difficulties associated with regulating services under a regulatory framework designed for commercially manufactured and distributed products.

Next slide.

CLIA regulations explicitly require the laboratory director to insure that selected test methodologies are capable of providing the quality of results required for effective patient care, which implicitly requires the selection of medically relevant tests that have an effective clinical purpose.

Likewise, CLIA regulations require the laboratory to have a clinical consultant who is responsible for providing information about the appropriateness of a test in a clinical context. Systematic and rigorous enforcement of these requirements by CMS could approximate the independent validation of clinical relevance that FDA seeks to achieve for IVDMIAs through the IVDMIA draft guidance.

CLIA regulations also require the laboratory to validate the performance characteristics of laboratory developed tests, including any algorithm or formula that the laboratory relies upon to issue a result, and further require the laboratory director to insure that an ordering clinician can properly interpret results by including pertinent interpretive information in the reports and making consultation available.

Thus, the foundations for algorithm transparency and interpretive guidance for clinicians already exist within the CLIA regulations. Amendments to the CLIA interpretive guidelines or to the CLIA regulations themselves, if deemed necessary, coupled with systematic and rigorous enforcement by CMS, would be consistent with the FDA's emphasis on smart regulation and following the least burdensome approach to address the issues which prompted FDA to issue the draft guidance.

Thus, we encourage FDA to consider working with CMS in this matter.

Last slide.

In conclusion, we look forward to working with the FDA in an ongoing dialogue to achieve our shared goals of providing continued access to safe, effective, and innovative clinical laboratory services for patient care.

Thank you.

DR. KESSLER: Thank you.

We'll continue with Michael Goldberg from the Mohr Davidow Ventures Group.

MR. GOLDBERG: Good morning. Thank you very much.

I'm here first as a patient, second as a parent, and third as a child. My parents are fortunately still alive.

I spend a lot of time professionally as a venture capitalist. I'll get to that in a moment, but principally I'm a patient advocate, and I've been on the board of the National Childhood Cancer Foundation as a trustee for the last 12 years. I was also a founder of that organization. I was instrumental in the passage of Prop 71, the Stem Cell Act in California two years ago where seven million Californians stood up and voted on behalf of patient advocacy to liberate funds for embryonic stem cell research, which our federal government at the moment is severely limiting.

I have since been appointed to the oversight committee of the California Institute of Regenerative medicine, where I spend many days sitting as you do listening to the public, and I have extraordinary respect and regard for the time you give to your service.

Professionally, I've been involved in the biotechnology industry for the last 25 years. I've watched recombinant DNA go from being a gleam in scientists' and clinicians' eyes to treating hundreds of millions of patients daily around the globe. It has taken billions of dollars of capital to get there. I think we're all better served as a result of it.

The FDA has been a magnificent partner with industry in causing that to occur.

My concern today has to do with not your intent, but simply the tactical implementation of what you're proposing to do, and with that if you'll permit me to make two comments before I begin my remarks.

Do any of you know how to get a one armed venture capitalist out of a tree? You know that joke. You wave at him.

Secondly, for the first time in California, which is where I arrived from last evening, I saw a personalized license plate. Actually it said IVDMIA. You should be pleased to know it was on a Prius.

(Laughter.)

MR. GOLDBERG: Next slide, please.

My background isn't relevant.

DR. KESSLER: You can have more than ten minutes.

(Laughter.)

MR. GOLDBERG: So at the risk of stating the obvious, the diagnostic and laboratory industries really are in the cusp of dramatically innovating in the field of medicine and in health care. We're excited in the venture capital community and in the entrepreneurial community, where I spent most of my career before I became a venture capitalist, because new, innovative diagnostics, we believe, can expand the scope of personalized medicine, improve outcomes, reduce costs in many cases, and hopefully reduce adverse events.

Next slide, please.

Many of the companies and laboratories, as you know, developing these innovative diagnostics are small and entrepreneurial. They aren't the large corporations that frequently pay homage to Rockville.

And in order ot make the benefits of their products a reality, these small companies and laboratories really need access to capital.

Funding for diagnostics for research has historically been much lower than funding for drug research or other devices. Furthermore, funding for diagnostics continues to lag behind that of drug and other devices.

My concern personally is if implemented in its current form, the draft guidance may leave even less funding for diagnostics. You have to understand in the context of a broad technology based Silicon Valley venture capital firm, my projects compete for capital with projects to invest in Clean Tech, projects to invest in the next generation of high technology infrastructure, and regulatory uncertainty creates a disincentive around our partnership table as we make these decisions.

The ambiguity and regulatory uncertainty can be, I think, captured from our standpoint, and not having clarity as what type of lab services will be subject to regulation by you, if laboratory service is subject to regulation, it's not clear what the level of regulation will be.

I know that's your goal to clarify all of this for us and we appreciate that.

Next slide, please.

It's not clear how labs will deal with the competing requirements of both the FDA and CLIA requirements, how products or services determined as IVDMIAs will actually be labeled, if labeled, and what, of course, the costs of compliance are as young companies are trying to forecast what their capital requirements are to actually bring products to market.

So to attract investors, young companies and laboratories need to know whether their product or service is going to be regulated by the FDA, what the nature of that regulation is, and what the cost of complying with those regulations are.

Under the draft guidance, we simply don't know this.

From an investor perspective, we need to understand and evaluate the risk and benefits of competing investments in different fields and an ambiguous regulatory scheme and regulatory uncertainty makes this evaluation very, very difficult.

The ambiguities and uncertainty under the draft guidance we believe have the risk of deterring investment in innovative diagnostics. If the draft guidance is implemented, investors looking for opportunity in technology or health care will look to alternative opportunities, I fear personally, and without these investments in innovative diagnostics, we won't be able to experience the benefits of personalized medicine, better health outcomes, lower health care costs, and reduced adverse events as we're all seeking to achieve.

Thank you very much, and I'm a big fan of the critical path, and I hope wherever you end up on this issue it enhances that regulatory scheme.

Thank you.

DR. KESSLER: Thank you. We do as well.

I want to thank the morning speakers, and before we take a break, here's what we're going to do. I'm going to take a 20 minute break now. The line down the hall at Starbucks will get quite long. I'm aware of that. So we may take a couple extra minutes, but we'll try to convene promptly at ten after ten, and because we are fairly far ahead, some of the speakers who would normally be speaking right after lunch we'll take in the morning.

So I'd like the panel, who should be here for the afternoon, to check in with Susan to make sure you're here and so that we can get moving. So I'd like to make sure that David Levison, Stuart Hogarth, Jonathan Cohen, Sherry Black, Robert Erwin-Marty, Elda Railey, Carol Berry, and Elissa Passiment, please check in with Susan.

Let's take a 20-some odd minute break. We'll see you at ten after ten.

(Whereupon, the foregoing matter went off the record at 9:49 a.m. and went back on the record at 10:12 a.m.)

DR. KESSLER: Thank you all.

We're going to begin. Dr. Arthur Beaudet from Baylor College of Medicine.

DR. BEAUDET: Thank you.

I appreciate the opportunity to be here today. I'm going to focus more specifically on one particular test.

I think you can go to the next slide.

One of the more comment tests done in genetics is chromosome analysis, and this is sort of the traditional appearance of the result that's been available for decades now, and most of the chromosomes there are two copies, and many of the diagnoses you want to make involve the gain or loss of a copy so that a region that should have two copies now has only one or has three.

Next.

The chromosome analysis has gotten extended by a method called fluorescence in situ hybridization, or FISH, so that you can detect particular spots in the DNA here, a normal chromosome with a green and a red spot, and here a deleted chromosome with a green spot but not red spot present.

And the next slide shows another example of this kind of FISH at a different stage in the cell cycle where there's a normal chromosome with a red and a green dot, and a chromosome that has one green dot and two red dots, the extra red dot indicating additional copies.

So we can have a gain of copy or loss of copy.

The method that is replacing this is called array comparative genomic hybridization, or array CGH or sometimes called chromosomal microarray analysis or CMA, and they're equivalent in the meaning.

Next.

In this test, DNA from a test sample like a patient is labeled with a fluorescent dye and DNA from a control is labeled with a second fluorescent dye, and this red and green combination will, if the mixes are equal representations of the genome, give a balanced yellow color.

Go to the next slide.

If you then hybridize these onto bits of DNA on a glass, and these could be large pieces of DNA, kilo bases size like BACs or it could be small bits of DNA like allogonucleotides of 50 or 60 base pairs.

If there's a region in the test genome that has a duplication here, it would give a greener color or a deletion would give a redder color.

Next.

This is a demonstration of what a result looks like in our laboratory. The red data are from one hybridization and then the dyes have been reversed to give a second hybridization shown in blue, and Chromosomes 1 through 22 are here, and you see that the data fall on a single line, but here we've hybridized a normal male to a normal female, and you see the difference in the X and the Y chromosome down here, and you can very easily see gains and losses in the genome.

Next slide.

This is one of the most common genetic diagnoses, Trisomy 21, where the old test shows three copies of Chromosome 21, and here on the new test you see that all of the clones on Chromosome 21 are showing a gain being shifted to the right.

This is just an example of now many diagnoses which the old tests have not made, but the new tests can make. So this is a child with various abnormalities in the neonatal period with cleft lip and palate, congenital heart disease, and a normal chromosome analysis.

And the next slide shows the test detects that many of the clones on the short one of Chromosome 21 are shifted to the left, meaning a deletion.

This is usually missed. This is what the chromosomes can look like in their most stretched out form, and maybe in retrospect you can suspect a difference here, but in general these kinds of chromosomes are usually interpreted as normal.

And this test can be confirmed with the FISH method. Again, so we always have the old and the new tests side by side to work with.

Now, there's a lot of potential here for platform equivalency where many different platforms can detect gains or losses in the genome, and we currently use a back chromosome array in the clinic, but we're in the process of switching to an oligonucleotide array and dead arrays are also possible.

So the results can be specified for particular parts of the DNA, the genomic segments with precise locations in the genome now that the genome is sequenced and available in various browsers.

Next slide.

This is an attempt to show the same patient I showed you a minute ago with the back array, but now with a oligonucleotide array from adjulent (phonetic). You see here each black dot is an oligonucleotide, and you can see that there are lots of black dots here at the tip that are normal. Then you have a whole bunch that are involved in a deletion, and if you do a dye reversal and smooth the curve, you get this very precise detection of this deletion, and this is a lesion which by chromosome analysis is not detectable in any kind of consistent way.

So array CGH detects many abnormalities missed by chromosome analysis. They're missed for two reasons actually. Some are just absolutely not detectable by the karyotype method, and another problem is that there's great variability in the quality of chromosome analysis that's performed out there. We see many abnormalities that should have been detected by karyotype, but they were not. They were missed by the group that did the karyotype.

So this test allows you to do hundreds or even thousands of FISH test equivalence on a single slide at a low cost. It's also particularly good for detecting extra copies, which most of the FISH methods are more difficult to use to detect extra copies.

So our approach is to suggest that what we are proposing is a test that detects copy number changes in the genome, and we think there's a lot of analogy to say that an MRI of the brain or a mammogram, many different machines can detect and give an image that's useful, even, say, a CAT scan versus an MRI.

There's multiple components to this process. There's a raw image of the data. Then there's an algorithm to process the data. In fact, in this case there's not that really that much of an algorithm. It's more a statistical analysis to determine is there a gain or a loss at a particular site.

Then there's some need for interpretation that's typically provided by some Board certified laboratorian that says gains or losses in this region usually are associated with a particular syndrome or NOD or benign or whatever, and I think this, I think, is parallel to what the radiologist does.

The radiologist says there's something on this brain MRI that means one or another possible clinical implication, but then the clinician has to integrate this result further. The neurosurgeon or neurologist needs to take the radiologist's interpretation and integrate that back into the family, and that's what's going on in our situation.

Many times you'll have a parent and a child with the same gain or loss in the genome, but maybe the child has a severe phenotype and the parent may have a much milder phenotype. So there's not a perfect correlation of the genotype with the clinical findings in the patient.

So we believe that array CGH is the biggest advance in genetic diagnosis in decades. We believe that it is rapidly replacing the standard chromosome analysis or karyotype.

Delay in this transition is actually depriving many families of valuable diagnostic and counseling information. People are having the old test and coming up with no abnormal result and not knowing the cause of their child's problem, would know the cause of their child's problem if they had the newer test.

This ultimately is a test that will be less costly than a karyotype. You don't need to do tissue culture. You don't need technologists doing lots of work, and you don't need a qualified cytogeneticist to scrutinize the chromosomes and try to interpret them.

And so ultimately we are going to have the good fortune of having a test that is cheaper than the old test and better than the old test.

Array CGH is applicable to prenatal diagnosis, but 99 percent of the work is now being done on pediatric patients with blood samples.

thank you.

DR. KESSLER: Thank you very much.

Our next speaker is Michael Ostrolenk from the Association of American Physicians and Surgeons.

MR. OSTROLENK: Good morning, and thank you.

The Association of American Physicians and Surgeons is a national organization of physicians in all specialties. Founded in 1943 to preserve and promote the practice of private medicine, the sanctity of the patient-physician relationship and ethical medical practices according to the oath of Hippocrates, physicians are obliged to prescribe for the good of their patients according to the best of their ability and judgment.

We are very concerned about the destructive impact of the proposed guidance for several reasons.

One, professional discretion is essential if the medical profession is to serve individual client needs. The guidance constitutes (unintelligible) of regulations of the practice of medicine.

Physicians undergo a lengthy period of rigorous education, including scientific reasoning and standards, to prepare them to function as independent professionals. Independent professionals' judgment is essential, as has long been recognized in law, if physicians are to serve the needs of the patients competently.

There is tremendous individual variations in clinical problems as they present and in the individual responses of patients to various diseases and other insults. Increasingly, we are recognizing a wide range of biochemical individuality, which results in great variations in response of patients due to therapeutic regimens, particularly drugs based on the genetic endowment.

This guidance would not only deprive physicians of their clinical tools that they need to meet their patients' needs, but new regulations encroach upon the practice of medicine itself. The FDA is supposed to be regulating products to assure their safety, not services.

But with this guidance, it appears they're trying to expand its scope even as far as to declare which methods of mathematical analysis may or may not be used by professionals.

Number two, innovation is needed to meet new threats. Human health is endangered by an increasing array of new threats, as microorganisms adapt to antibiotics and as mutant organisms, including influenza viruses and vector borne diseases, such as the West Nile virus, gain the ability to proliferate rapidly throughout the world, as a consequence of modern transportation.

Genetic engineering also raises the sinister threat of bioengineered organisms being used as a terrorist weapon.

Then there is the continuing AIDS epidemic, which is changing manifestations demanding constant advances in therapeutic strategy. As diseases change, physicians must have the ability to respond rapidly. The physicians' ability to serve their patients would be crippled by blocking innovation and laboratory testing and data analysis.

This innovation can only be achieved if laboratories are able to use their personnel, facilities, and other resources in creative, efficient ways determined by the needs of the clinical situation rather than by rigid, ambiguous, bureaucratic dictate.

Number three, the FDA lacks the authority to expand its power as contemplated in the guidance. We are strenuously to the FDA efforts to overreach its statutory limits in its attempts to regulate laboratory developed tests that have previously been explicitly exempt. It lacks both constitutional and statutory authority to do this.

Number four, the proposed guidance will stifle innovation. Neither scientists nor investors will have any interest in using their talents and resources in ways that could be instantly stifled at bureaucratic whim. It's not rational to take the risk that efforts will simply be thrown away because of an arbitrary or capricious change of government policy.

It appears that the FDA proposed regulations can only make it more difficult and expensive for laboratories to comply, but may make it altogether impossible to comply with conflicting demands from the FDA, the Center for Medicare and Medicaid Services under the clinical laboratory Improvement Act.

The effect of contradictory demands goes beyond freezing medical progress, but will likely also cause regression as techniques are withdrawn because of regulatory fiat or ambiguity.

Our member physicians and the millions of patients that they serve need access to innovation, including laboratory developed tests, and also the freedom to practice their profession without constant fear of violating bureaucratic guidelines concerning allowable methods for diagnosing or analyzing a problem.

Number five, the proposed guidelines will increase the cost of innovation already extremely burdensome, possibly to reportable levels. We know that life style drugs have been delayed by years or decades because of FDA requirements and that the cost of bringing a new drug to market has rapidly escalated.

Everyone is concerned about the high and rising costs of medical care, regulations making a tremendous and unusually acknowledged contribution to these costs. A large portion of the regulatory burden is counterproductive. We believe that the FDA should not be allowed to impose new regulations without employing the equivalent of evidence based medicine to show that the regulations do not do more harm than good, with the waste of resources being included in the calculation of harm.

No such methodology has been applied to the proposed guidance.

Number six, the net effect of the guidance is likely to imperil patient safety rather than improving it. The FDA attempts to justify delays in regulatory barriers as necessary to protect patient safety. Its record of protecting safety is not impressive, as recent drug recalls have shown, but it has never ever attempted to calculate the lives that are lost because better products are prevented from entering the marketplace, some of them permanently because the cost barriers cannot be overcome

The cost of regulatory delay needs to be measured in lost lives as well as dollars. We agree with the concerns expressed by the Coalition for the 21st Century Medicine that the new FDA guidance documents are impermissibly vague and are also in violation of statutes such as the Administrative Procedures Act. Their effect will be to increase costs enormously while crippling physicians' ability to serve clinical needs.

Proposed changes would impose an unlawful straightjacket upon clinical practice. They would force laboratories, if they continue to function at all, to develop wholly new, expensive and nonproductive infrastructure in an attempt to do what is impossible, to begin with, namely, comply with conflicting obligations.

The FDA has not stated a problem that this guidance is supposed to solve. In fact, it apparently cannot even define such terms as service product or device in a clear and rational manner. This guidance should simply be rejected in its entirety. If the FDA is able to define the problem, then new guidance to address the need should be the least costly and intrusive manner in compliance with existing law.

It is not acceptable for the FDA to transgress the boundaries that forbid it to engage in or interfere with the practice of medicine.

Thank you.

DR. KESSLER: Thank you.

And our next speaker is Mara Aspinall from Genzyme Genetics.

MS. ASPINALL: Thank you.

Good morning. I am Mara Aspinall, president of Genzyme Genetics, and I very much appreciate the opportunity to be here today and to focus on one aspect of the draft IVDMIA guidance.

But first I'd like to say that Genzyme greatly appreciates that the FDA in response to concern with the guidance took two important steps:

First, to extend the deadline for the comment period; and

Secondly, to convene this session today.

These two steps are necessary, we believe, to insure that we begin the dialogue to look at what is essential in having new regulations and the potential of those, to make sure that they're necessary and appropriate and, most importantly, that any changes to the regulatory environment improve physician access to and confidence in diagnostics that help health care today.

Thank you for taking these steps.

However, because of the legal, administrative, and time and other constraints, neither a public docket or a public meeting such as this can truly provide the optimal opportunity for an active exchange. That active exchange of information or scientific information between FDA experts and those outside, we believe that we would like the agency to convene an additional meeting before proceeding further with an independent third party, if appropriate, a session that's a workshop or a similar format where true interactive dialogue can occur.

Such a format would give us the opportunity to listen and hear, to engage in an open dialogue with the agency, with you about the details that are so important in producing this guidance.

This kind of truly interactive format will allow us to hear your response issue by issue, question by question. So we look forward and would like you to consider a potential future opportunity to do that.

Today, however, I want to focus my comments on a concern amongst the many that have been discussed today, and this issue is the impact of the draft guidance on innovation, directly and indirectly through the reimbursement system and, therefore, on the timely physician and patient access to the most up to date and newest science and technology.

Health care today is moving from traditional medicine to personalized medicine, and personalized medicine involves getting more specific information on the detailed health status of a patient and will require more and more targeted tests to smaller and smaller patient populations.

To fulfill this promise of personalized medicine, we will need to insure that innovation is possible and is fostered in the laboratory developed part of the industry. If we fail to do that, we will be unable to carry out the promise or personalized medicine and our unwaiving commitment to excellent patient care and to patient safety.

To highlight that point, I want to take a moment to talk about what laboratory developed tests are, how they come into use, and the benefit that they bring to physicians who order them and the patients who need them.

These tests often have their beginning in academic centers in research that results in scientific publications about the usefulness of particular biomarkers or assays. Academic centers then typically look to independent laboratories to make these tests available to the relevant patients. In some cases the laboratories themselves develop the test based on scientific and medical information in the literature as presented at scientific meetings and conferences, indicating both the utility and the importance of these tests.

Laboratories then validate the test, insure the scientific underpinnings are robust, and develop processes that guarantee the test will be produced accurately and reproducible, and that they are offered and appropriate to the physicians.

Tests are developed and validated under the direction of Board certified pathologists and clinical scientists. In every case it is the treating physician that makes the choice about which validated test is appropriate for a particular patient and to insure that each test is medically necessary.

Treating physicians make the decision regarding specific tests based on patient need, their own clinical knowledge, and information from the medical and scientific literature.

So today what typically happens is unless and until a new diagnostic test reaches a critical and relatively large volume, no commercial test kit can be developed.

Lacking that critical volume, there is no market incentive to develop a kit and to spend the resources required to take this kit through a full FDA process.

The bottom line is that as a result, for conditions that affect a relatively small number of patients or, importantly in oncology and infectious disease, subpopulations of patients. The only access to valuable and necessary testing is through laboratory developed tests.

And just as balancing expenditures with potential returns on investment may dissuade a company from developing a test kit for a small market, financial realities will apply to laboratories as they develop cutting edge and innovative tests.

Extensive and costly regulatory requirements would serve as an extremely strong disincentive to the development of tests such as those for genetic disorders or from diseases, and very importantly and increasingly so, cancers that affect targeted subpopulations.

Why is this the case? It simply is that while diagnostics comprise less than five percent of hospital costs and 1.6 percent of Medicare costs, their findings influence as much as 70 percent of health care decision making.

That said, the current reimbursement system does not compensate laboratories adequately even now. The added cost associated with an FDA clearance or approval would be impossible to recoup. The end result would be that laboratories could not afford to develop new tests. Diagnostic testing, a key piece of personalized medicine today, in the future would suffer enormously. Treating physicians would be seriously limited to access to the important cutting edge tests that would help them determine the best course of treatment for their patients and, above all, patients would lose.

As we look to the future, we envision many new complex tasks that Genzyme Genetics would like to develop that would focus on specific and relatively small populations of patients. Many of these tests are expected to be in the area of oncology patient management and will provide critical diagnostic information essential to selecting the most appropriate therapies for each and every patient

We believe that most of those potential future tests will meet the definition as currently defined in the draft guidance of an IVDMIA that would potentially require additional regulation and/or costly premarket approval.

Because these tests are truly in the realm of personalized medicine, the market for them would be small, and even currently the reimbursement system is a challenge for laboratories making decision, such as us and others to invest in these new tests.

An additional level of regulation would make such an investment virtually impossible. Because we believe every patient and every treating physic