[Senate Hearing 114-803]
[From the U.S. Government Publishing Office]




                                                        S. Hrg. 114-803
 
          LABORATORY TESTING IN THE ERA OF PRECISION MEDICINE

=======================================================================

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                    ONE HUNDRED FOURTEENTH CONGRESS

                             SECOND SESSION

                                   ON

     EXAMINING LABORATORY TESTING IN THE ERA OF PRECISION MEDICINE

                               __________

                           SEPTEMBER 20, 2016

                               __________

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          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                  LAMAR ALEXANDER, Tennessee, Chairman

MICHAEL B. ENZI, Wyoming               PATTY MURRAY, Washington
RICHARD BURR, North Carolina           BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia                BERNARD SANDERS (I), Vermont
RAND PAUL, Kentucky                    ROBERT P. CASEY, JR., Pennsylvania
SUSAN COLLINS, Maine                   AL FRANKEN, Minnesota
LISA MURKOWSKI, Alaska                 MICHAEL F. BENNET, Colorado
MARK KIRK, Illinois                    SHELDON WHITEHOUSE, Rhode Island
TIM SCOTT, South Carolina              TAMMY BALDWIN, Wisconsin
ORRIN G. HATCH, Utah                   CHRISTOPHER S. MURPHY, Connecticut
PAT ROBERTS, Kansas                    ELIZABETH WARREN, Massachusetts
BILL CASSIDY, M.D., Louisiana                            
                                     
                                
                                       

               David P. Cleary, Republican Staff Director

         Lindsey Ward Seidman, Republican Deputy Staff Director

                  Evan Schatz, Minority Staff Director

              John Righter, Minority Deputy Staff Director             
              

                                  (ii)

  




                            C O N T E N T S

                               __________

                               STATEMENTS

                      TUESDAY, SEPTEMBER 20, 2016

                                                                   Page

                           Committee Members

Alexander, Hon. Lamar, Chairman, Committee on Health, Education, 
  Labor, and Pensions, opening statement.........................     1
Murray, Hon. Patty, a U.S. Senator from the State of Washington, 
  opening statement..............................................     3
Burr, Hon. Richard, a U.S. Senator from the State of North 
  Carolina.......................................................    34
Baldwin, Hon. Tammy, a U.S. Senator from the State of Wisconsin..    36
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah......    37
Bennet, Hon. Michael F., a U.S. Senator from the State of 
  Colorado.......................................................    39
Cassidy, Hon. Bill, a U.S. Senator from the State of Louisiana...    41
Warren, Hon. Elizabeth, a U.S. Senator from the State of 
  Massachusetts..................................................    48

                               Witnesses

Klimstra, David S., M.D., Attending Pathologist and Chairman, 
  Department of Pathology, James Ewing Alumni Chair in Pathology, 
  Memorial Sloan Kettering Cancer Center, Professor of Pathology 
  and Laboratory Medicine, Weill Medical College of Cornell 
  University, New York, NY.......................................     5
    Prepared statement...........................................     7
Spring, Brad, Vice President, Regulatory Affairs and Compliance, 
  BD Life Sciences, Baltimore, MD................................    11
    Prepared statement...........................................    13
Allen, Jeff, Ph.D., President and CEO, Friends of Cancer 
  Research, Washington, DC.......................................    15
    Prepared statement...........................................    17
Kaul, Karen L., M.D., Ph.D., Chair, Department of Pathology and 
  Laboratory Medicine, Duckworth Family Chair, NorthShore 
  University HealthSystem, Clinical Professor of Pathology, 
  University of Chicago Pritzker School of Medicine, Evanston, IL    23
    Prepared statement...........................................    25

                          ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
Response by David S. Klimstra, M.D., to questions of:
    Senator Murray...............................................    51
    Senator Enzi.................................................    51
    Senator Isakson..............................................    53
    Senator Casey................................................    53
Response by Brad Spring to questions of Senator Casey............    54
Response by Jeff Allen, Ph.D., to questions of:
    Senator Enzi.................................................    54
    Senator Casey................................................    56
Response by Karen L. Kaul, M.D., Ph.D., to questions of:
    Senator Murray...............................................    57
    Senator Enzi.................................................    57
    Senator Isakson..............................................    59
    Senator Casey................................................    60

                                 (iii)

  


          LABORATORY TESTING IN THE ERA OF PRECISION MEDICINE

                              ----------                              


                      TUESDAY, SEPTEMBER 20, 2016

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 10:06 a.m., in 
room SD-430, Dirksen Senate Office Building, Hon. Lamar 
Alexander, chairman of the committee, presiding.
    Present: Senators Alexander, Murray, Burr, Isakson, Hatch, 
Cassidy, Casey, Bennet, Baldwin, Murphy, and Warren.

                 Opening Statement of Senator Alexander

    The Chairman. The Senate Committee on Health, Education, 
Labor, and Pensions will please come to order. This is our 45th 
hearing of the last 2 years, and virtually all of them have 
been what we call bipartisan hearings where we invite witnesses 
to help inform us about the issues rather than sit around and 
castigate each other. I thank Senator Murray for working in 
that way.
    This morning's hearing is about laboratory-developed tests 
to help us understand and get a better understanding of how 
diagnostics and testing fit into the promise of personalized 
medicine that we hear the President talk about so much. Senator 
Murray and I will each have an opening statement. Then we'll 
introduce our panel of witnesses. After our witness testimony, 
Senators will have 5 minutes of questions.
    Laboratory-developed tests are medical tests that are 
designed, manufactured, and used in a single laboratory. These 
are labs in doctors' offices, hospitals, universities, State 
public health departments, private companies--places where 
scientists both develop and use tests to determine whether you 
have a disease or whether a certain drug will work for you. 
There are more than 60,000 lab-developed tests available to 
Americans today to help screen for and diagnose diseases and 
conditions such as rare or emerging infectious diseases and 
different types of cancer.
    As I will mention in a minute, these 60,000 laboratory-
developed tests are regulated by a process that includes the 
Center for Medicare and Medicaid Services, CMMS, but they're 
not regulated by the FDA. Let me share two examples of lab-
developed tests.
    Last year, President Obama announced the Precision Medicine 
Initiative which will involve mapping 1 million genomes and has 
the potential to transform medical treatment in our country. I 
attended a summit the President convened on the topic in 
February. There, he recommended expanding access to a breast 
and ovarian cancer test developed by a commercial lab called 
Color Genomics. To take this test, anyone can ask their doctor 
to order it, pay about $250, provide a simple saliva sample, 
send the package back in the mail, and work with your doctor to 
understand your genetic risk for developing these cancers.
    As part of the President's Precision Medicine Initiative, 
Color Genomics said it is going to double the number of free 
tests offered to women. This test is an example of a lab-
developed test, in this case, one developed by scientists in a 
commercial lab regulated by CMMS, not by the FDA.
    Here's another example: A woman in her 80's goes to 
Vanderbilt University Medical Center for care. At Vanderbilt, 
someone puts a needle in her vein, takes blood and sends it to 
Vanderbilt's laboratory. Four days later, her doctor gets the 
results back from the lab and finds out that a certain blood 
thinner won't work for this patient. The patient would respond 
poorly to it. He prescribes something different.
    Using that one blood test, scientists at Vanderbilt can 
find out whether the patient has one of 184 changes within 34 
genes that might affect the way their body absorbs, 
distributes, metabolizes, or excretes a drug. Through its 
award-winning PREDICT program, Vanderbilt has been able to put 
important drug interaction information into patients' medical 
records so that doctors can know how they'll respond to 
medication. The blood test they use for this is a lab-developed 
test, in this case, developed in the lab of an academic medical 
center, Vanderbilt. Again, this is a test regulated by CMMS, 
not by FDA.
    Both of these examples involve the President's Precision 
Medicine Initiative. I visited Vanderbilt last month. The 
medical center has received a $71 million, 5-year grant to 
store and help make useful all the data in the Precision 
Medicine Initiative. Dr. Zutter of Vanderbilt estimated that 95 
percent of tests used in the practice of precision medicine or 
personalized medicine at Vanderbilt are their lab-developed 
tests. Let me emphasize that. She said that 95 percent of the 
tests they use in their practice of precision medicine at 
Vanderbilt are laboratory-developed tests regulated by CMMS, 
not regulated by the FDA.
    I received a lesson on these tests on my tour there. It's a 
good place to learn. The doctors in Vanderbilt's lab run about 
4 million individual tests annually. Of those 4 million, 80,000 
are run using tests developed by the doctors in Vanderbilt's 
own lab. Vanderbilt has developed 105 of its own tests. 
Vanderbilt has 105 lab-developed tests which it uses 80,000 
times on patients there. The rest of the 4 million are done 
using FDA-approved diagnostic kits that are developed by 
manufacturers and sold to laboratories in hospitals and 
doctors' offices where they are performed.
    We're holding this hearing today to learn more about lab-
developed tests and their importance to the advancement of 
medicine. We also want to discuss a draft guidance released in 
2014 by the FDA that would require each of these 60,000 lab-
developed tests to be individually approved by the FDA.
    This would change things. It would change the way lab-
developed tests are currently regulated. They're currently 
regulated at the Centers for Medicare and Medicaid Services, as 
I mentioned, through something called CLIA, the Clinical 
Laboratory Improvement Act of 1988, which Senator Mikulski of 
this committee led. It was a bipartisan effort, and I want to 
recognize her for her leadership in that.
    The FDA's guidance about regulating laboratory tests is a 
draft guidance, but it proposes that all of the lab-developed 
tests that are currently under the CMMS CLIA program also be 
submitted to FDA for approval before they can be used. That 
would appear to me to be double regulation. Tests would need to 
meet the CLIA regulations, and then each one would need to be 
individually approved by FDA.
    So what would FDA approval mean for Americans relying on 
the more than 60,000 different laboratory-developed tests 
available in the country today, which each one would have to be 
approved by the FDA before they were used? First, patients 
might lose access to tests until they are approved by FDA. I 
don't know how many labs would have the resources to put their 
tests through that approval process.
    For reference, as of 2010, it took about $75 million to 
bring just one high-risk device to market through the FDA 
process. Vanderbilt, for example, has 105 tests. If just one, 
the PREDICT test, is high risk, that could cost Vanderbilt $30 
million to $75 million. You can quickly see how costs just to 
that institution could add up to billions.
    We've heard from infectious disease doctors who have said 
in comments to the FDA about this draft guidance that they 
were, ``very concerned that this oversight currently proposed 
could impede patient access to existing high-quality or state-
of-the-art tests and threaten needed innovation.'' The Chair of 
the Department of Laboratory Medicine at the University of 
Washington wrote Senator Murray and me, suggesting that the 
proper approach would be to modernize the CLIA system, the CMMS 
system, to, ``promote continued patient access to affordable, 
high-quality tests without duplicative regulations.'' Under the 
draft guidance, the biggest loser, it seems to me, would be 
Americans who stand to benefit from the rapid pace of science 
and discovery.
    The Vice President is leading the Cancer Moonshot. Lab-
developed tests have enabled much of the progress made in 
cancer research, allowing physicians to practice at the speed 
of science rather than the speed of the FDA. In one example, 
doctors began testing for mutations in the KRAS gene in 2008-
2009 using lab-developed tests. There wasn't an option approved 
by the FDA until 5 years later in 2013-14. I am concerned that 
the FDA already has a full plate of responsibilities, and the 
agency has said it needs more money to meet those 
responsibilities.
    I look forward to hearing today whether additional or 
different regulation of laboratory-developed tests is 
necessary.
    Senator Murray.

                      Statement of Senator Murray

    Senator Murray. Thank you very much, Chairman Alexander, 
and thank you to all of our witnesses for being here today.
    Maintaining our country's leadership in science and 
biomedical innovation is a top priority for all of us here. I'm 
excited about the President's Precision Medicine Initiative and 
the Vice President's Cancer Moonshot which can help ensure that 
the next generation of treatments and cures are developed right 
here in the United States. The promise of precision medicine 
and new targeted therapies for cancer hinge on doctors' ability 
to treat a patient with the right drug at the right time. That 
means they will rely on diagnostics and new innovative tests 
more than ever before.
    I am proud to represent a State that leads in developing 
both cutting-edge therapies and tests. I'm inspired by the work 
they do, how far science has advanced, and the promise that the 
future of medicine holds. But that promise cannot be realized 
unless doctors and patients have the assurance that when a test 
result demonstrates risk of a disease, provides an early 
diagnosis, or suggests a treatment, that result is correct and 
reliable. I'm concerned that our regulatory system currently 
can't provide that assurance.
    Before most drugs and devices come to the market, they've 
been reviewed by the FDA and meet the gold standard for safety 
and effectiveness, a standard that our patients and families 
have come to trust. But many of the lab tests on which medical 
decisions are based are not subject to FDA review, something 
that most Americans are not aware of when they go to a doctor.
    While the labs themselves are regulated, as mentioned by 
our Chairman, thanks to important legislation that Senator 
Barbara Mikulski championed, that law does not require the 
tests to be clinically meaningful, and that law doesn't ensure 
that a patient will get the same result no matter what lab they 
go to.
    Some tests are subject to FDA review--tests that are 
marketed by medical device companies or are used with a 
particular new drug. Developers of these tests must demonstrate 
to the FDA that they are accurate, precise, and clinically 
meaningful. This discrepancy has created an uneven playing 
field for innovative companies and laboratories, including many 
in Washington State, and uncertainty for patients and 
physicians.
    It also presents potential risk for patients who may seek 
the wrong treatment or no treatment at all based on test 
results. Just this month, the FDA alerted women and their 
doctors that certain tests marketed as screening tools for 
ovarian cancer lacked evidence to support their use. We 
certainly need new ways to screen for ovarian cancer, but we 
don't need tests that offer false security or cause unnecessary 
worry.
    More than ever, physicians and patients and their families 
must be able to rely on test results in making treatment 
decisions. And it's also important that patients can be assured 
that the test results will be the same whether their physician 
uses a laboratory across the street or across the country.
    Nearly 2 years ago, in pursuit of these goals, the FDA 
proposed a new approach to regulating lab tests. I've heard 
views from a wide range of stakeholders about this proposal and 
how the FDA's policies would impact their work. I think that 
there are ways the agency's proposal could be improved. But 
even though everyone wants to make sure the tests offered to 
patients work as advertised and that we allow researchers and 
clinicians to continue to innovate and advance precision 
medicine, there is not wide agreement about the best regulatory 
approach.
    The two questions I'm most interested in exploring today 
are: How can we help make sure patients are getting the highest 
quality and most innovative tests possible? And how can we 
provide regulatory certainty and a level playing field for test 
developers? I look forward to hearing from our witnesses today. 
I'm confident that your insight today will help us inform some 
bipartisan efforts to make sure that the promise of precision 
medicine and the Cancer Moonshot are realized.
    Thank you very much, Mr. Chairman.
    The Chairman. Thank you, Senator Murray.
    I'm delighted to welcome our four witnesses. Thank you for 
taking the time to be here.
    First, we'll hear from Dr. David Klimstra, Attending 
Pathologist and Chairman of the Department of Pathology at 
Memorial Sloan Kettering Cancer Center. He is Professor of 
Pathology and Laboratory Medicine at the Weill Medical College 
at Cornell University.
    Next is Brad Spring, Vice President of Regulatory Affairs 
and Compliance at BD Life Sciences located in Sparks, MD. Mr. 
Spring has over 27 years of experience in the diagnostics 
industry and is responsible for executing global regulatory 
strategies, global product registration processes, and ensuring 
regulatory compliance.
    We will then hear from Dr. Jeff Allen, President and CEO of 
Friends of Cancer Research. Friends of Cancer Research 
advocates for cancer patients, collaborating with all the 
healthcare sector to improve patient care. I thank Dr. Allen 
for working with this committee, especially with Senator Burr 
and Senator Bennet and Senator Hatch, to help pass the 
Breakthrough Drug Pathway, which has been a great success with 
over 100 drugs designated and 46 approved in a relatively short 
period of time since its enactment.
    Last, we'll hear from Dr. Karen Kaul, Chair of the 
Department of Pathology and Laboratory Medicine at NorthShore 
University HealthSystem, Clinical Professor of Pathology at the 
University of Chicago Pritzker School of Medicine. She and her 
lab have been deeply involved in the development of laboratory 
tests for cancer, heritable conditions, and microbial diseases.
    We thank the four of you for coming. If you would each try 
to summarize your comments in about 5 minutes, that will leave 
more time for the Senators to ask questions.
    Dr. Klimstra, let's begin with you.

STATEMENT OF DAVID S. KLIMSTRA, M.D., ATTENDING PATHOLOGIST AND 
CHAIRMAN, DEPARTMENT OF PATHOLOGY, JAMES EWING ALUMNI CHAIR IN 
PATHOLOGY, MEMORIAL SLOAN KETTERING CANCER CENTER, PROFESSOR OF 
  PATHOLOGY AND LABORATORY MEDICINE, WEILL MEDICAL COLLEGE OF 
                CORNELL UNIVERSITY, NEW YORK, NY

    Dr. Klimstra. Good morning, Mr. Chairman, Ranking Member 
Murray, and committee members. My name is David Klimstra, and 
I'm Chairman of the Department of Pathology at Memorial Sloan 
Kettering Cancer Center in New York. I'm grateful for the 
opportunity to share our experience with molecular diagnostic 
testing in the era of precision medicine.
    President Obama's Precision Medicine Initiative challenges 
pathologists to characterize each patient's cancer at a much 
more fundamental level than ever before, describing not only 
its origin and subtype, but also its genetic features, which 
make it unique to the individual patient. One way to do this is 
to sequence the cancer genes, which is now easier, faster, and 
cheaper. Specific genetic abnormalities can point to targeted 
treatments, ensuring that the most effective therapies are 
employed and treatments without benefit are avoided.
    At MSK, we now routinely sequence most advanced solid 
cancers, like breast, prostate, colon, lung, and pancreas 
cancer, using an assay called MSK-IMPACT, which simultaneously 
studies 468 cancer related genes. Over the past couple of 
years, we've reported MSK-IMPACT results for nearly 12,000 
patients, helping shape their treatment recommendations.
    MSK-IMPACT is just one of approximately 350 laboratory-
developed molecular tests we currently perform. We use LDTs 
because the tests can be customized to provide the specific 
information we need. They can be adapted to study a range of 
different types of specimens, and they can bring the tests to 
clinical care quickly, relative to FDA-approved tests which 
have been slow to come to market.
    To help you understand how these LDTs become established at 
MSK, let me explain the basic process in our labs, which are 
regulated by New York State and subject to premarket approval. 
The concept for a new LDT begins with a clinical need. 
Appropriate testing methods are then developed by our 13 board 
certified molecular pathologists and laboratory scientists. The 
reliability of the methods is verified following standardized 
procedures to ensure sensitivity, specificity, and 
reproducibility. The tests are further validated using 
different testing methodology or using similar methods in a 
different laboratory.
    Then a highly detailed description of the new test is 
submitted to the State for approval. The MSK-IMPACT submission 
was 535 pages long, for instance. Generally, the State raises 
some questions that require a revised submission or additional 
validation experiments. Approval of the revised submission 
allows the rest results to be released to the medical record.
    This approval process works reasonably well, although it 
can be slow. From the conception of a new test through 
submission to the State for approval can take 12 to 15 months. 
Formal State review can also take months. The very first 
complex sequencing assay we developed was submitted for State 
review in December 2012. Final approval was obtained in March 
2014. But the review process has improved, based in part on the 
dialog we maintain with the State. MSK-IMPACT received final 
approval in 8 months, and the State provides even more rapid 
conditional approval that allows us to offer tests clinically 
before final review.
    Once approved, all of our test results are reported by 
physicians with advanced molecular diagnostics training and 
interpreted in the context of the patient's entire medical 
situation. Further, LDT performance is monitored by 
participating and ongoing proficiency testing. There is also a 
formal quality assurance process, and any test performance 
issues are subjected to rigorous review and reporting.
    For these reasons, we believe that additional regulatory 
oversight of our labs, such as that proposed by the FDA in 
their draft guidance of 2014, would be duplicative and 
unnecessary. I would also raise concerns about the cost of 
additional regulations, both monetary and in terms of patient 
access to cutting-edge diagnostics. Maintaining a regulatory 
infrastructure is already costly, and additional costs of 
obtaining regulatory approval for individual tests may prohibit 
academic laboratories from developing LDTs.
    The current cost of an FDA premarket approval submission is 
over $260,000, and although a modified fee schedule could be 
developed, it is easy to see how a lab with dozens or hundreds 
of LDTs could not afford to obtain FDA approval. This could 
drive innovative molecular testing out of the academic 
environment and into only larger commercial labs which have the 
resources to maintain regulatory compliance.
    But most importantly, I worry about the delays in test 
availability from overly stringent regulations. Many important 
cancer gene mutations, such as the EGFR mutations critical for 
the treatment of lung cancer, were being detected with 
academically developed LDTs 5 years or more before an FDA-
approved assay became available. Can we afford to deny our 
patients access to practice-changing tests for years while 
their cancers progress?
    Of course, it is critical to ensure that we have safe, 
reliable, and meaningful laboratory results, and rational 
regulation can help that. But we urge Congress and the FDA to 
create a flexible regulatory process that does not delay access 
to important treatment information and that does not impede 
significant contributions to precision medicine coming from 
academic institutions.
    When Vice President Biden visited MSK to discuss the Cancer 
Moonshot, he asked for a decade's worth of advances in 5 years. 
Let's not throw an unnecessary roadblock in that path.
    Thank you for providing me this important opportunity to 
present these views.
    [The prepared statement of Dr. Klimstra follows:]

             Prepared Statement of David S. Klimstra, M.D.

                                summary
    I am the chairman of the Department of Pathology at Memorial Sloan 
Kettering Cancer Center (MSKCC), where the Department of Pathology 
conducts a wide array of custom-developed molecular assays to 
characterize the genetic changes in patients' cancer tissues, and we 
have extensive experience with the development, validation, execution, 
and regulation of these laboratory-developed tests (LDTs).
    Achieving the promise of the Precision Medicine Initiative requires 
characterizing cancers at the genetic level. Broad-spectrum genomic 
analysis performed using DNA and RNA sequencing technologies has been 
developed for clinical use in some of the top academic and commercial 
pathology laboratories. Many tests employed in molecular diagnostics 
are developed and validated within individual laboratories and are 
therefore regarded to be LDTs, which have been the subject of proposed 
enhanced regulation by the Food and Drug Administration (FDA).
    LDTs at MSKCC are all initiated based on clinical needs, developed 
using standard, verifiable methods with a rigorous validation process, 
and interpreted by expert molecular pathologists.
    Our laboratories are CLIA compliant and are inspected by the Joint 
Commission on Accreditation of Health Care Organizations (JCAHO) and 
the New York State Department of Health (NYS DOH). LDTs we develop must 
undergo extensive pre-test review and approval by the NYS DOH prior to 
being offered to patients. The process of LDT development, validation, 
and approval can require 12-15 months to complete.
    Additional regulation of our LDTs would be redundant and 
unnecessary; it would slow the process of test development, restricting 
availability of advanced diagnostic tests to patients; it would add 
significant cost and effort to the administration of pathology 
departments; it would stifle innovation of critical novel diagnostics; 
and it would threaten to preclude the involvement of academic pathology 
departments in molecular testing, driving these assays completely into 
the commercial sector where large companies isolated from the input of 
academic oncology would be the only adequately resourced entities 
capable of maintaining regulatory compliance. Rational regulation of 
LDTs requires assessment of the risks involved in the test but also the 
nature of the testing technology and validation process already in 
place, to ensure optimal patient safety as well as optimal patient 
access to practice-changing technology.
                                 ______
                                 
    My name is David Klimstra, M.D., chairman of the Department of 
Pathology at Memorial Sloan Kettering Cancer Center (MSKCC) in New York 
City, and I am grateful for the opportunity to share our experiences 
related to molecular diagnostic testing in the era of precision 
medicine with the U.S. Senate Committee on Health, Education, Labor, 
and Pensions. At MSKCC, we are committed to exceptional patient care, 
cutting-edge research, and the rapid translation of scientific 
discoveries into clinical advances. The MSKCC Department of Pathology 
plays a central role in fulfilling this promise by ensuring precise and 
timely diagnosis through the use of state-of-the-art equipment and 
advanced diagnostic techniques to analyze more than 100,000 patient 
samples annually. My department conducts a wide array of custom-
developed molecular assays to characterize the genetic changes in 
patients' cancer tissues, and we have extensive experience with the 
development, validation, execution, and regulation of these laboratory-
developed tests.

    The promise of precision medicine requires access to sophisticated 
molecular diagnostic testing.

    In President Barack Obama's State-of-the-Union address on January 
30, 2015, he stated,

          ``Doctors have always recognized that every patient is 
        unique, and doctors have always tried to tailor their 
        treatments as best they can to individuals. You can match a 
        blood transfusion to a blood type--that was an important 
        discovery. What if matching a cancer cure to our genetic code 
        was just as easy, just as standard?''

This basic premise of the Precision Medicine Initiative is predicated 
on an enhanced understanding of the characteristics of each patient's 
individual cancer, including knowing not only the organ in which it 
arose and the specific subtype of the cancer but also its genetic 
characteristics--the features that distinguish it from other seemingly 
similar cancers arising in other patients. The technology to decipher 
the genetic abnormalities that uniquely characterize each individual 
cancer has become rapidly more accessible in recent years, allowing 
comprehensive genetic analysis as a routine test for patients with 
advanced cancers. Broad-spectrum genomic analysis performed using DNA 
and RNA sequencing panel technologies that assess 100's of genes 
simultaneously, termed ``next-generation sequencing,'' has been 
developed for clinical use in some of the top academic and commercial 
pathology laboratories and is now increasingly available, even outside 
of major centers. Thus, the field of molecular pathology has rapidly 
emerged as a critical cornerstone of cancer diagnostics.
    Much of the technology employed in molecular diagnostics is 
developed and validated within individual laboratories, although 
sequencers, robotics, and other pieces of equipment employed in these 
multi-step assays are manufactured elsewhere. These tests are therefore 
regarded to be ``Laboratory-Developed Tests (LDTs),'' which have been 
the subject of proposed enhanced regulation by the Food and Drug 
Administration (FDA). At Memorial Sloan Kettering Cancer Center 
(MSKCC), our molecular diagnostics laboratories perform approximately 
350 different tests that meet at least some interpretation of the 
definition of LDTs, provided in the FDA draft guidance of October 3, 
2014. At MSKCC, our LDTs allow the rapid translation of impactful 
research findings to the clinic (``from bench to beside''), meaning 
that patients can benefit from new types of predictive testing very 
quickly--even years before the appearance of an FDA-approved diagnostic 
test. Many of the more recently developed LDTs we perform are genomic 
sequencing tests, designed to provide a thorough genetic 
characterization of each individual patient's cancer, and nearly 12,000 
cancers have been subjected to clinical sequencing using our MSK-
IMPACTTM assay, which currently analyzes 468 cancer-related genes. The 
results of MSK-IMPACTTM testing are used to better understand each 
patient's cancer, to aid in classification and prognostic 
stratification, and to identify genetic changes that predict the 
sensitivity--or resistance--of the tumor to specific therapeutic 
interventions. Ultimately the use of molecular pathology is reducing 
overall treatment costs as well as pain and burden for patients by 
ensuring that the ``right'' therapies (i.e., those therapies most 
effective for that individual) are employed as first-line treatments 
and therapies without efficacy are avoided.
    One of the benefits of the current technology is the ability to 
analyze hundreds of genes simultaneously, without significantly 
increasing the cost of the test compared to single-gene or small panel 
assays. This provides a wealth of data regarding clinically actionable 
alterations but also a broad array of potential genetic targets that 
are the focus of active research. Accumulation of this valuable 
research data is essentially a byproduct of studying the known 
actionable genes, and having voluminous data from our Center and others 
will allow a much expanded understanding of the interplay of cancer 
genetic changes and the role of novel genes in tumor progression, 
therapeutic sensitivity, and treatment failure. Our data are being 
shared with numerous other investigators around the Nation through 
Project GENIE (Genomics, Evidence, Neoplasia, Information, Exchange) of 
the American Association for Cancer Research (AACR), and currently 
MSKCC is the largest contributor to this collaborative data base. It is 
essential that efforts to offer and further develop these assays are 
able to move forward quickly, as the technology is rapidly advancing, 
requiring continuous test development research to offer the most 
effective molecular testing to our patients.
    Attention to the safety, accuracy, and reproducibility of our 
molecular diagnostic tests is paramount, and a well-established process 
exists to ensure that results are reliable. Our team of 13 board-
certified molecular pathologists is involved in every step of the 
process, and they review and formally report the findings of every 
case, to ensure that the test worked properly, that all relevant genes 
were adequately analyzed, and that the genetic findings are interpreted 
within the context of the patient's clinical findings. We believe that 
the delicate balance between assuring quality in molecular diagnostics 
and moving forward cutting-edge advances as quickly a possible is being 
achieved. In order to meet the objectives of Vice President Biden's 
``Cancer Moonshot,'' which he explained directly to us when he visited 
MSKCC last May, we hope to accelerate progress in cancer research--``to 
make a decade worth of advances in 5 years''--moving forward our 
molecular diagnostic technology without unnecessary impediments that 
would be caused by excessive or redundant regulation. This objective 
will not only allow important future research advances, but it will 
also more quickly deliver vital treatment information to aid cancer 
patients who are afflicted today.

    A standardized process is in place to develop, validate, and 
release LDTs for clinical testing.

    The development of a new molecular pathology LDT at MSKCC begins 
with the identification of a clinical need for additional data used to 
make patient management decisions. Academic oncologists work closely 
with our molecular pathologists to review new scientific findings--
including manydiscovered at MSKCC--to recognize when additional 
molecular characterization of patient cancer samples may allow novel 
therapeutic options. Molecular methods are then developed that will 
permit the acquisition of the needed findings, and these methods are 
adapted by the molecular pathology service for use in a clinical 
diagnostic setting. A series of validation experiments is then 
performed in our Clinical Laboratory Improvement Amendments (CLIA) 
compliant laboratories to test the performance of the assay, using 
positive and negative controls that have been already studied using a 
different technology. This process ensures that the test is reliable, 
specific, and reproducible. The number of validation experiments varies 
depending upon the test parameters and the specific requirements of our 
regulatory agency, the New York State Department of Health (NYS DOH; 
see http://www.wadsworth.org/regulatory/clep/clinical-labs/obtain-
permit/test-approval/submission-checklists).
    Upcoming guidelines prepared by the Association for Molecular 
Pathology and the College of American Pathologists, written in 
collaboration with our own molecular pathologists, will help 
standardize the validation process for sequencing-based assays 
nationwide. Once the validation experiments are completed, a detailed 
description of the new test, including the specific conditions, 
reagents, and data analysis process, along with the results of the 
validation experiments, is prepared for submission to the NYS DOH. This 
process--from the conception of the new test through submission for NYS 
pre-test approval--takes up to 12-15 months depending on the complexity 
of the test and the novelty of the technology employed. For example, 
assays developed in our labs over the past 3 years required 6-8 
months--after all of the text conditions had been established--simply 
to compile sufficient validation data to submit the package for NYS DOH 
approval. Formal NYS DOH review can also take months. Generally, there 
are questions raised by the NYS DOH, requiring clarification or 
additional experiments, with resubmission of a revised document. 
Acceptance of the revised submission finally allows the test to be 
offered to patients, with release of the results to the medical record. 
The first next-generation sequencing assay developed at MSKCC was 
submitted for NYS DOH pre-test review in December 2012; final approval 
was not obtained until March, 2014.
    Our current next-generation sequencing assay for solid cancers, 
MSK-IMPACTTM, required 8 months for final approval. Other recent assays 
have also taken nearly a year or longer, but the NYS DOH provides more 
rapid conditional approval, given the long track record our laboratory 
has established with the agency, allowing us to offer the tests 
clinically pending final review, provided any concerns raised in that 
final review are addressed successfully within 60 days. All of the LDTs 
employed in our laboratories use well-established methods and 
technologies, which can be performed in other laboratories to verify 
their accuracy, and the results can also generally be confirmed using 
other technologies.
    As part of the CLIA-mandated quality assurance program, test 
performance at MSKCC is assessed through annual participation in 
proficiency testing (e.g., conducted by the CAP), in which test samples 
with known findings are analyzed to ensure consistent and accurate 
results. Proficiency testing is one of the central safeguards of 
laboratory quality under the CLIA program. Furthermore, there is a 
strong institutional commitment to Quality Assurance, reflecting the 
National Patient Safety Goals, and test performance issues are 
subjected to rigorous review and reporting, with corrective measures 
instituted whenever systems issues may be discovered.
    Through all of these measures, LDTs preformed at MSKCC are 
subjected to substantial oversight to protect patient safety and ensure 
accurate results. The cost of these measures is challenging to assess 
but annual NYS DOH inspections cost $140,000 per year and biennial 
JCAHO laboratory accreditation costs $54,000 per year, and the 
Pathology Department devotes the aggregate time of approximately five 
full time faculty and administrators to maintaining regulatory 
compliance.
    Nationwide, the CLIA program regulates laboratories that perform 
testing on patient specimens in order to ensure accurate and reliable 
test results. When a laboratory develops an LDT, the CLIA program 
prohibits the release of any test results for patient care prior to the 
laboratory establishing certain performance characteristics relating to 
analytical validity for the use of that test system in the laboratory's 
own environment [42 CFR 493.1253(b)(2)--establishment of performance 
specifications]. CLIA requires that laboratories performing LDTs and 
modified FDA-approved tests establish the same performance 
characteristics that are required for unmodified FDA-approved tests, as 
well as determining analytic sensitivity, analytic specificity, and any 
additional performance characteristics that may be important to 
establish (e.g., sample preparation, specimen stability, data analysis 
process). The details of these validations are carefully reviewed by 
outside inspectors as part of periodic CLIA-mandated laboratory 
inspections. Biennial inspections are completed by laboratory 
accrediting agencies with CMS deemed status, such as the Joint 
Commission (JCAHO) or College of American Pathologists (CAP).

    Regulation of LDTs must protect public health but not deter 
innovation or patient access to testing.

    Academic departments of pathology and associated clinical 
laboratories have been intimately involved in the non-commercial 
development and implementation of LDTs used for patients cared for in 
their institutions. Many of the scientific and clinical discoveries 
that underlie and allow the development of LDTs have been made first in 
academic departments of pathology, in close development and 
collaboration with clinical caregivers and cancer researchers.
    Any oversight framework implemented by the Federal Government must 
be appropriate to the way modern clinical laboratories provide patient 
testing. LDTs include a vast range of tests--from minor modifications 
of FDA approved tests or kits to assays fully developed and performed 
in a single laboratory. The FDA should make a distinction between 
``black box'' tests with proprietary algorithms provided by a single 
for-profit company, which may not adequately provide patient safeguards 
and cannot readily be verified by testing in other laboratories, versus 
tests that are interpreted by a physician, and the analytical and 
clinical validity of the test can be verified by an independent third 
party or an alternative methodology (i.e., the test does not use a 
proprietary algorithm or technology). A distinction must also be made 
between assuring the diagnostic accuracy of a test (i.e., ensuring that 
the test result reflects the presence or quantity of the parameter 
being measured) versus the clinical utility of a test (i.e., ensuring 
that the information provided by the test is truly useful for clinical 
decisionmaking). Active engagement of clinicians in defining the need 
for specific tests is key to the latter metric.
    LDTs have rapidly evolved with advances in technology and business 
models, resulting in tests that are more complex, have nationwide 
reach, are available for common diseases, and involve higher risks to 
patients if inaccurate. In some instances, LDTs are being marketed 
directly to the patients. Due to the increased application of LDTs for 
genetic testing and precision medicine, the use of LDTs outside of the 
physician-patient context, and the development of LDTs by larger 
corporations, there is a concern that some LDTs may not be properly 
validated for their intended use, putting patients at risk via 
inaccurate diagnoses and incorrect treatment decisions. The FDA, with 
its extensive experience in regulating IVDs, may be better suited to 
protecting patients especially for tests that may pose a ``high risk.'' 
In contrast, when LDTs utilize publicly available diagnostic technology 
and interpretation algorithms and are reviewed and reported by licensed 
medical professionals, FDA regulatory oversight is duplicative and 
unnecessary. The current cost of a Premarket Approval (PMA) submission, 
for a single LDT, is $261,388 for a standard application, and $65,347 
for small businesses (http://www.fda.gov/ForIndustry/UserFees/
MedicalDeviceUserFee/ucm452519.htm); busy academic molecular 
diagnostics laboratories currently offer dozens or even hundreds of 
different LDTs. The costs of FDA regulations, along with the delays 
they will entail, would simply prevent these types of laboratories from 
functioning, driving all of molecular diagnostics into the large 
commercial lab setting. An overbearing regulatory environment is highly 
likely to limit the significant innovation occurring in many academic 
diagnostic laboratories.
    The FDA should limit duplication of regulatory efforts by not only 
utilizing third-party review, but also by granting deeming authority to 
agencies that have already established a formal pre-market review 
process, such as the previously mentioned NYS DOH's Laboratory Specific 
Assay Validation Review and Approval Program. The longstanding NYS DOH 
approach to regulating LDTs is among the most rigorous in the country 
and may provide a framework to build on for enhanced FDA oversight of 
LDTs.
    The key to effective test regulation is to recognize the diversity 
of testing currently defined as LDTs and the existing level of 
regulatory and quality assurance oversight, to assure that currently 
unrestricted LDT development has appropriate safeguards without 
subjecting well-regulated laboratories to additional costly and time-
consuming regulations. If the entire LDT compendium is ``painted with 
one brush'' from the regulatory perspective, the result will likely be 
the constraint of many outstanding efforts, delaying delivery of 
practice-changing innovation to patients and hindering academic centers 
from participating in molecular diagnostic testing altogether.

    The Chairman. Thank you, Dr. Klimstra.
    Mr. Spring.

 STATEMENT OF BRAD SPRING, VICE PRESIDENT, REGULATORY AFFAIRS 
        AND COMPLIANCE, BD LIFE SCIENCES, BALTIMORE, MD

    Mr. Spring. Chairman Alexander, Ranking Member Murray, and 
members of the committee, I'm Brad Spring, Vice President of 
Regulatory Affairs and Compliance for BD Life Sciences based in 
Sparks, MD. I've worked in the in vitro diagnostic field for 
nearly 28 years, and I'm honored to have the opportunity to 
participate in today's panel on behalf of BD.
    BD is a U.S.-based global medical technology company that 
is advancing the world of health by improving medical 
discovery, diagnosis of disease, and the delivery of care. 
Diagnostic tests play an important role in the diagnosis of 
disease, genetic disorders, infection, and other health 
conditions. These tests may be performed in a clinical 
laboratory, a doctor's office, hospital bedside, or in the 
home.
    The issue of how to best regulate diagnostic tests to 
ensure the public's health while allowing for innovation and 
rapid access to these tests has been debated for many years. BD 
is grateful to the committee for taking time to study this 
complex issue very carefully. During my remarks, I hope to shed 
light on the regulatory process under which BD currently brings 
tests to market and to share a set of principles that could 
help guide future reforms.
    Under current regulations, diagnostic test manufacturers 
like BD are required to provide data to FDA demonstrating how 
accurately and precisely a test measures an analyte or a target 
and how well it works in leading to a correct diagnosis. 
Diagnostic tests that are developed and used by laboratories 
are not regulated by FDA. CLIA provides CMMS the authority to 
regulate laboratory operations to ensure reliable test results 
by focusing on the quality of laboratory procedures and the 
competency of personnel.
    FDA regulates diagnostic tests as medical devices based on 
the level of risk to patients and public health posed by their 
intended use. Class 1 tests are the lowest risk, and most are 
exempt from premarket review, but these tests are still subject 
to good manufacturing practices and other controls. Class 2 
tests pose a moderate level of risk based on their intended use 
and require clinical evidence and extensive analytical testing. 
Class 3 tests, most of which go through the premarket approval 
or PMA process, require the greatest amount of analytical and 
clinical data as well as manufacturing information.
    Over the past year, I have had the opportunity to 
collaborate with colleagues from the diagnostic industry, 
clinical laboratories, and academic institutions to gain 
consensus on a diagnostic regulatory construct that advances 
innovation, protects patients, provides a predictable and 
timely path to market, and ensures reasonable risk-based 
regulation. New insight from genomics and engineering fields 
has led to important advances in diagnostic test development.
    Determining the appropriate regulatory oversight for 
cutting-edge diagnostic tests, whether they are produced by BD 
or another manufacturer or in a clinical laboratory, is 
critical for the future of medicine. While certain issues 
remain and additional stakeholder input is needed, our efforts 
have gone considerably farther than prior attempts at bridging 
differences between the manufacturing and the lab communities. 
Stakeholders, including BD, are beginning to coalesce around 
the following seven key principles of a comprehensive 
regulatory reform proposal, and I'll list those principles now.

    (1) A new regulatory framework must protect patients and 
ensure timely access to innovative diagnostic tests.
    (2) The framework needs to apply the same regulatory 
requirements for the same tests regardless of the entity type.
    (3) Regulatory standards should be focused on test accuracy 
and reliability through evidence of analytical and clinical 
validity.
    (4) The level of oversight should be based on the level of 
risk to patients and the public health.
    (5) There needs to be a clear jurisdiction between FDA, 
CMMS, and the States.
    (6) Improved transparency and predictability regarding 
approval requirements is needed.
    (7) Expedited pathways should be created for tests serving 
unmet needs.

    In conclusion, we offer these principles as a roadmap to 
help guide the committee's important work on diagnostic 
regulatory reform. While challenges remain, I firmly believe we 
can finally accomplish the mission of ensuring patients are 
getting accurate and reliable tests while still benefiting from 
the latest in innovative diagnostic technologies.
    I greatly appreciate your commitment to public health, and 
I look forward to answering your questions.
    [The prepared statement of Mr. Spring follows:]

                   Prepared Statement of Brad Spring

                                summary
    I appreciate the opportunity to appear before the committee to 
discuss ``Laboratory Testing in the Era of Precision Medicine'' on 
behalf of BD. BD is a U.S. based global medical technology company that 
is advancing the world of health by improving medical discovery, 
diagnosis of disease and the delivery of care. The company is a leader 
in patient and healthcare worker safety and technologies that enable 
medical research and clinical laboratory practices. We work in close 
collaboration with customers and partners to help enhance outcomes, 
lower healthcare delivery costs, increase efficiencies, improve 
healthcare safety and expand access to health.
    Over the past year, I have had the opportunity to collaborate with 
colleagues from industry, labs, and academic institutions to gain 
consensus on a diagnostic regulatory construct that advances 
innovation, protects patients, provides a predictable and timely path 
to market, and ensures reasonable risk-based regulation.
    In my testimony today I will discuss the following:

     The current regulatory process for diagnostic tests and 
BD's experience with the process.
     The need for regulatory reform focused on improving 
patient care and accelerating clinician access to new tests.
     Seven key principles of a comprehensive regulatory reform 
proposal, which are as follows:

        1. A regulatory framework that protects patients and ensures 
        access to innovative diagnostic tests.
        2. An approach that applies regulatory principles regardless of 
        entity type.
        3. Regulatory standards are focused on test accuracy and 
        reliability through analytical and clinical validity.
        4. The level of oversight is based on level of risk to 
        patients.
        5. There is clear jurisdiction between FDA, CMS and States.
        6. Improved transparency and predictability regarding approval 
        requirements.
        7. Expedited pathways for tests serving unmet needs.
                                 ______
                                 
                              introduction
    Chairman Alexander, Ranking Member Murray and members of the 
committee, I am Brad Spring, vice president of Regulatory Affairs and 
Compliance for BD Life Sciences based in Sparks, MD. I am honored to 
have the opportunity to participate in today's panel on behalf of BD.
    BD is a U.S. based global medical technology company that is 
advancing the world of health by improving medical discovery, diagnosis 
of disease and the delivery of care. The company is a leader in patient 
and healthcare worker safety and technologies that enable medical 
research and clinical laboratory practices. We work in close 
collaboration with customers and partners to help enhance outcomes, 
lower healthcare delivery costs, increase efficiencies, improve 
healthcare safety and expand access to health.
    Scientific advances arising from the Nation's investment in 
biomedical research enable the development of new diagnostic tests that 
can prevent disease or detect it early when treatment is often more 
effective and less costly. Diagnostic tests play an important role in 
the diagnosis of disease, genetic disorders, infection or other 
conditions. Depending upon the type of test, it may be performed in a 
clinical laboratory, a healthcare professional setting such as a 
doctor's office or a hospital bedside, or at home.
    The issue of how to best regulate diagnostic tests to ensure the 
public's health while allowing for innovation and rapid access to these 
tests has been debated for many years. BD is grateful to the committee 
for taking the time to study this issue carefully, including holding 
today's hearing. During my remarks, I hope to shed light on the 
regulatory process under which BD currently brings tests to market and 
to share a set of principles that could help to guide future reforms.
            current regulatory process for diagnostic tests
    Currently, the Federal Food, Drug and Cosmetics Act directs the 
Food and Drug Administration (FDA) to regulate diagnostic tests 
developed by manufacturers, like BD. For a diagnostic test to receive 
FDA clearance or approval, manufacturers are required to provide data 
demonstrating how accurately and precisely a test measures an analyte 
and how well it works in leading to a correct diagnosis.
    There is also a second route to market for diagnostic tests that 
are developed by clinical laboratories. The Centers for Medicare and 
Medicaid Services (CMS) provides oversight over laboratory developed 
tests (LDTs). CMS has authority to regulate laboratory operations 
through the Clinical Laboratory Improvement Amendments of 1988 (CLIA). 
Under CLIA, CMS seeks to ensure reliable test results by focusing on 
the quality of the laboratory procedures and competency of personnel.
                        manufacturer experience
    Diagnostic tests developed by BD and other manufacturers are 
reviewed and either cleared or approved by the FDA before they can be 
provided to clinical labs, physician offices or directly to patients. 
The FDA regulates these tests as medical devices based on the level of 
risk to patients and public health posed by their intended use.
    Class I tests are the lowest risk and exempt from pre-market 
review, but these tests are still subject to good manufacturing 
practices and other controls. Class II tests pose higher risks and 
require prospective clinical data and extensive analytical testing. 
Class III tests, most of which go through the premarket approval (PMA) 
process, require the greatest amount of clinical data and manufacturing 
information as part of a submission to the FDA.
  regulatory reform is needed to improve patient care and accelerate 
                     clinician access to new tests
    New insights from genomics and engineering fields such as optics 
and fluid dynamics have led to important advances in diagnostic test 
development. Determining the appropriate regulatory oversight for 
cutting edge diagnostic tests, whether they are produced by BD or 
another manufacturer or in a clinical laboratory, is critical for the 
future of medicine.
    Over the past year, I have had the opportunity to collaborate with 
colleagues from the diagnostic industry, clinical laboratories, and 
academic institutions to gain consensus on a diagnostic regulatory 
construct that advances innovation, protects patients, provides a 
predictable and timely path to market, and ensures reasonable risk-
based regulation.
    While unresolved issues certainly remain and additional stakeholder 
input is needed, our efforts have gone considerably farther than prior 
attempts at bridging differences between the manufacturing and lab 
communities. Stakeholders, including BD, are beginning to coalescence 
around the following seven key principles of a comprehensive regulatory 
reform proposal:

    1. A new regulatory framework must protect patients and ensure 
access to innovative diagnostic tests.
    2. The framework needs to apply regulatory principles regardless of 
entity type.

    The current structure, under which regulatory requirements are tied 
to the type of entity (i.e., a manufacturer or a laboratory), results 
in different standards for accuracy and reliability for the same test 
and other discrepancies between the types of oversight.
    In an approach that applies regulatory principles regardless of 
entity type, diagnostic tests would be regulated the same way 
regardless of whether they are developed by a manufacturer or a lab. 
This would allow for clear, consistent lines of jurisdiction. As noted 
earlier, clinical laboratories are regulated by CMS through CLIA while 
manufacturers are regulated under FDA but the agencies regulate 
different aspects of the diagnostic test process.
    3. Regulatory standards should be focused on test accuracy and 
reliability through analytical and clinical validity.
    Any regulatory standard for a diagnostic test should focus on 
analytical and clinical validity to ensure that clinicians and patients 
are getting the most accurate result to make critical health care 
decisions.
    Analytical validity considers the ability of the tests to identify 
measure or analyze one or more analytes, biomarkers, or substances.
    Clinical validity evaluates the reliability and accuracy with which 
a test in a specific population identifies, measures, predicts, 
monitors, and/or assists in selecting treatment for a disease or 
condition, or characteristics related to an individual's clinical 
status.
    4. The level of oversight should be based on level of risk to 
patients.
    The higher the risk, the more evidence would be required to be 
reviewed and approved by FDA. All tests would be classified as high-
risk, moderate-risk, or low-risk tests. The premarket, quality, and 
post-market requirements will vary by risk class.
    High Risk: a clinically significant inaccurate result for the 
intended use would cause serious or irreversible harm, or death, to the 
patient or public based on failure to treat, incorrect treatment, 
invasive procedures, or prolonged disability if such inaccurate result 
were undetected when used as intended in medical practice.
    Moderate risk: a clinically significant inaccurate result for the 
intended use would cause non-life-threatening injury, injury that is 
medically reversible, or delay in necessary treatment if such 
inaccurate result were undetected when used as intended in medical 
practice.
    Low Risk: a clinically significant inaccurate result for the 
intended use would cause minimal or no harm, immediately reversible 
harm, or no disability if such inaccurate result were undetected when 
used as intended in medical practice.
    There are other mitigating factors in risk classification. Among 
these are whether the technology and clinical use is well-characterized 
and whether there are other tests (confirmatory or adjunctive) used in 
the diagnosis.
    5. There needs to be clear jurisdiction between FDA, CMS and 
States.
    The following table illustrates a proposed jurisdiction of process 
activities by agency and level of government:

 
------------------------------------------------------------------------
 
------------------------------------------------------------------------
Test Development................  Design,             FDA
                                   Development,
                                   Validation,
                                   Preparation of
                                   Reagents,
                                   Platform
                                   manufacturing.
Laboratory Operations...........  Reagent             CMS
                                   Preparation, Run
                                   tests, Report
                                   results.
Medical application.............  Practice of         States
                                   medicine
                                   (interpret and
                                   consult on
                                   results).
------------------------------------------------------------------------

    6. Improved transparency and predictability regarding approval 
requirements is needed.
    7. Expedited pathways should be created for tests serving unmet 
needs.
                               conclusion
    We offer these principles as a road map to help guide the 
committee's important work on diagnostic regulatory reform. While 
challenges remain, I firmly believe we can finally accomplish the 
mission of ensuring patients are getting accurate and reliable tests 
while still benefiting from the latest in innovative diagnostic 
technologies. I greatly appreciate your commitment to public health and 
look forward to answering your questions.

    The Chairman. Thank you, Mr. Spring.
    Dr. Allen.

 STATEMENT OF JEFF ALLEN, PH.D., PRESIDENT AND CEO, FRIENDS OF 
                CANCER RESEARCH, WASHINGTON, DC

    Mr. Allen. Chairman Alexander, Ranking Member Murray, and 
members of the committee, I'm Jeff Allen, President and CEO of 
Friends of Cancer Research. It's an honor to testify before you 
today and provide the perspective of my organization on behalf 
of patients as you continue this committee's effort to examine 
how laboratory testing can best support the future of medicine 
and patient care.
    The therapies patients have access to today to treat many 
different diseases are far more effective but are also more 
complex than their predecessors. Adding to this complexity is 
the increased reliance on molecular tests to provide optimal 
medical care. The development of new drugs that are targeted 
toward specific alterations has resulted in numerous compelling 
examples of more effective treatments. In fact, nearly two-
thirds of the drugs that have received a Breakthrough Therapy 
Designation have a biomarker associated with their research 
program.
    Given the role that medical tests play in determining 
patient care, it's imperative that the accuracy of these tests 
be well characterized. The ramification of inaccuracy can be 
quite significant. An inaccurate test could result in a patient 
not receiving the most appropriate treatment or expose them to 
a potentially harmful one.
    When a patient is told that they have cancer or any other 
debilitating disease, they are flooded with confusion, fear, 
anger, and the thought oftentimes of losing the life of a loved 
one or their own. While their journey will undoubtedly include 
periods of confusion and uncertainty, they shouldn't be left to 
wonder if the results of a test which their physician used to 
decide their course of treatment was right or not.
    Molecular tests may, indeed, be the key to precision 
medicine. I and millions of people across this country hope 
that the work of this committee will be a catalyst to 
accelerating getting the right medicines to the right patients 
at the right time. In order to achieve this goal, the approach 
to regulating these tests needs to be realigned. Tests 
manufactured and sold as diagnostic kits undergo premarket 
review by the FDA. Conversely, those made and performed within 
a single laboratory, or LDTs, have historically not had FDA 
premarket review.
    The laboratories that perform LDTs are subject to oversight 
established by CLIA, but this assessment focuses on laboratory 
processes and personnel, not on analytical and clinical 
validity to determine if the test actually performs as claimed. 
The presence of two separate regulatory processes and 
incongruent requirements has resulted in a system where certain 
tests with known high quality that ought to be trusted exist 
alongside a vast array of tests that remain relatively 
uncharacterized. This is not the reliable path to precision 
medicine.
    Today, due to great advancements in science and technology, 
clinical laboratories and commercial manufacturers are 
developing molecular tests that may have the same use. In a 
recent study that we published with the Deerfield Policy 
Institute, we audited hundreds of medical records from across 
the country to explore the use trends of molecular tests that 
assess two critical alterations in lung cancer known as ALK and 
EGFR. The results of this audit showed that 49 percent of 
patients tested for ALK alterations and 87 percent for EGFR 
mutations where evaluated with an LDT, despite the availability 
of an FDA-approved assay.
    Given the large number of tests currently in use, there 
exists a potential for wide variability in test performance and 
claims. Any test that produces a result intended to be used to 
guide medical decisionmaking should be evaluated in its 
clinical context for risks that may be incurred. For patients, 
consumers, and healthcare providers, it's the result of the 
test that's important, not where it's manufactured.
    Without a uniform regulatory approach for molecular tests, 
variability is likely to be exacerbated by rapidly advancing 
technology. This is further complicated by the fact that the 
traditional approach of developing a single drug with an 
individual test is becoming obsolete. Next-generation 
sequencing and other genomic platforms can analyze hundreds of 
genetic markers from the same sample and are being developed by 
different institutions around the country. Steps should be 
taken to understand variability and improve consistency.
    As members of this committee decide how best to address the 
regulation of molecular tests, I believe that we can find 
common ground. First, the primary basis for regulating 
molecular tests should be what medical decision the test is 
used to inform. Tests that are used to guide medical 
decisionmaking, LDT or diagnostic, ought to be subject to the 
same regulatory oversight and requirements.
    Second, the FDA should work with the laboratory and 
diagnostic industry to standardize techniques to characterize 
variability between tests. And, third, advanced genomic 
screening may require a regulatory framework of its own, taking 
into consideration the rapid pace of technological advancement, 
in ensuring that patients have access to high-quality, reliable 
testing. The future of precision medicine in the health and 
lives of patients depends on the accuracy of these tests.
    Thank you, and I look forward to your questions.
    [The prepared statement of Mr. Allen follows:]

                Prepared Statement of Jeff Allen, Ph.D.

                                summary
    The therapies patients have access to today to treat many different 
diseases are far more effective, but also more complex than their 
predecessors. Adding to this complexity, and the more exacting nature 
of science today, is the increased reliance on molecular tests for 
providing optimal medical care. Molecularly defining diseases and 
developing new drugs that are targeted toward specific alterations has 
resulted in numerous compelling examples of new and more effective 
treatments for previously untreatable conditions. This provides the 
motivation and rationale for researchers to pursue new potential drug 
targets, and great hope for patients waiting for potential cures.
    It's not unusual for a variety tests to be used by healthcare 
providers to help identify elevated risks, diagnose certain conditions, 
inform the best treatment option, or even measure if a treatment is 
working. In some cases, entire treatment regimens are being prescribed 
based upon the results of such tests. Given the role that medical tests 
play in optimizing and determining patient care, it's imperative that 
these tests' performance and accuracy be well characterized before 
placing important treatment decisions on the results that they provide.
    The ramifications of uncertainty or inaccuracy can be quite 
significant. An inaccurate test could result in a patient not receiving 
the most appropriate treatment or expose them to an unnecessary or 
potentially harmful treatment.
    Regulatory oversight of tests has been inconsistent, and puts 
patients at considerable risk as tests evolve and become more complex. 
Tests manufactured and sold as ``diagnostic kits'' undergo premarket 
review by the Food and Drug Administration (FDA). Conversely, those 
made and performed within a single laboratory, called laboratory 
developed tests (LDTs), have not historically had FDA premarket review, 
as the Agency has generally exercised enforcement discretion. The 
laboratories that perform LDTs are subject to oversight established by 
the Clinical Laboratory Improvement Amendments (CLIA), but this 
assessment focuses on laboratory processes and personnel--not on 
premarket assessment of analytical and clinical validity to determine 
if they actually perform as claimed. The presence of two separate 
regulatory processes and incongruent requirements has resulted in a 
system where certain tests with known high quality, that ought to be 
trusted, exist alongside a vast array of tests that remain relatively 
uncharacterized. This is not the reliable path to precision medicine.
    Today, due to great advancements in science and technology clinical 
laboratories and commercial manufactures are developing molecular tests 
that may have the same use. In a recent study, we explored the use 
trends for molecular tests that assess two critical alterations in lung 
cancer, EGFR and ALK. It showed that 87 percent of patients tested for 
EGFR mutations and 49 percent for ALK alterations were evaluated with 
an LDT, despite the availability of an FDA approved assay. Given the 
large number of tests currently in use, some which have been subjected 
to pre-market review by FDA while others have not, there exists the 
potential for wide variability in test performance and claims. Any test 
that produces a result that is intended to be used to guide medical 
decisionmaking should be evaluated in its clinical context for risks 
that may be incurred. For patients, consumers, and healthcare providers 
it is the information provided by the test that is important, not the 
place it is manufactured or how it is distributed.
                                 ______
                                 
    Good morning, Chairman Alexander, Ranking Member Murray, and 
members of the committee. I am Dr. Jeff Allen, President & CEO of 
Friends of Cancer Research, an advocacy organization that drives 
collaboration among every healthcare sector to power advances in 
science, policy, and regulation that speed life-saving treatments to 
patients. I would like to thank all members and the staff of this 
committee for putting together this important hearing. It is an honor 
to testify before you today and provide the perspective of my 
organization, and on behalf of patients, as you continue this 
committee's efforts to examine how laboratory testing can best support 
the future of medicine and patient care.
    Advancements in basic science have never been more profound. The 
remarkable advancements being made at the National Institutes of Health 
(NIH), at medical and academic centers all across the country and 
within private sector industry are rapidly changing how we look at 
disease, and are in some cases leading to new and markedly improved 
treatments for patients. Exciting new initiatives like the President's 
Personalized Medicine Initiative (PMI) and the Vice President's Cancer 
Moonshot are important opportunities to continue along this promising 
trajectory and build on the remarkable progress to date.
    The therapies patients have access to today to treat many different 
diseases are far more effective, but also more complex than their 
predecessors. Adding to this complexity, and the more exacting nature 
of science today, is the increased reliance on molecular tests for 
providing optimal medical care. It's not unusual for a variety of tests 
to be used by healthcare providers to help identify elevated risks, 
diagnose certain conditions, inform the best treatment option, or even 
measure if a treatment is working. In some cases, entire treatment 
regimens are being prescribed based upon the results of such tests.
    Given the role that medical tests play in optimizing and 
determining patient care, it's imperative that these tests' performance 
and accuracy be well characterized before placing important treatment 
decisions on the results that they provide. The ramifications of 
uncertainty or inaccuracy can be quite significant. An inaccurate test 
could result in a patient not receiving the most appropriate treatment 
or expose them to an unnecessary or potentially harmful treatment. A 
recent report from the National Academies concluded that diagnostic 
errors, including some from molecular tests, account for 6-17 percent 
adverse events in hospitals, and played a role in 10 percent of patient 
deaths.\1\ I don't raise these statistics to be alarmist, to suggest 
that medical tests are not vital to the future of patient health, or to 
ignore that there are currently numerous, highly beneficial tests that 
facilitate the use of life-saving treatments. But as this field rapidly 
moves forward and becomes more complex, it is important to create 
policies that can help patients and medical professionals be confident 
in the results that a test provides.
---------------------------------------------------------------------------
    \1\ Balogh, EP et al. Improving Diagnosis in Healthcare. Committee 
on Diagnostic Error in Health Care; Board on Health Care Services; 
Institute of Medicine; The National Academies of Sciences, Engineering, 
and Medicine. 2015.
---------------------------------------------------------------------------
    When a patient is told that they have cancer, or any other 
debilitating disease, they are flooded with confusion, fear, anger, and 
the thought, often times, of losing the life of a loved one, or their 
own.
    While their journey will undoubtedly include periods of confusion 
and uncertainty, they shouldn't be left to wonder if the results of a 
test, which their physician used to decide the course of their 
treatment, was right or not. Molecular tests may indeed be the key to 
precision medicine. I, and millions of people across this country, hope 
that the work of this committee will be a catalyst to accelerate 
getting the right medicines to the right patients at the right time.
           scientific progress facilitated by molecular tests
    Past scientific and technological advancements have helped to 
demonstrate the potential promise of precision medicine in oncology. 
For example, decades ago many hematologic malignancies were classified 
as either simply leukemia or lymphoma. At that time the 5-year survival 
rate for patients diagnosed with those diseases was in the single 
digits. Through the advancement of microscopy techniques, researchers 
and physicians are now able to identify different cells and unique 
characteristics of cells that contribute to their abnormal growth and 
reclassify specific diseases. Today, there are nearly one hundred 
different histologically defined leukemia and lymphomas. This ability 
to identify different subsets of diseases allowed for treatments to be 
developed that were in some cases more tailored toward those specific 
cells and were more effective in the subgroup. Today, the number of 
patients that are still alive 5 years after their highly specified 
diagnosis is greater than 70 percent.\2\
---------------------------------------------------------------------------
    \2\ Allison, M. Is Personalized Medicine Finally Arriving? Nature 
Biotech. Vol. 26 N. 5; May 2008.
---------------------------------------------------------------------------
    While the technology is more complex, today a similar phenomenon is 
occurring based on the improved ability to identify molecular 
alterations and in some cases to develop treatments to target them 
accordingly. Many cancers and other diseases that had previously been 
grouped together are now being characterized based on the presence or 
absence of different molecular indicators, or biomarkers. The 
identification of certain biomarkers may indicate elevated risk for 
developing a disease, the presence of a disease, or the likelihood (or 
not) of responding to a treatment. In most cases, the assessment of a 
biomarker requires the use of a molecular test. As more and more 
reliance is placed upon molecular tests, both in research and routine 
clinical care, the importance of their accuracy cannot be understated.
            molecular tests are changing the approach to r&d
    The rapid evolution of precision medicine through the 
identification of biomarkers and the increased utilization of molecular 
testing has brought a paradigm shift to the biomedical research 
enterprise. Molecularly defining diseases and developing new drugs that 
are targeted toward specific alterations has resulted in numerous 
compelling examples of new and more effective treatments for previously 
untreatable conditions.
    Products such as imatinib for patients with Ph+ chronic myelogenous 
leukemia, trastuzumab for treating patients with HER2+ breast cancer, 
and crizotinib or other inhibitors toward ALK-translocated non-small 
cell lung cancer are all examples of targeted therapies that have 
transformed different types of cancers. This provides the motivation 
and rationale for researchers to pursue new potential drug targets, and 
great hope for patients waiting for potential cures. In a relatively 
short period of time, the movement toward precision medicine has 
resulted in the rapid expansion of a high-quality diagnostic testing 
industry, impacted care delivery practices in terms to tests that are 
provided to patients, changed patients' awareness of their health data, 
are affecting economic models for payment for medical services, and 
significantly shifted both the opportunities and challenges associated 
with developing and regulating new medicines.
    It has been estimated that 87 percent of the oncology research 
pipeline is devoted to targeted therapies, of which a large proportion 
are used with a biomarker test.\3\ Among some of the most potentially 
transformative new therapies--those that have received FDA Breakthrough 
Therapy Designation--64 percent have a biomarker associated with their 
research program.\4\ Among some of the most transformative therapies in 
recent years--those that have been approved after being designated as a 
Breakthrough Therapy--38 percent have biomarker selection criteria as 
part of their indication.\5\
---------------------------------------------------------------------------
    \3\ IMS HealthGlobal Oncology Trend Report 2015: https://
www.imshealth.com/files/web/IMSHpercent20Institute/Reports/
Global_Oncology_Trend_Report_2015_2020/IMSH_The
_Oncology_Pipeline.pdf. Accessed 9/14/16.
    \4\ Brookings Center for Health Policy--Breakthrough Therapy 
Designation: Exploring the Qualifying Criteria 4/24/15: https://
www.brookings.edu/wp-content/uploads/2015/03/Breakthrough-therapy-
slide-deck.pdf. Accessed 9/14/16.
    \5\ Breakthrough Therapy Designations: http://www.focr.org/
breakthrough-therapies. Accessed 9/14/16.
---------------------------------------------------------------------------
    While the shift toward a more personalized approach to medical 
research and care has been enabled by molecular diagnostics, it has 
also presented challenges that require modifications to traditional 
R&D. For example, by identifying molecularly defined subsets of 
disease, it is hoped that tailoring treatment to these subsets rather 
than the broader disease will result in the reduction of non-responders 
to treatment. However, due to the increasing number of disease subsets 
that have been identified, many of which represent less than 5 percent 
of patients with a particular cancer, this significantly reduces the 
number of patients who are eligible to receive a targeted therapy. When 
a molecular subset of a disease is a small fraction of the total number 
of patients, it requires broad screening to identify the patients for 
existing targeted treatments and novel approaches to study new drugs in 
those settings.
    To begin to address this issue directly, drawing on advances in 
molecular testing that enable researchers to identify clinically 
meaningful alterations in dozens of genes, Friends of Cancer Research 
is currently working with a large, diverse set of partners from 
academia, industry, government and advocacy to develop a modern day, 
innovative precision medicine clinical trial. In this project, called 
Lung-MAP, a ``master protocol'' governs how multiple drugs, from 
multiple companies, each targeting a different biomarker, are tested as 
potential treatments for lung cancer. Each arm of the study tests a 
different therapy that has been determined to target a unique genetic 
alteration. Lung-MAP utilizes cutting-edge screening technology to help 
identify which patient may better match each arm. This trial is 
creating a rapidly evolving infrastructure that can simultaneously 
examine the safety and efficacy of multiple new drugs.\6\ Lung-MAP 
provides a model for future research designs that can efficiently 
incorporate cutting-edge molecular testing and facilitate clinical 
trials that support the future of personalized medicine. This approach 
will have the ability to improve enrollment, enhance consistency, 
increase efficiency, reduce costs, and most importantly improve 
patients' lives.
---------------------------------------------------------------------------
    \6\ Herbst, RS, et al. Lung Master Protocol (Lung-MAP)-A Biomarker-
Driven Protocol for Accelerating Development of Therapies for Squamous 
Cell Lung Cancer: SWOG S1400. Clin Cancer Res. 2015 Apr 1;21(7):1514-
24. doi: 10.1158/1078-0432.CCR-13-3473. Epub 2015 Feb 13.
---------------------------------------------------------------------------
                 current regulation of molecular tests
    In the case of new therapies, the Food & Drug Administration (FDA) 
is responsible for regulatory oversight of new drugs and to approve 
them before they enter the market. For molecular tests, however, the 
regulatory paradigm is more complex. Two broad categories of tests--
those manufactured and sold as ``diagnostic kits'' by companies and 
those made and performed within a single laboratory, often called 
laboratory developed tests (LDTs)--have historically been treated 
differently by regulatory authorities. Since the 1970s, the FDA has 
provided regulatory oversight for kits that are manufactured and sold 
by companies to health professionals. Conversely, the Agency has 
exercised enforcement discretion in requiring premarket review for 
LDTs. For much of the period of FDA's enforcement discretion, LDTs were 
typically manufactured in small volumes and used by laboratories housed 
within the same institution where patients were treated. They were 
largely intended for rare diseases and were a lot less prevalent in the 
healthcare system.
    Laboratories themselves are subject to CMS regulation under the 
Clinical Laboratory Improvement Amendments (CLIA).\7\ The FDA approval 
process is designed to ensure that individual tests are properly 
designed and validated so that they are accurate, reliable, and 
clinically valid, before they are used in clinical practice whereas 
CLIA is designed to assure that tests are properly performed, largely 
through the oversight of laboratory personnel and procedures. Although 
both rigorous in their oversight processes, FDA and CLIA regulations 
serve very different purposes and so have different sets of regulatory 
requirements addressing different aspects of the quality of tests.
---------------------------------------------------------------------------
    \7\ Weiss RL. The Long and Winding Regulatory Road for Laboratory-
Developed Tests. Am J Clin Pathol. 2012; 138: 20-6.
---------------------------------------------------------------------------
    When this division of responsibility was set up, the methodologies 
and intended use of the data generated by tests regulated by FDA and 
those under CLIA was different.\8\ More recently, with the expansion of 
molecular testing and increased technical capabilities, the breadth of 
analytes and biomarkers for which there are LDTs and manufactured kits 
continues to grow. The intended use of the information generated from 
different tests has also evolved. Any test that produces a result that 
is intended to be used to guide medical decisionmaking should be 
evaluated in its clinical context for risks that may be incurred. For 
patients, consumers, and healthcare providers it is the information 
provided by the test that is important, not the place it is 
manufactured or how it is distributed. The regulatory framework and 
standards used to ensure the safety and quality of tests should reflect 
this principle. It is important to acknowledge concerns that have been 
raised about the potential consequences of an increase in oversight of 
molecular testing. These concerns raise the possibility that small 
laboratories will not have the means to handle the administrative 
burden of complying with new regulations. However, it is worth noting 
that many molecular tests are not subject to a full FDA pre-market 
approval application (PMA) and instead go through the FDA de novo 
process, which provides significant flexibility. Moreover, patients and 
healthcare providers need to confidently rely on a tests' results, no 
matter the test's origin. The presence of two separate regulatory 
processes and incongruent requirements has resulted in a system where 
certain tests with known high quality, that ought to be trusted, exist 
alongside a vast array of tests that remain relatively uncharacterized. 
This is not the reliable path to precision medicine.
---------------------------------------------------------------------------
    \8\ US Food and Drug Administration. Draft Guidance for Industry, 
Food and Drug Administration Staff, and Clinical Laboratories: 
Framework for Regulatory Oversight of Laboratory Developed Tests 
(LDTs). October, 2014.
---------------------------------------------------------------------------
                     use trends of molecular tests
    An additional challenge encountered as use of molecular testing 
expands is the growing number of cases in which analytes being assessed 
by LDTs developed and performed in single labs may be identical to the 
analytes assessed with kits manufactured to be marketed. To better 
understand this current landscape, our research team, in conjunction 
with the Deerfield Policy Institute, conducted a study to examine 
trends in molecular testing of non-small cell lung cancer (NSCLC) 
patients with advanced-stage adenocarcinoma, with a focus on testing to 
detect EGFR mutations and ALK-rearrangements. Testing for these 
alterations is recommended by medical guidelines and both LDTs and FDA-
approved tests are available. The study was just published yesterday 
and provides several key findings. Overall rates of testing of patients 
with advanced non-small cell lung cancer (NSCLC) were high: 95 percent 
(550 of 579) of patients were tested for EGFR, and 84 percent (489 of 
579) were tested for ALK. Our study also showed that large number of 
patients who underwent molecular testing were tested with a non-FDA 
approved test. Specifically, 87 percent (369 of 424) for EGFR and 49 
percent (195 of 399) for ALK were tested with an LDT, despite the 
availability FDA approved assays for those alterations.
    While our study was not intended to assess any differences between 
FDA-approved tests and LDTs that are used to detect EGFR or ALK 
alterations, it does reveal a high prevalence of use of tests that have 
not been subject of FDA review. There are pros and cons to the 
widespread use of LDTs. On the one hand, LDTs may offer rapid technical 
advances and facilitate innovation in molecular testing, and have been 
demonstrated in some cases to offer advantages beyond existing FDA 
regulated alternatives.\9\ \10\ On the other hand, concerns exist that 
LDTs are not currently subjected to pre-market review by the FDA and 
thus are not required to meet the same evidentiary standards as FDA 
regulated tests. Additionally, LDTs have in at least some instances 
been reported to perform poorly, as noted in a report of case studies 
released by the FDA. \11\ The FDA's most recent safety communication 
warning against use of ovarian cancer screening tests is one more case 
where FDA premarket review would have been critical to prevent women 
from being exposed to tests that simply do not perform as claimed. \12\ 
Given the large number of tests currently in use, some which have been 
subjected to pre-market review by FDA while others have not, there 
exists the potential for wide variability in test performance and 
claims, and the reality that some patients making major medical 
decisions based on inaccurate test results.\13\ \14\ \15\
---------------------------------------------------------------------------
    \9\ Association for Molecular Pathology: Facts FDA Ignored: An 
analysis of the FDA report, ``The Public Health Evidence for FDA 
Oversight of Laboratory Developed Tests: 20 Case Studies'' (2015). 
http://amp.org/emailads/documents/AMPResponseFDACaseReportFinal.pdf. 
Accessed 9/15/16.
    \10\ Evans J, Watson M. Genetic testing and FDA regulation: 
overregulation threatens the emergence of genomic medicine. JAMA. 2015; 
313: 669-70.
    \11\ US Food and Drug Administration: The Public Health Evidence 
for FDA Oversight of Laboratory Developed Tests: 20 Case Studies. 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/
UCM472777.pdf. Accessed 9/15/16.
    \12\ FDA Safety Communication: http://www.fda.gov/MedicalDevices/
Safety/AlertsandNotices/ucm519413.htm. Issued 9/7/15. Accessed 9/15/16.
    \13\ Conway P: Congressional Testimony before the Committee on 
Energy and Commerce, Subcommittee on Health U.S. House of 
Representatives. ``Examining the regulation of diagnostic tests and 
laboratory operations.'' Nov. 17, 2015.
    \14\ Yorczyk A, Robinson LS, Ross TS. Use of panel tests in place 
of single gene tests in the cancer genetics clinic. Clin Genet 2015; 
88: 278-82.
    \15\ Polley MY, Leung SC, McShane LM, et al: An International Ki67 
Reproducibility Study. J Natl Cancer Inst 2013; 105: 1897-906.
---------------------------------------------------------------------------
    Without a uniform regulatory approach for molecular tests, the 
potential for uncharacterized variability is likely to be exacerbated 
by rapidly advancing technology. This situation is further complicated 
by the fact that the traditional approach of developing a single drug 
with an individual test may be becoming obsolete. Testing many analytes 
simultaneously on a single platform is greatly preferred to testing one 
analyte at a time due to limitations in the quantity of patient tumor 
tissue available for testing and the potential for streamlining 
previously separate workflows. Indeed, next-generation sequencing (NGS) 
technology and other genomic analysis platforms that can analyze 
hundreds of genetic markers from the same sample are being developed 
and widely used at hospitals around the country. The information 
generated by NGS testing in clinical laboratories may be used to 
identify potential risk factors, prognostic information, or predictors 
of adverse reactions to drugs, all of which may contribute to a larger 
body of evidence used by physicians to manage patient care. These 
powerful NGS technologies are being developed and performed in clinical 
laboratories whose operations are subject to oversight and 
accreditation, but are not subject to FDA review, meaning that a 
thorough review of the accuracy and reliability of the test results is 
not performed.
    While NGS and other emerging technologies present transformational 
opportunities, steps should be identified to understand variability and 
improve consistency among different testing platforms. Several studies 
have shown that different platforms can frequently yield different 
results.\16\ \17\ Due to technological capabilities and expertise 
residing at clinical laboratories, numerous institutions are developing 
and utilizing their own genetic screening platforms. While this may 
present the opportunity to improve time and resource efficiencies, 
there currently is no requirement to assess inter-institutional 
variability of genetic platforms. Therefore, the results of tumor 
molecular analysis may differ from hospital to hospital. Without new 
approaches to oversight it will remain difficult to assess and optimize 
clinical outcomes. Therefore, appropriate standards and requirements 
should be identified and implemented to ensure that patients are being 
tested with high-quality, reliable tests regardless of where the test 
are performed.
---------------------------------------------------------------------------
    \16\ Boland, JF et al. Hum Genet 2013; 132: 1153-1163.
    \17\ Dickson, DJ, Pfeifer JD. Clin Pharmacol Ther 2016 Feb; 99(2): 
186-97. Epub 2016 Jan 12.
---------------------------------------------------------------------------
    FDA has taken steps to begin to work with stakeholders to identify 
new approaches and explore how data obtained from different genetic 
screening platforms may be able to be compared and potential variations 
between platforms be better understood. This effort is part of the 
Obama administration's Personalized Medicine Initiative and two draft 
guidance documents were recently made available for public comment.\18\ 
The agency plays a critical role in PMI; its flexible approach on NGS 
and work to convene all sectors of the community will support advancing 
the science so innovative new NGS tests come to market, and have 
accurate results for patients.
---------------------------------------------------------------------------
    \18\  FDA Draft Guidances Designed to Streamline Regulatory 
Oversight for Next-Generation Sequencing Tests: http://www.fda.gov/
ScienceResearch/SpecialTopics/PrecisionMedicine/ucm
510027.htm. Accessed 9/15/16.
---------------------------------------------------------------------------
                               conclusion
    As the members of this committee decide how best to address the 
regulation of molecular tests, I would like to lay out a few points 
that I believe are important to consider. First, the primary basis for 
regulations governing molecular testing should not be where a test is 
performed but rather what medical decisions the test is used to inform. 
Thus, tests that are used to guide the same medical decisionmaking 
ought to be subject to the same regulatory oversight and requirements 
no matter where they are developed or performed. Second, medical 
professionals need to be able to compare the strengths and weaknesses 
of tests that claim to measure the same analyte(s). Currently there is 
no means for them to complete this task. The FDA should work with the 
laboratory and diagnostics industry to standardize techniques to 
characterize variability between tests. Third, advanced genomic 
screening technologies may require a regulatory framework of their own, 
which takes into consideration the rapid pace of technological 
advancement and ensures that patients have access to high quality, 
reliable testing. The future of precision medicine and the health and 
lives of patients depends on the accuracy of these tests.
                                 ______
                                 
                    about friends of cancer research
    Friends of Cancer Research drives collaboration among partners from 
every healthcare sector to power advances in science, policy and 
regulation that speed life-saving treatments to patients. www.focr.org.
    For more information, please contact: Ryan Hohman, JD, Managing 
Director, Policy & Public Affairs, Friends of Cancer Research at 
[email protected] or 202.944.6708.

    The Chairman. Thank you, Dr. Allen.
    Dr. Kaul.

 STATEMENT OF KAREN L. KAUL, M.D., PH.D., CHAIR, DEPARTMENT OF 
  PATHOLOGY AND LABORATORY MEDICINE, DUCKWORTH FAMILY CHAIR, 
   NORTHSHORE UNIVERSITY HEALTHSYSTEM, CLINICAL PROFESSOR OF 
 PATHOLOGY, UNIVERSITY OF CHICAGO PRITZKER SCHOOL OF MEDICINE, 
                          EVANSTON, IL

    Dr. Kaul. Thank you, Chairman Alexander, Ranking Member 
Murray, and Senators. I very much appreciate the opportunity to 
participate in this morning's hearing on an important topic 
that is the focus of my life's work, pathology and laboratory 
medicine, and, specifically, how we support precision medicine.
    I'm a pathologist, a medical professional who provides 
results and consultation to other physicians, and I also 
oversee testing services that touch every patient in our 
healthcare system. I'll mention that the assays that we're 
talking about this morning are not performed in doctors' 
offices. We're not manufacturing kits, or manufacturing at all, 
but instead are optimizing procedures that we can use as part 
of our delivery of care to provide the best information to take 
care of patients. This is my practice of medicine.
    The regulatory oversight of testing must make these new 
tests available safely and expeditiously, and we need to 
carefully consider the roles of CLIA and the FDA, how they'll 
be optimized and how they will work together to support 
precision medicine. The FDA requires prospective clinical 
trials and review. I've served on an FDA panel and see the 
value in this. However, the investment required drives IVD test 
kit manufacturers to choose what to submit for approval. They 
must recover the cost in the market in the end, and the menu of 
FDA-approved test kits we have reflects this.
    We currently have two FDA-approved kits for BRAF mutations 
for melanoma, but nothing approved for the other tumors that 
require BRAF testing to optimize treatment--thyroid, brain, 
colorectal, and others. In order to serve those patients, we 
must treat the kit as a lab-developed test, repeat all of the 
validation as now is required under CLIA because we're using it 
for a non-FDA cleared purpose, even though this is a purpose 
recognized in national consensus treatment guidelines.
    Another example is the KRAS gene mutation which you've 
already heard about from Senator Alexander, which predicts 
response to targeted therapy. Laboratories banded together in 
order to respond a decade ago when it became clear that this 
was needed for optimal patient care, worked across the country 
to ensure that the results arriving in one test matched those 
in another, and put together an enormous effort to make sure 
this truly worked, all done under CLIA.
    As we have heard, the test kit finally did become 
available. But, unfortunately, by the time this was the case, 
new information indicated that KRAS testing alone was not 
enough, and the test kit was obsolete. These 6 years caused a 
great delay for patients and indicate that an inadvertent 
outcome of the FDA review process is to delay necessary testing 
to patients as well as to increase costs, because the kit, as 
it did become available, was severalfold more expensive than 
the procedures we had been using with great success for a 
decade.
    A similar story is that of chronic myelogenous leukemia, or 
CML, and the BCR-ABL translocation that is causative of the 
disease. Identification of this abnormality has been a valuable 
diagnostic tool in labs for decades. Many labs set this testing 
up around 1990. In fact, we were doing precision medicine even 
back then. Methods developed by the lab have been incorporated 
in clinical management to monitor patients for years.
    The first FDA-approved kit for BCR-ABL was just approved 
this past summer in 2016. It's not approved for diagnosis but 
only monitoring, and it doesn't cover all the chromosomal 
translocation breakpoints that we need. For those purposes, we 
need to continue to use lab-developed tests, all performed 
under CLIA.
    DNA-based testing has also saved thousands of lives through 
rapid diagnosis of infections. Testing for microbes using DNA 
can allow results in hours rather than days or weeks. An 
excellent example is HSV encephalitis, a life-threatening 
infection that can cause death within hours. Previous 
diagnostic methods include virus culture from cerebrospinal 
fluid, which was slow and often failed, or a brain biopsy.
    A landmark study in 1995 demonstrated that DNA detection 
provided superior results for patients, and, again, labs 
rallied together to set up assays, compare results, set 
standard protocols, proficiency testing--all the things that we 
do regularly under CLIA. And I'll add that CLIA does look at 
the results of our validation studies and does look at the 
performance of the lab, so it's an important part. It's not 
just the processes in the labs. At any rate, PCR became the 
standard of care.
    Twenty years later, an FDA-approved assay finally became 
available for HSV detection. So during those 20 years, should 
we have waited for the kit and not performed this testing? This 
would have required that many patients who did have the disease 
got treatment much later, too late to save their lives, and 
many patients who didn't have the disease would have stayed in 
the hospital on IV antiviral agents at great cost when they 
didn't need to be treated. We think this makes a big difference 
for patients.
    There are many examples of other infectious diseases for 
which molecular assays have had an enormous benefit for rapid 
detection as well as characterization of antimicrobial 
resistance genes, important now in the battle against 
superbugs, hospital-acquired infections, and new agents 
threatening our public health.
    The overarching goal for all of us is the safety and 
efficacy of our lab tests and procedures. Labs have a history 
of operating successfully under CLIA, and there's published 
data to support this. CLIA does need expansion and 
modernization, however. Goals for test performance can be 
defined by clinical groups prior tests being launched, and we 
do need an expanded review of data coming out of labs who are 
performing this testing.
    We also need very desperately appropriate reference 
materials for labs to demonstrate their quality before the 
testing is launched to the public. Labs that are not able to 
meet these quality goals, whether they choose to use a kit or 
an in-house procedure, should not be allowed to do the testing, 
period.
    Labs currently have the infrastructure to support an 
expanded CLIA program without expensive additional programs. 
But this is not so for FDA oversight. FDA has an important 
role, but only for those products that are truly IVD kits 
manufactured to work in an array of settings across the 
country.
    Thank you.
    [The prepared statement of Dr. Kaul follows:]

            Prepared Statement of Karen L. Kaul, M.D., Ph.D.

                                summary
    I am a pathologist, a medical professional who provides results, 
consultation and guidance to other physicians, and I oversee testing 
services and procedures that touch every patient in our health care 
system. Lab results constitute the majority of data in a patient's 
electronic medical record, and our procedures dictate the majority of 
downstream medical decisions for patients. We have a great 
responsibility to patients who deserve the most accurate and up-to-date 
information so that they receive the most appropriate, complete and 
efficient course of care. We owe this to our patients, and to our 
physician colleagues who care directly for them.
    We find ourselves in an interesting and exciting time with an 
explosion of knowledge and technology that can revolutionize patient 
care; this is the promise of precision medicine. We must bring this to 
the clinic with safety and accuracy, while also faced with demands to 
lower the cost of medical care in the U.S. We are talking today about 
the regulatory oversight of laboratory developed testing procedures 
(LDPs), the extent that medical practice should be regulated, and what 
models will balance the needed accuracy with ensuring new tests are 
made available to patients safely and expeditiously. Oversight provided 
by the Clinical Laboratory Improvement Amendments (CLIA) and the Food 
and Drug Administration (FDA) currently both exist in the lab, and 
appropriately so. We need to carefully consider their best roles and 
how they will affect testing to support and facilitate precision 
medicine. I will provide real examples of the impact of these two 
pathways for oversight:

    1. The FDA approval process is expensive, leading manufacturers to 
submit those assays for which they can recover cost afterward, to 
submit certain sample types but not others (leaving labs perform these 
off-label IVDs as LDPs under CLIA. Examples of BRAF and BCR-ABL testing 
are provided)
    2. The FDA approval process is slow, making many tests obsolete by 
the time they are offered (KRAS example) so that LDPs are still needed 
to provide the information needed for standard patient care.
    3. There are many examples of critical lab tests in cancer and 
infectious disease that have been performed with great benefit to 
patients as LDPs under CLIA for years to decades (BCR-ABL, HSV and many 
tests for infectious diseases, KRAS and other gene mutation tests). For 
a few of these, FDA-approved tested were developed much later, based on 
the body of knowledge and literature produced by the labs, and were 
ultimately more expensive to purchase and perform. Often, these tests 
do not fully serve the needs of the labs, physicians and patients.
    4. Next generation sequencing methods have replaced single gene 
tests in many labs as they provide needed data more efficiently and 
reliably, with the flexibility to incorporate new gene targets as 
needed. Performance standards have already been developed, along with 
lab inspection checklists and proficiency testing samples.
    5. CLIA modernization would be beneficial to expand its scope and 
include defined standards and reference materials for labs to use to 
demonstrate their performance and quality before offering a new 
clinical test.
    6. Getting a correct, complete and timely answer from the lab is 
the most important outcome for patient care.

    It is often thought that when ``lab tests'' are done to reach a 
diagnosis, they are done with a kit or on a machine, but in fact, most 
are done with the direct involvement of a laboratory professional or 
physician, with years of specialty training after medical school. We 
have had ACGME certified fellowships and board certification in 
Molecular Genetic Pathology for nearly 20 years. And what we do in the 
lab is generally not encompassed by a ``test kit,'' but starts with the 
pathologist examining the tissue section, or bone marrow aspirate, or 
gram stain, and determining what additional studies are needed to 
provide the complete package of information to the clinician so that 
patient can be treated appropriately. Some of these will be FDA cleared 
kits, and others will be LDPs performed under CLIA; both have their 
place. And when performed locally, these procedures can be integrated, 
interpreted as a whole, completed in a timely fashion, and used for 
training of the next generation of physicians, for whom we hope, 
maximal use of this genomic information will be a way of life as they 
treat human disease. That is the promise of personalized medicine!
                                 ______
                                 
    Chairman Alexander, Ranking Member Murray, and other members of the 
committee, thank you very much for the opportunity to participate in 
this morning's hearing on a very important topic that is the focus of 
my life's work: Pathology and laboratory medicine, and specifically how 
we support precision medicine.
    The field of pathology offers the opportunity to understand the 
science of disease, to lead innovation and quality efforts, and to have 
enormous impact on the lives of patients every day. I most often 
interact with ordering physicians, and I am your doctor's specialist: a 
medical professional whose testing services and procedures touch every 
patient in our health care system. Patients benefit from laboratory 
medicine throughout their life beginning with newborn screening. Lab 
results constitute the majority of data in a patient's electronic 
medical record, and our procedures dictate the majority of downstream 
medical decisions for patients. Medical professionals in clinical 
laboratories have a great responsibility to patients to provide the 
most accurate and fastest information so that they can have the most 
appropriate and most efficient course of care. We owe this to our 
patients, and to our treating physician colleagues who care directly 
for them.
    We find ourselves in an interesting and exciting time. The human 
genome has been sequenced and we are seeing an explosion of knowledge 
and technology that we can apply to patient care; this is the promise 
of precision medicine, and we need to continue to innovate and 
integrate it into the clinic. This has been most evident in oncology--
every cancer patient should have access to the testing needed to best 
guide their treatment, as early as possible in their treatment 
planning. As always, we must provide highest level of safety and 
accuracy. At the same time, we are faced with growing demands to lower 
the cost of medical care in the U.S.
    We are talking today about the regulatory oversight of laboratory 
developed testing procedures (LDPs), the extent that medical practice 
should be regulated, and what models will balance the needed accuracy 
with also ensuring new tests are made available to patients safely and 
expeditiously. Oversight provided by the Clinical Laboratory 
Improvement Amendments (CLIA) and the Food and Drug Administration 
(FDA) currently exist in the lab and are not mutually exclusive 
options, but we need to carefully consider their best roles and how 
they will affect testing to support and facilitate precision medicine.
    The FDA traditionally requires prospective clinical trial data and 
a lengthy review process--I have served on an FDA panel as an expert, 
and there is value in the process. However, the investment required 
drives in vitro diagnostic (IVD) test kit manufacturers to carefully 
choose what tests, what applications, and even what sample types to 
submit for FDA approval--a company will rarely go through this process 
unless the costs can be recovered at the end, and the cost of a 
prospective clinical trial will understandably influence the trial 
design and breadth. As a result, physicians in laboratory medicine have 
access to two FDA-approved IVDs for BRAF oncogene mutation testing, 
important in determining treatment, that that can be used for melanoma 
samples, but nothing approved for analysis of thyroid, glioma, 
colorectal or other cancers for which the BRAF gene mutation is needed. 
In order for us to serve our patients, we are required to turn the IVD 
into an LDP, since we are using it for a non-FDA-cleared purpose, and 
thus it will be regulated under CLIA. Alternatively, we could better 
utilize our limited resources by developing and validating a laboratory 
testing procedure capable for testing all sample types while providing 
high quality, accurate testing to our patients. In fact, labs are doing 
that through the implementation of gene panels analyzed by next 
generation sequencing.
    Lab testing done under CLIA has been extremely beneficial to 
patient care. An illustrative example is testing for the KRAS gene, 
known for several years to predict which patients with metastatic 
colorectal cancer will respond to targeted therapy. Testing has been 
standard for several years, since a landmark study was presented at the 
American Society of Clinical Oncology (ASCO) meeting in 2007.\1\ I 
clearly recall the deluge of requests we had from oncologists and 
patients following that meeting because the treatment, used for 
appropriate patients defined at the gene mutation level, made a 
difference in outcome. However, there were no clinical tests, no kits, 
nothing available at that time to test for mutated KRAS gene. In 
molecular pathology labs across the country, we had a great deal of 
experience detecting single mutations in human DNA and had been doing 
so for other genes and purposes for quite some time, all done under the 
quality standards as defined by CLIA. Labs across the country quickly 
shared information and protocols, debated at length as to the details 
of reliable assays, and shared samples and data to define the best 
approach and to ensure that test results done in one lab matched those 
done in another.\2\ Hours were spent on conference calls and at 
professional meetings debating and comparing details, and one might 
argue, examining a breadth of information not seen during the FDA 
review of a single manufacturer's assay. After a few months, several 
labs were able to offer fully validated KRAS assays that worked 
reliably and were safe for patient care. Under CLIA, the validation 
data collected by these labs was subject to ongoing peer review, and 
labs participate in ongoing proficiency testing to demonstrate assay 
quality.
    In less than a year, the profession was able to translate a 
meaningful and significant scientific discovery into a well validated 
clinical tool for oncologists. Yet, it took fully 6 more years for the 
first FDA-approved KRAS mutation kit to hit the market, at a cost 
severalfold higher than the LDP assays we had been using for several 
years. Unfortunately, by the time this FDA approved kit reached the 
market, new data demonstrated that KRAS analysis alone was not enough; 
mutation analysis of other RAS family genes was necessary, and the FDA-
approved assay was largely obsolete. Thus, an inadvertent outcome of 
the FDA review process is to delay or make necessary testing 
unavailable to patients, as well as to increase cost, neither of which 
are good for patient care. The tests that go through this process do 
not keep up with the standard of care as dictated by nationally 
accepted NCCN guidelines and are essentially frozen in time at the time 
of FDA approval.
    Another clear illustration of both the innovation occurring within 
the lab, and the significant benefit to patient care is the story of 
chronic myelogenous leukemia, or CML, and the Philadelphia chromosome 
causing the BCR-ABL gene translocation. The abnormal chromosome was 
first described and characterized in the 1960s, and the genes affected 
by the translocation were identified in the 1980s. Identification of 
this gene translocation at the molecular level gave hematopathologists 
a definitive tool to use when making a diagnosis of CML, and testing 
was set up in my lab around 1990. Truly, even then this was precision 
medicine! Over time, as targeted therapy (Gleevec) became available, we 
developed assays that could quantify the abnormal genes in blood, 
allowing the monitoring a patient's response to treatment and detection 
of early relapse, and this was included in the consensus guidelines for 
clinical management. This work was all done by hospital labs, molecular 
pathologists, hematopathologists and lab scientists, working together 
in every setting from their labs to national meetings to international 
consensus conferences. Reams of documentation, study data, comparisons 
and peer-reviewed literature have been published, transparency being 
important to all.\3\ \4\ Clearly, this work has had a major clinical 
impact, has been good for patients, and has served as a model for 
precision medicine in general! The first FDA approved kit for BCR/ABL 
became approved this past summer, 2016, and is ONLY approved for 
monitoring, not diagnosis, and does not include the entire spectrum of 
breakpoints. For initial diagnosis, we must continue to use the 
necessary in-house procedures, all performed as procedures under CLIA.
    The Clinical Laboratory Improvement Amendments (CLIA) provide for 
oversight of clinical laboratories, and defines extensively the details 
for laboratory operation, assay validation, reagent quality and 
testing, staff requirements and training, and much more in an effort to 
ensure that lab results are accurate, reproducible and reliable. The 
checklists and details are developed and reviewed via consensus of 
laboratory experts, and constitute hundreds of pages of requirements 
and data points. In the lab, we think about the patient everyday, and 
are well aware of the impact our work has on their lives. CLIA for us 
is a way of life, and we have built into our lab operations, mechanisms 
for data collection, training, proficiency testing and other processes 
to ensure our compliance with CLIA. We are subject to unannounced 
inspections, and must demonstrate satisfactory performance 
characteristics for any test that we offer in the lab to ensure that 
our results are accurate. For testing not reviewed by the FDA, we go 
through an even more rigorous validation process before offering the 
test for clinical use. CLIA works, and the outcome of published 
laboratory comparisons demonstrate the quality results achieved under 
CLIA regulations. However, the science of laboratory medicine has 
advanced dramatically in the almost three decades that CLIA was 
enacted, and it's time to modernize the CLIA regulations. Personally, I 
would like to see consensus goals for test performance--such details as 
what percent tumor cells should an assay be able to detect, what 
mutations should be included, and what sample types should be tested--
that would be defined by professional expert groups early in the 
process as labs begin to design an validate assays for a newly relevant 
gene. Labs would work toward these quality goals, and any lab not able 
to meet them should not offer the assay for clinical use. Ideally, we 
would also have available an appropriate set of reference materials for 
labs to demonstrate the ability of their assays to perform well--this 
is a major need and would be of great benefit, but will require 
funding. Currently a multidisciplinary pilot is being organized to test 
this strategy: the Tapestry pilot.\5\ In this model, labs would be 
allowed to utilize assays that best served the needs of their patients 
and needs of their labs, with the most important endpoint being getting 
the correct answer!
    In fact, this is how it works for most testing in the clinical 
laboratory--labs generally have a variety of assays to choose to 
implement, so they base that choice on clinical need and fit with the 
lab--it is not critical that labs all use the same assay or platform, 
provided that all are able to get the correct answer. Ongoing 
proficiency testing (the testing of unknown samples at intervals during 
the year, another use for reference materials) is used to demonstrate 
the ongoing quality in the lab.
    Now, however, most of our single gene and small gene panel assays 
for cancer are becoming obsolete. Thanks to testing that looks at a 
larger number of genetic mutations in tumors, an oncologist has an 
arsenal of information to help design a treatment plan specific to the 
complex nature of that patient's tumor. Many labs have implemented Next 
Generation Sequencing (NGS) which looks at larger panels of genes 
relevant in cancer, has a very high degree of sensitivity and 
reliability, and is less expensive than individual gene analysis 
approaches. Labs performing this testing onsite can maximize the 
benefit to patients by providing results rapidly and integrate the data 
and professional consultation into interdisciplinary treatment-planning 
conferences. Consensus laboratory guidelines, inspection checklists and 
proficiency materials have already become available to clinical 
laboratories, under CLIA. With proven proficiency in this method, labs 
will be able to respond quickly to clinical needs as new gene mutations 
are found to make a difference in patient care. In that model, the 
strength of the data supporting the clinical use of that gene will be 
the key challenge and target for medical professional consensus 
discussions.
    While most of the conversation regarding precision medicine focuses 
on cancer testing, it is equally important to highlight that DNA-based 
diagnostic testing has saved thousands to millions of lives through 
rapid diagnosis to determine appropriate treatment in infectious 
disease. Nearly all testing for viruses is done using DNA and RNA-based 
methods, for the simple reason that this allows labs to get more 
information, often much faster. Viruses grow slowly in laboratory 
culture, and may require weeks for a diagnosis, far too long for 
patient care. However, detection of the viral nucleic acid can be done 
in hours. An excellent example of this is Herpes Simplex virus. HSV can 
cause a life-threatening infection of the brain, and without rapid 
identification and treatment with IV antiviral agents, a patient could 
die within 48 hours. Older diagnostic options included viral culture 
from cerebrospinal fluid, which was slow and often grew no virus, or a 
very invasive brain biopsy. A sentinel study was published in 1995 
demonstrating that PCR technology could be used for HSV detection with 
superior results.\6\ Labs rallied to develop and validate assays, 
define needed detection limits, set up standard protocols and 
proficiency testing, all the usual things we do, and PCR quickly became 
the standard of care. Twenty years later an FDA approved assay finally 
became available--Should we have withheld testing during those years, 
waiting for an FDA approved test kit? Rapid and accurate diagnosis 
using an LDP validated and performed under CLIA allowed many patients 
who did not have HSV infections to go home, rather than remain in the 
hospital on IV drugs (a great cost savings!) and those who did have an 
infection were able to get the needed treatment started within hours. 
There are many other examples of microbes for which molecular assays 
have had an enormous benefit, both in terms of rapid detection as well 
as characterization of antimicrobial resistance genes, important in the 
battle against spread of superbugs and hospital-acquired infections.
    Labs are often faced with new infectious agents threatening our 
public health, as we currently are with Zika. While testing for these 
agents is often developed and performed under the auspices of the CDC 
and public health labs, hospital labs at academic centers and in the 
community are often on the front lines in these outbreaks. Programs 
coordinating broader access to testing would be greatly beneficial.\7\ 
\8\ Recall the H1N1 swine flu epidemic in 2009, for example--our 
emergency rooms were swamped, our State public health labs buried in 
samples they were unable to test, hospitals and physicians were trying 
to determine who to treat, who to isolate, who to hospitalize . . . We 
happened to have been studying Tamiflu resistance in seasonal influenza 
at the time using a lab developed procedure that detected flu A, and 
fortunately differentiated the swine flu type; as this test was 
validated under CLIA, we were able to use it to our patients' 
advantage.\9\ Whether confronted with another respiratory virus, or 
Ebola, or Zika, or something else, a more coordinated effort between 
the public health and hospital labs would be beneficial for all. We 
simply cannot be satisfied with the current situation with pregnant 
patients waiting weeks for viral test results!
    To close, the overarching goal for all of us is the efficacy and 
safety of our lab tests and procedures for patients. We are physicians 
and healthcare providers and our focus is on the patient at all times. 
Labs have a long history of success operating under CLIA, which allows 
a greater flexibility and faster responsiveness to new tests that are 
needed to improve patient care. This process would benefit from some 
expansion, particularly to define pre-launch consensus performance 
guidelines and provision of reference materials. Labs currently have 
the infrastructure to support even an expanded CLIA compliance program 
without extensive additional expense. FDA has an important role in the 
lab as well, but one limited to those products that are truly IVD test 
kits and instrumentation which are designed to work in multiple labs 
and settings across the country.
    It is often thought that when ``lab tests'' are done to reach a 
diagnosis, they are done with a kit or on a machine, but in fact, most 
are done with the direct involvement of a laboratory professional or 
physician such as myself. Anatomic and Clinical Pathology residency 
training is 4 years in length (after medical school) and our residents 
go on to do at least 1, and sometimes 2 or 3 year-long subspecialty 
fellowships. We have had ACGME certified fellowships and board 
certification in Molecular Genetic Pathology for nearly 20 years. We 
train to do this, just as surgeons train for 5 years to do surgery. And 
what we do in the lab is generally not encompassed by a ``test kit,'' 
but starts with the pathologist examining the tissue section, or bone 
marrow aspirate, or gram stain, and determining what additional tools 
are needed to provide the complete package of information to the 
clinician so that patient can be treated appropriated. Pathologists 
need the best and most up to date tools to do their jobs, and they are 
doing this for patients. Some of these will be FDA clears kits, and 
other will be lab procedures performed under CLIA; both have their 
place. As much as possible, these capabilities need to be onsite to 
insure that the results can be integrated, interpreted as a whole, 
completed in a timely fashion, and also for training of the next 
generation of physicians, for whom, we hope, maximal use of this 
genomic information will be a way of life as they treat human disease. 
That is the promise of personalized medicine!
                               references
    1. Di Fiore F, Le Pessot F, Lamy A, et al. KRAS mutation is highly 
predictive of cetuximab resistance in metastatic colorectal cancer. 
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proc.; Vol 25, 
No 18S (June 20 Supplement), 2007: 10502.
    2. Kamel-Reid S, Zhang T, Persons DL, et al. (Molecular Oncology 
Resource Committee of the College of American Pathologists) Validation 
of KRAS testing for anti-EGFR therapeutic decisions for patients with 
metastatic colorectal carcinoma. Arch Pathol Lab Med. 2012;136:26-32. 
doi:10.5858/arpa.2011-0220-OA. http://www.
ncbi.nlm.nih.gov/pubmed/22208484.
    3. Kantarjian HM, Talpaz M, Cortez J, et al. Quantitative 
polymerase chain reaction monitoring of BCR-ABL during therapy with 
imatinib mesylate (ST1571, Gleevec) in chronic phase chronic 
myelogenous leukemia. Clinical Cancer Research 2003; 9: 160-166. http:/
/clincancerres.aacrjournals.org/content/9/1/160.full-text.
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    4. Hughes TP, Branford S. Molecular monitoring or BCR-ABL as a 
guide to clinical management in chrominc myelogenous leukemia. Blood 
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    5. http://www.tapestrynetworks.com/initiatives/healthcare/onco-
logy-therapeutics
-and-diagnostics/diagnostic-quality-assurance-pilot.cfm.
    6. Lakeman FD, Whitely RJ, and the National Institute of Allergy 
and infectious Diseases Collaborative Antiviral Study Group. Diagnosis 
of Herpes Simplex Encephalitis: Application of Polymerase Chain 
reaction to Cerebrospinal Fluid from Brain-biopsied Patients and 
Correlation with Disease. Journal of Infectious Diseases, 1995:171:857-
63.
    7. Nowak J and Kaul KL. The role of community molecular diagnostics 
labs in the H1N1 Pandemic. Journal of Molecular Diagnostics 
2009;11:366-370. http://jmd.amjpathol.org/article/S1525-1578(10)60253-
X/pdf.
    8. Crawford JM, Stallone R, Zhang F, et al. Laboratory Surge 
Response to Pandemic (H1N1) 2009 Outbreak, New Your Metropolitan Area 
USA. Emerg. Infect. Dis. 2010. DOI 10.3201/eid1601.091167.
    9. Kaul KL, Mangold KA et al. Influenza A subtyping: Seasonal H1N1, 
H3N2, and the appearance of novel H1N1. Journal of Molecular 
Diagnostics 2010: 12:664-669. DOI: 10.2353/jmoldx.2010.090225.

    The Chairman. Thank you very much for the terrific and very 
helpful testimony. We'll now go to a series of--a round of 5-
minute questions.
    Dr. Klimstra, in my short 5 minutes, I'm going to 
acknowledge the incongruity of kits being regulated one way and 
laboratory tests being regulated another way. But I'm 
interested in the consequences to patients of what happens if 
we regulate laboratory-developed tests the way we regulate kits 
today. My information says there are about 60,000 laboratory-
developed tests in the country. Am I correct that the 2014 
guidance proposed by the FDA would require each one of those 
60,000 tests to be individually approved by the FDA?
    Dr. Klimstra. Thank you for the question. I believe the----
    The Chairman. Can you give me a yes or no?
    Dr. Klimstra. Maybe, unfortunately.
    [Laughter.]
    The Chairman. Most of the 60,000 tests?
    Dr. Klimstra. A large number of them, depending upon how--
--
    The Chairman. Tens of thousands of tests?
    Dr. Klimstra. Tens of thousands.
    The Chairman. Tens of thousands would have to be regulated 
by the FDA. Price Waterhouse did a study that showed that the 
cost of such FDA approval might be in the range of $30 million 
to $75 million for each test. Does that sound plausible to you?
    Dr. Klimstra. That sounds a little high to me, but I 
believe if you add all of the costs of the experiments together 
with the charges that would be incurred for undergoing the 
review, it will certainly be a substantial amount of money.
    The Chairman. At Sloan Kettering, you said that you have 
350 laboratory-developed tests.
    Dr. Klimstra. That's correct.
    The Chairman. You engage in a lot of what we call 
personalized medicine. Is that correct?
    Dr. Klimstra. Yes, it is.
    The Chairman. At Vanderbilt, the head of personalized 
medicine told me that 95 percent of their personalized medicine 
practice used their own laboratory-developed tests. Is that 
comparable to what you do?
    Dr. Klimstra. Yes, it is.
    The Chairman. What would happen if you had to submit each 
of the 350 laboratory-developed tests that you have to the 
current FDA approval practice?
    Dr. Klimstra. We would close the lab. There's no way that 
the institution could afford the cost associated with formal 
FDA review and approval of all of those tests. It would simply 
be economically impossible.
    The Chairman. Did you testify that one of those 350 tests 
had helped 12,000 cancer patients?
    Dr. Klimstra. That's correct.
    The Chairman. You are already regulated by CMS and the 
State of New York, you testified. If you were then to be also 
regulated by the FDA, that would be triple regulation, if I 
understand it correctly.
    Dr. Klimstra. That's right.
    The Chairman. Dr. Kaul, in your practice of personalized 
medicine, what percent of your institution's personalized 
medicine practice relies on your own laboratory-developed 
tests?
    Dr. Kaul. We're a somewhat smaller institution but also 
have a big investment in personalized medicine and have been 
developing tests for several decades. If there is an FDA-
approved assay that works well and is affordable and is not a 
test that we've already had in-house for several years, we 
certainly look at that very seriously. But in many situations 
where we have a test that appropriately covers the mutations 
needed, we'll stick with an in-house test. So the majority of 
our personalized medicine tests----
    The Chairman. Majority is the answer. Is that right?
    Dr. Kaul. Majority.
    The Chairman. The majority of your personalized medicine 
practice uses laboratory-developed tests.
    Dr. Kaul. Yes.
    The Chairman. You're at the University of Chicago. Is that 
correct?
    Dr. Kaul. Yes, an affiliate of the University of Chicago.
    The Chairman. An affiliate of the University of Chicago. 
What would happen to your laboratory if the FDA required you 
to--how many laboratory-developed tests do you have at your 
institution?
    Dr. Kaul. In personalized medicine, I would say we have 50 
or 60. But there are lab-developed tests across the lab in 
other areas, not just personalized medicine.
    The Chairman. More than 50 or more than 100?
    Dr. Kaul. Many more. Hundreds.
    The Chairman. Hundreds of tests. What would happen if the 
FDA required FDA approval in addition to CMS approval in your 
institution?
    Dr. Kaul. I think the regulatory and expense burden would 
be such that we wouldn't continue in personalized medicine, and 
I think it would have a big impact on the way that medical care 
is delivered today for testing in general.
    The Chairman. To be specific about that, what would the 
effect be on patients at your institution?
    Dr. Kaul. They would not get the care they need. And I 
believe this care, as much as possible, needs to be delivered 
onsite so that we can put together all of the information, 
deliver it at multidisciplinary tumor boards, discuss with the 
clinicians, and teach our residents and fellows. This would all 
go away.
    The Chairman. I'm sure questions will be directed to Mr. 
Spring and Dr. Allen. But just my observation is that we're in 
a rapidly changing world here, but it's been changing longer 
than for the last year or two. Laboratory-developed tests are 
well established, and it's clear that we have, in the case of 
Sloan Kettering, two areas of regulation already. It doesn't 
make much sense to me to solve the problem by slowing down the 
use of laboratory tests so they can be at the same slow pace of 
kits. I recognize that those may be two different kinds of 
regulation.
    But I think our goal is to speed up the development of safe 
and effective tests so that institutions may use them to help 
patients while the patients are still alive. I'm delighted that 
we're having this hearing and hope to learn from it.
    Senator Murray.
    Senator Murray. Thank you very much.
    As I mentioned in my opening statement, in a recent 
announcement, FDA stated that lab tests marketed as screening 
tools for ovarian cancer were not supported by definitive 
evidence and results from that unproven test may have led women 
to delay or forego treatment or undergo unnecessary treatment. 
As we move toward a greater emphasis now on precision medicine 
in our healthcare system, patients and their physicians are 
going to be relying on these types of tests more and more to 
guide their own treatment.
    Dr. Allen, I wanted to ask you: How do we know that claims 
made by labs about cancer screening tests or other tests are 
supported by strong scientific evidence?
    Mr. Allen. Unfortunately, particularly when they are for 
newly discovered markers, I don't think we do know what 
evidence is behind them if they don't go through the FDA 
process.
    Senator Murray. Dr. Klimstra, the tests that are offered by 
Memorial Sloan Kettering--they do have to be reviewed by New 
York State Department of Health if they're not reviewed by the 
FDA. So patients in New York can be assured that their test 
results are accurate and that results are clinically 
meaningful. But do patients in other States across the country 
have that same assurance?
    Dr. Klimstra. If patients are in other States, not being 
tested in New York, they don't have the same pre-test review 
requirements. No, they do not.
    Senator Murray. Dr. Allen, in your experience, are patients 
outside of New York State told or even generally aware that 
their tests may not have been reviewed by FDA or any external 
organization to assure that their test results are meaningful?
    Dr. Allen. I think that's probably a difficult number to 
assess. But as a supplement to the publication that I 
mentioned, we conducted a survey of national oncologists to see 
what they knew about their test status, and one in five 
practicing oncologists did not know whether their tests that 
they ordered were FDA approved or not. So I strongly suspect 
patients do not.
    Senator Murray. Mr. Spring, before you market a test, what 
studies do you need to perform to demonstrate to the FDA that 
your tests work and are clinically meaningful?
    Mr. Spring. It depends on the risk of the test and the 
classification of the test. But the majority of our tests will 
go through what we call analytical testing, some sort of bench 
testing that challenges the ability of the test to detect the 
analyte or target. We'll look at things like what substances 
might interfere with that test and so forth.
    Then we take it out, say, into the real world and do some 
sort of clinical testing, either prospectively on patients or, 
in the cases of maybe rare disease or low-prevalence diseases, 
we'll go to some sort of tissue bank or a specimen bank to do 
that testing. It's a balance of analytical and clinical 
testing.
    Senator Murray. After all of that work, is there anything 
preventing a lab without FDA review from marketing a test 
making those very same claims?
    Mr. Spring. No, there's nothing preventing them today.
    Senator Murray. I think that is what sets up the uneven 
playing field that actually undermines public trust in the 
sustainability of innovators in this diagnostic field. It kind 
of seems like to me if we want precision medicine to advance, 
we need to make sure we are incentivizing innovation and 
assuring patients' tests will work as promised. Right?
    Mr. Spring. Exactly.
    Senator Murray. Dr. Kaul, let me move to you. In your 
testimony, you spoke about your work to ensure the tests you 
offer are accurate and give meaningful information to doctors 
and patients. In this era of precision medicine, patients' 
treatments may vary widely, depending on test results, and 
that's why it's so important that patients get the same result 
regardless of the lab that their doctors use.
    Tell me what safeguards are in place to ensure that the 
results from your lab would match the results from, like, Dr. 
Klimstra's lab or a lab in my home State of Washington?
    Dr. Kaul. I'll make a couple of comments here. No. 1, the 
CLIA lab validation process requires that labs take their lab-
developed procedures through the same protocols that happens at 
the FDA. We don't go through the FDA review, but we're doing 
the same quality assessment of the effectiveness of those tests 
up front. This data can be collected over CLIA. I think we need 
some broader oversight here. But right now, that is reviewed 
when we have lab inspectors dropping in unannounced to look at 
our validation data, and if they're not happy with it, we can't 
offer the testing. I think some of this activity could be moved 
proactively.
    But we do have assurances because of the CLIA process 
currently. We're also required for all of these to participate 
in proficiency testing, so we get unknown samples multiple 
times a year that the labs are asked to test, return the 
samples to CAP--CAP is the purveyor of CLIA oversight in this 
situation--and we get extensive and detailed publications 
looking at how our results compared to those of other labs. 
Much of this has been published, and the quality is there. 
There's not so much variation in these assays that we're 
talking about.
    We can look to see how the in-house tests stack up against 
the results of a test kit manufactured that did go through the 
FDA, and, again, there's generally no difference. The lab tests 
perform well, and there's published data to support this.
    I'll also add that we are concerned about screening tests. 
Those are not the tests that Dr. Klimstra and I are talking 
about. I think there's a big difference between the validity of 
a test looking at a gene mutation where there's extensive 
published literature about the value of that mutation in 
determining treatment response in a patient and looking ahead 
at who might produce ovarian cancer and needs to be treated 
differently down the road, and that does need a higher level of 
scrutiny as well. But those are not the tests we're talking 
about today.
    Senator Murray. My time is up. Thank you.
    The Chairman. Thank you, Senator Murray.
    Senator Burr.

                       Statement of Senator Burr

    Senator Burr. Thank you, Mr. Chairman.
    Dr. Kaul, thank you for that last comment, because I think 
you draw a big distinction. We're trying to put all these 
things in one bucket and they don't belong in one bucket. I'm 
just going to turn to you as a pathologist with a lab. How many 
times do you do an LDT knowing that the LDT isn't going to 
prove--isn't going to identify what you're looking for?
    Dr. Kaul. I'd say we don't. We have LDTs that we have never 
launched because they didn't make our quality guidelines, and 
we don't put those in practice.
    Senator Burr. My point is you're a healthcare professional 
that's making a healthcare decision----
    Dr. Kaul. Yes.
    Senator Burr [continuing]. Based upon the tools that are 
available for you. It's somewhat shocking to me--I'm sitting 
here almost having an out-of-body experience, because we're 
having a debate about whether we set up a regulatory 
architecture that makes it slower and more costly to determine 
a diagnosis, yet all the diagnoses that we're looking for--
every medical professional would agree that if we find it 
earlier, we have more options to treat. If we identify it 
earlier, we have the ability on a longer glide path to 
customize the treatment to the particular condition that we 
find.
    Isn't our responsibility here as policymakers and as 
healthcare professionals to do whatever is in the best interest 
of the health outcome of the patients, regardless of the 
territorial battles that we fight up here?
    My question would be to anybody that would like to take a 
stab at it: I've heard everybody agree that technology's pace 
is beginning to increase, that what took us 6 years maybe to 
accomplish before, we're doing it in 6 months. What's taking us 
6 months today, Mr. Spring, is going to take us 1 month down 
the road. Is there anybody here that believes that the FDA 
architecture or the FDA talent exists today to be able to 
handle an approval--a process of an application or an approval 
3 years from now?
    Mr. Spring. I can take a stab at that.
    Senator Burr. Sure. Go for it.
    Mr. Spring. I think that the current framework does need to 
change. I'm not going to comment on the talent that FDA has, 
but I think they've shown innovation in addressing some of 
these needs through issuance of recent guidance such as the 
next-gen sequencing guidance as well as reliance on existing 
evidence that's out there, such as literature and so forth. I 
don't think the current construct and framework will work in 
this situation. We do need to see legislative reform, and 
following the principles I outlined, I think we can get there.
    Senator Burr. I'll tell a story--go ahead, Dr. Klimstra.
    Dr. Klimstra. Thank you. I'd just like to respond as well. 
I think one of the critical points to keep in mind relates to 
the comment Dr. Kaul made a few minutes ago, that there are 
vastly different types of LDTs that are being considered under 
this legislation. The idea of risk stratification, not only for 
the impact of the results of the test on the patient, but for 
the nature of the technology being employed, whether it can be 
validated with other types of technology in other laboratories 
or not, whether it uses proprietary algorithms that cannot be 
validated by others. These are critical points to consider in 
deciding which tests are highest risk, and if we are to 
institute additional regulatory structure, it should focus on 
those very high-risk tests.
    Senator Burr. Dr. Allen.
    Mr. Allen. I think what we're looking for here in terms of 
predictability is assurance that tests are safe and clinically 
valid. How to get there is up to the developer. We're looking 
from a regulatory standpoint at the floor----
    Senator Burr. Do you trust Dr. Kaul to make that decision 
in her lab as a pathologist on a laboratory test?
    Mr. Allen. I would absolutely trust Dr. Kaul to make those 
calls as a medical professional. But I think what we're looking 
for is assurance that the tools she's using to make those calls 
have the same predictability no matter where they're developed.
    Senator Burr. So a quick story. I've got 33 seconds. In the 
mid 1990s, we created a new diagnostic tool called contrast 
imaging. The only problem was it didn't have a reimbursement 
code. And I remember calling Dr. Hatch, who was then the 
director at CMS, and I explained this to him. Contrast imaging 
gave us the ability to actually diagnose on the first guess 
versus to do non-contrast and have 17 options as to what we can 
do after that--more precise.
    After 2 weeks of deliberation, he came back and he told me 
that he had solved the problem. He was going to give a 20 
percent bonus to non-contrast imaging to make up for the lack 
of reimbursement that contrast imaging was going to get. I 
started a very elementary point at seeing how government looks 
at technology and advancement. It played no role--there was no 
role that was played about the quality of care that could be 
provided. It was about how we fit something in an old 
architecture.
    I'm going to be fascinated as we go through this. I think 
all of you said we can reach an agreement. I think we can. But 
understand that if we don't do this in an organic way, we will 
be back here 12 months from now when technology has changed, 
where the capability to do even further lab-developed tests is 
that much greater, and where the challenges that are faced in a 
PMA or in a trial are so great that the talent may not be there 
or the architecture may not be there to allow that to happen in 
a way that impacts positively patients' lives, and we cannot 
take that out of the equation. That should drive the discussion 
we have.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Burr.
    Senator Baldwin.

                      Statement of Senator Baldwin

    Senator Baldwin. Thank you, Mr. Chairman and Ranking 
Member. This is a really great panel and an opportunity to 
delve into this topic, and I know we'll return to this in the 
future, in part because this has been a key focus of the HELP 
Committee, the idea of encouraging more advanced cures, and we 
know the first step to that is the precise diagnosis and 
screening of a condition to help best target and inform 
therapy.
    My home State of Wisconsin has seen notable progress in 
this field, from things like critical antibody tests for 
transplant patients developed at the University of Wisconsin's 
academic laboratory to the first FDA-approved stool-based DNA 
test for colorectal cancer developed by a Wisconsin company 
called Exact Sciences. I will say, however, I am concerned that 
the growth of the laboratory-developed test industry--with that 
growth, there is too much that we still don't know, and it's an 
entire sector of the diagnostic set of tests that patients rely 
on.
    So I have a couple of questions. If a patient doesn't know 
if, say, their cancer test or their Lyme's Disease test is an 
LDT, which has, say, not been FDA approved, or even if it 
hasn't been subject to the type of examination that shows that 
it's been proven to work, but they have this expectation, of 
course, as patients that that test is accurate, because of this 
uneven oversight, we might not know or find out too late 
whether a test is harming patients or giving them false hope or 
a wrong diagnosis.
    Dr. Allen, I want to hear from you, first, the impact on 
patients when they don't have information about their tests. 
I'm not even talking about the test results yet, but sort of 
what sort of review that test has had that they're relying on.
    Mr. Allen. I think there's an expectation that when you go 
into your doctor's office, you're going to get told the best 
information that that medical professional can provide to you 
based on a whole host of tests, of analyses, their medical 
interpretation of the symptoms that you're describing to them, 
and, frankly, patients shouldn't have to worry about this. If 
there's one thing that we can take out of the challenges that 
they're facing, could it be the evenness around the tests so 
that they have at least one portion of their care that they can 
be confident in and can expect are giving them the best 
possible information without variability.
    This isn't about the competence of the individual who is 
interpreting the test or using it, because they're extremely 
educated, extremely talented. But they may not even know if 
there's variability in a test that they're using, and that's 
what we're trying to reduce here and have a level playing field 
for all of these tests, because complex decisions are made upon 
them.
    When you think about, PSA tests, for example, this spurs a 
conversation between men and their doctors about what options 
they should be pursuing. Let's reduce some of the variability 
and make sure that those tests are producing the same result no 
matter who's performing the test or providing the information 
back to the patients.
    Senator Baldwin. Thank you. I want to talk a little bit 
about the CMS overseeing CLIA process. Throughout 2015, the 
Milwaukee Journal Sentinel published a watchdog report entitled 
``Hidden Errors,'' and it revealed deficiency in lab testing 
procedures across the country. It showed that our current 
system to regulate labs under CMS has gaps that we need to 
address, and the series outlined a number of specific instances 
where patients received incorrect results from individual labs 
to larger lab companies and their practices.
    They outlined examples, of course, to readers which were 
quite shocking, incorrect paternity test results, false HIV 
test results, issues due to technician mistakes, or machines 
that were simply not properly calibrated. Many of these labs 
had been inspected and accredited under CMS guidelines. I'm 
concerned about the gaps that may exist.
    Dr. Klimstra, you've mentioned this already. But I wonder 
if you could explain some of the important lab quality control 
differences that exist in a State like New York, whether it's 
State law that requires robust lab inspection and oversight. 
These laws differ from State to State. What protections do New 
Yorkers have that others might not?
    Dr. Klimstra. I think the key difference in New York is the 
requirement for premarket approval in which the tests and the 
validation experiments done in order to establish them must be 
submitted for State approval before the tests can be offered. 
In other States, the mandate to maintain that regulatory level 
falls on the directors of the laboratories, and to the extent 
that they are medical professionals and they have an enormous 
investment in accurate results, I believe many of them are 
maintaining the same level of compliance. But the actual 
validation experiments would not be reviewed until after the 
test has been released. That's the fundamental difference 
between New York and other States.
    The Chairman. Thank you, Senator Baldwin.
    Senator Hatch.

                       Statement of Senator Hatch

    Senator Hatch. Thank you, Mr. Chairman.
    I want to thank all of you for being here and for the 
excellent testimony.
    In today's ever changing healthcare landscape, clinicians 
and patients need stability and a clear process to feel 
confident about the tests influencing their healthcare 
decisions. I'm not certain that the current FDA structure could 
provide that stability.
    We have great clinical and diagnostic test companies in 
Utah. These thought leaders have been at the forefront of 
molecular testing for decades, from the BRCA gene to the 
response to the H1N1 outbreak, bringing hundreds of tests to 
market.
    A more recent and pressing example involves ARUP 
Laboratories with infectious disease experts at the University 
of Utah and other test developers around the country. This past 
winter, as the FDA and CDC were seeking to prepare for Zika 
outbreaks at the Rio Olympics and in the United States, 
infectious disease experts around the country were working 
diligently to complete EUAs or Emergency Use Authorizations 
with the FDA.
    Several excellent reference tests were developed by labs 
and manufacturers in the spring and were able to detect Zika's 
presence in blood. ARUP and others also worked to validate 
testing for urine testing general guidance specified in the 
FDA's EUA document. These groups were able to develop sensitive 
and robust Zika tests early in the spring using Zika sequences 
widely available to developers at that time.
    A major barrier for all test developers has been the EUA 
validation requirement, requiring clinical samples from 
infected patients that have a medical history. These samples 
have been extremely challenging to obtain, and Brazil, which 
has been at the center of the outbreak, has prohibited the 
export of Zika genetic materials. In addition, new tests must 
be compared to existing EUA-approved assays, and these have 
limited availability, especially in the early days of the Zika 
outbreak.
    This has impeded timelines for rapid test validation and 
approval, which is the goal of an emergency test initiative. 
The Utah team finished prescribed FDA requirements at the end 
of the summer but was recently asked to perform almost 500 
additional development tests using FDA-developed Zika 
validation material. This requirement was not included in the 
original EUA guidance document issued by the FDA, and it is not 
clear if such testing has been a requirement for all test 
submissions.
    None of this is to say that the FDA has been anything but 
thoughtful and flexible toward the research team. But it 
appears to me that there is no clear and expeditious process to 
follow in this situation. Test developers have been confronted 
with new requirements during the development window, and while 
flexibility matters, so does a clear process to ensure proper 
oversight of LDTs. Based on this example, I have basically two 
questions.
    Dr. Kaul, have you experienced standards changing in this 
way during your career? Again, the FDA leads have been 
considerate scientists, so this is not an attack on the people 
working there, but an inquiry into the process for approval of 
clinical diagnostic tests.
    Dr. Kaul. I'd like to answer this in two ways. You 
mentioned the EUA and the influenza outbreak, and, actually, 
our laboratory found ourselves in the midst of this in 2009 
because we had a lab-developed test that was extremely 
effective at detecting swine flu. We had validated it for other 
purposes but worked with our public health lab, and within the 
space of a few weeks, because the sequences were published, 
this assay worked beautifully, and I can't say we missed a 
single case.
    We did then go on to help two other companies develop their 
own EUA reagents, and 10 months later, the EUA approval was 
received after the outbreak was over. So I think there are some 
concerns here. Lab-developed tests, I think, provided a 
service, and it would be a lovely thing to allow those labs who 
are on the front lines of these outbreaks to work in a more 
integrated fashion with the public health labs and the CDC.
    I do think the other comment you're mentioning is the need 
for reference materials, and labs struggle for this, whether 
they are trying to validate a new assay--which is why the two 
companies trying to develop swine flu assays turned to us in 
the labs because we had characterized samples we could share 
with them to validate their FDA assay.
    But it's a struggle, and oftentimes it slows this process, 
not only in assay development, but I think also--as I mentioned 
earlier, we really need well characterized reference materials 
in cancer and infectious disease to help labs be able to 
demonstrate, pre-offering the test, that they can hit certain 
quality targets. There's a group called Tapestry that's working 
on a pilot project in cancer, and this is an area that would 
benefit us all.
    In the end, it shouldn't matter what test kit we're using 
or what procedure as long as we can get the right answer for 
patients. That's the truth we're all after in the end.
    Senator Hatch. Thank you.
    Mr. Chairman, may I ask just one more question?
    The Chairman. Sure.
    Senator Hatch. Dr. Klimstra, you've seen the impacts of 
changing guidance practices over time, and separately from this 
Zika example, it would seem to me that the FDA believes these 
tests can be regulated as devices using existing authorities. 
But these tests are not all the same, and they are certainly 
not devices, in my opinion. Legislative solutions that 
incorporate all stakeholders are more transparent and could be 
more appropriate to ensuring oversight for high-risk tests.
    In your opinion, would it be wiser to delay finalizing this 
LDT guidance in favor of discussing whether the FDA needs the 
authority to provide proper oversight for these tests?
    Dr. Klimstra. Yes. I think this is obviously a very complex 
issue with different types of tests, with different risks to 
patients, and different testing scenarios. I think that a 
thorough consideration of all of the options and the practical 
ramifications of certain choices needs to be carefully 
discussed. I fear that, as has been intimated, the current 
review process that the FDA has would not be adequate to 
accommodate all of the tests that fall under their definition 
of LDTs, and that without further refining the highest risk 
tests, there would not be an adequate infrastructure to 
expeditiously review these tests, delaying diagnoses and 
delaying innovations reaching the clinic.
    Senator Hatch. Thank you so much.
    Thanks, Mr. Chairman.
    The Chairman. Thank you, Senator Hatch.
    Senator Bennet.

                      Statement of Senator Bennet

    Senator Bennet. Thank you, Mr. Chairman. Thank you very 
much for holding this hearing.
    And thank you to all the witnesses for being here today.
    Just for the benefit of the committee, I'd love to go down 
the line here and ask you what the one or two things are that 
you would like us to keep in the forefront of our minds as we 
think about and as we consider legislating in the area of lab-
developed tests.
    Dr. Klimstra. Thank you, Senator Bennet, for that 
opportunity. The key point I would like to make is that you've 
heard throughout the panelists that we all agree that safe, 
effective, reliable diagnostic testing is very important. But 
it's also critically important to keep in mind the 
ramifications and the process for additional regulation to 
ensure that we don't inadvertently remove these tests from the 
hands of academic institutions and that we don't delay access 
of patients to valuable innovative testing.
    Senator Bennet. Mr. Spring.
    Mr. Spring. Thank you, Senator. I'm going to echo what Dr. 
Klimstra said. We do need to ensure that these tests are 
accurate and reliable. But with that said, we have to assure 
that the same test follows the same regulatory framework, and 
the same level of evidence for that test should apply, no 
matter where that test is developed or implemented.
    Second--and we heard this from Senator Hatch--we need a 
more predictable and transparent process. We don't like to see 
surprises halfway through the validation of our tests, and we 
need to improve upon that. Those are the two areas I'd like to 
see.
    Senator Bennet. Thank you.
    Dr. Allen.
    Mr. Allen. Any test that is used to guide medical 
decisionmaking should be held to the same standards, no matter 
where it's developed. It's important in that context to explore 
flexibility in demonstrating safety and accuracy, but the 
standards should be the same.
    Senator Bennet. Dr. Kaul.
    Dr. Kaul. Thank you again for the question. We're all on 
the same page that we want safe and effective testing for 
patients and that it needs to be regulated. The key is the 
pathway to regulation, and whether that is the FDA that will 
create some considerable challenges, as we've heard, in terms 
of time and expense, or CLIA, where the labs already have a 
significant infrastructure and are already reporting 
information required by CLIA, is the decision that needs to be 
made.
    I obviously believe the CLIA course with necessary 
expansion, premarket approval, those sorts of things, would be 
most useful and less onerous to the laboratory and would allow 
us the flexibility to get these very much needed assays out to 
patients to cover the mutations and the testing that they need 
as we move forward under personalized medicine.
    Senator Bennet. Along those lines, for anybody on the panel 
who would like to answer, what do you think the implications 
are for the President's vision of precision medicine in light 
of the FDA's proposed guidance?
    Dr. Kaul. I will take a crack at that. As enthused as I am 
about the President's endeavors, how we bring that to clinical 
care in a responsible way with the FDA proposal leaves me 
puzzled.
    Senator Bennet. Anybody else?
    Mr. Spring. Yes, I'll comment on that and I think echo some 
of the comments made earlier. If you look at precision 
medicine, we're looking at a number of tests that are 
addressing unmet needs. We need to find a way to rapidly get 
these tests to market but still follow the same standards of 
ensuring accuracy and reliability.
    Senator Bennet. Dr. Allen, I have one other question for 
you. Since we signed the Breakthrough Therapy--or the President 
signed it about 4 years ago, we've seen more and more therapies 
using a diagnostic tool. I wonder if you have a view about how 
important it is to have a regulatory structure around tests and 
how what we're discussing here would specifically affect 
breakthrough drugs.
    Mr. Allen. First, let me thank you and Senator Hatch and 
Senator Burr and the committee for really jump-starting the 
Breakthrough Therapy Designation and getting it passed into 
law. It certainly had a profound effect on the current State of 
drug development. In fact, as you mentioned, the use of 
molecular diagnostics is really critical to the effective 
implementation of the designation. In fact, 18 of the 48 drugs 
that have been approved with a breakthrough designation had a 
test associated with their use.
    It's important, with the Breakthrough Therapy Designation, 
the underlying safety and efficacy standard for the drug does 
not change. It's the flexibility and the collaboration and how 
to demonstrate that. We have an opportunity here on the testing 
side to make sure that the development of the tests is not the 
rate-limiting step to making sure that breakthroughs reach 
patients, but also that there is flexibility in demonstrating 
the safety and accuracy of the tests in that expedited context 
so that you're still reliable in the test and providing timely 
access to both the test and the effective drug.
    Senator Bennet. Thank you to the panel.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Bennet.
    Senator Cassidy.

                      Statement of Senator Cassidy

    Senator Cassidy. Dr. Klimstra, now, I gather that in New 
York, you get this approval pretty quickly, and it is not that 
expensive. Is this better than what CLIA does? Not to put you 
on the spot, but----
    Dr. Klimstra. Is it better? I can speak to the second part 
of the question. In New York State, we pay an annual fee to New 
York to provide our laboratory inspections. It's based on our 
gross billings. And in addition to that, the costs of premarket 
review for each LDT that we develop and submit to them are 
zero. There's no added expense to us----
    Senator Cassidy. And what's their turnaround time?
    Dr. Klimstra. The turnaround time at this point--because we 
have a well established relationship with the State and they 
recognize the quality of our lab and we already have hundreds 
of LDTs approved by them, within several weeks of submission, 
they give us conditional approval, and then they----
    Senator Cassidy. This is true for Memorial Sloan Kettering, 
which is famous, interstellarly, for your abilities.
    Dr. Klimstra. Thank you.
    [Laughter.]
    Senator Cassidy. What would it be for a lab less well 
known?
    Dr. Klimstra. It would depend on the complexity of the 
test. New York State is in the process of putting forward a 
revised structure of test complexity----
    Senator Cassidy. Go back to CLIA. I don't mean to 
interrupt. I've just got limited time. Go back to CLIA. Do you 
feel if CLIA is looking for clinical and analytic validity, do 
they provide that adequately? Because I think that's one of the 
questions here.
    Dr. Klimstra. I think the pretest review is an added layer 
of protection. We are allowed to offer our tests with 
conditional approval pending final review. There's a period of 
time when we are offering clinical tests----
    Senator Cassidy. Moving beyond Memorial Sloan Kettering 
into a startup lab, which may be really good--some post doc who 
left your place. But there is not a history with CLIA. Would 
they have this effective, low-cost turnaround time?
    Dr. Klimstra. I would not think so.
    Senator Cassidy. If they did, are you as confident that if 
they were not very good, that the detection of a not very good 
product would be--that it would be detected, be it CLIA or be 
it New York State?
    Dr. Klimstra. I think that if there were high-quality 
people who have maintained the standards that CLIA mandates, 
they would detect their own quality issues before releasing----
    Senator Cassidy. But if they are not, would CLIA have 
sufficient mechanisms to say, ``Ah, you are not maintaining 
high-quality X, Y, and Z. Therefore, we are not going to 
approve you and have further review.''
    Dr. Klimstra. Under their current structure, prior to 
release of the test, the answer is no.
    Senator Cassidy. Under their current structure, no.
    Dr. Allen, I looked at your paper that you quoted--I think 
I got the right one--and I'm struck. Twenty-seven percent of 
the people tested for the pertinent mutation had the test 
before an FDA test was approved. Now--and I see Dr. Kaul back 
there nodding her head. Her thing about the herpes simplex 
virus is dramatic. We would have--years treating HSV.
    Are you advocating that until the FDA comes out with a 
product that we do nothing, knowing that herpes simplex virus--
people would have been getting Acyclovir for many days at a 
time--and/or for the cancer, 27 percent of the people had not 
got the testing prior to the FDA approval? How do you balance 
that?
    Mr. Allen. The facts that have been shared today in terms 
of the overlap between the availability of an LDT for tests 
like EGFR and KRAS are accurate. They were available as an LDT 
before a manufacturer brought a test to the FDA in order for it 
to be reviewed. That's because there's no requirement for them 
to do so. It's almost a voluntary nature for them, if they want 
to develop it as a kit, to take it to the FDA rather than 
perform it in their single lab.
    I think we absolutely need to acknowledge what these 
research institutions and universities are doing in terms of 
being the driver and the engine of----
    Senator Cassidy. But, again, my point being that 27 percent 
of the people tested were tested before there was an FDA-
approved test in your paper. So do we put on hold that testing 
until we have the FDA, through its laborious--oh, my gosh, how 
long does it take to brew a cup of coffee----
    Mr. Allen. We need to think about some transitional period 
to go through--those that are discovered in terms of--as an 
LDT. But how do we then make that LDT that was developed at a 
single institution--how do we make that test available beyond 
patients that are just treated and tested at that one 
institution? That may require the FDA to have oversight to make 
sure that those tests are clinically valid before they go into 
widespread use.
    Senator Cassidy. Mr. Chairman, can I ask one more question, 
please?
    The Chairman. Of course.
    Senator Cassidy. Thank you. It helps being the last guy 
here.
    Dr. Kaul, I really enjoyed your testimony. First, you made 
some summary points at the end which I did not see in your 
testimony. So either I was gathering wool or you slipped them 
in. But if you could submit those for the record, I would 
appreciate that.
    Dr. Kaul. Absolutely.
    Senator Cassidy. Second, you kind of point maybe to a 
resolution. It seems like you have a crowd sourced approach, 
different labs collaborating to come up with something which 
is, if you will, Memorial Sloan Kettering and the University of 
Chicago writ large, everybody participating, and you check each 
other. Is that a fair way to depict it?
    Dr. Kaul. Not being a millennial, I won't opt to use the 
word, crowd sourcing, but that's exactly what happens. We have 
a very active list serve. We sit at our professional meetings 
and talk like lab----
    Senator Cassidy. OK. Let me interrupt you. So how do you 
handle the IP?
    The Chairman. Go ahead and take your time, Senator Cassidy.
    Dr. Kaul. How do we----
    The Chairman. Go ahead and ask your question.
    Senator Cassidy. Thank you.
    Dr. Kaul. How do we handle the----
    Senator Cassidy. Intellectual property.
    Dr. Kaul. For the most part, we don't, because we are doing 
this for patients. We're not doing this to make money and 
patent a gene or a test kit for our laboratories. We are in 
this to do the right thing for patient care.
    Senator Cassidy. As a physician, I applaud you. But is your 
medical school provost as high-minded as you?
    [Laughter.]
    Dr. Kaul. I think that there is--they have never approached 
me and pushed the things that we're doing in the labs, because 
it does offer the best thing for patients, and that's why we're 
doing it.
    Senator Cassidy. Let me ask is that the way forward? 
Because I'm just nihilistic about the FDA's ability to do 
anything in a timely fashion. And, frankly, what happens in New 
York--it is your reputation that precedes you, but if you're 
the smart post doc with a paradigm shifting whatever, you're 
much less likely to be approved in a timely fashion. But the 
smart post doc would post, and everybody would look at what she 
had done and be envious and offer a big contract, but they 
would approve and vet. Make sense?
    Dr. Kaul. Makes sense. And that's essentially what we're 
doing already at national meetings. We all publish our data in 
peer review journals. We're presenting it at meetings where 
people can pick it apart, come up with the best assay, and in 
the BCR-ABL example, this was the basis for what then became 
and FDA-approved kit. There's a lot of work going on. I think 
we do need to tidy up our quality standards and the process for 
pre-review, as you've heard. But I think that this is already 
happening under----
    Senator Cassidy. There is a technology, and sometimes 
technology becomes--and I'll ask my two clinicians, if you 
will. If you're doing PCR, polymerase chain reaction, you can 
put herpes simplex virus out there, and you can--that's a 
pretty standard test.
    Dr. Kaul. Yes.
    Senator Cassidy. So everybody can make HSV. But some of 
this, for example, the tumor markers--it really would require 
not just conceptually how to do it, but actually validating 
that the person has implemented the concept correctly, and I 
think this is where everybody has a common ground. How do you, 
through the crowd source, if you will, also ensure that the 
implementation is as accurate as done at one of your 
institutions?
    Dr. Kaul. I can take a crack at that. I think we already 
share a lot of samples amongst labs to make sure that the 
correct answers are given by all parties, and when we find 
something that's discrepant, we spend a lot of time trying to 
figure out why. But I think this can be baked into a little bit 
more formal process where the answer that's most important to 
patients is getting the correct answer, and it shouldn't matter 
if it's in my lab or David's lab or whatever. We all need to 
drive toward that level of quality for patient care.
    Senator Cassidy. Last, as we know, publication cycles can 
be prolonged, and abstracts may be published, but abstracts may 
not, as it turns out, be exactly the way you would publish. Is 
there a way to speed up the cycle in which the research--going 
back to online crowd sourcing--granted, you want a peer review, 
but in a sense, when you put it up there, everybody's going to 
peer review it. Right? Is there a way to shorten that cycle 
time? Because I think if we go to precision medicine, we really 
need a faster and faster cycle time than next year's 
convocation in the Netherlands.
    Dr. Klimstra. Yes, I think we're moving toward real-time 
data sharing. Another point made by Vice President Biden when 
he spoke about the Cancer Moonshot was the difficulty in 
exchanging data among cancer researchers and the need to 
accelerate that. The data from our sequencing assays is 
released in publicly available form very quickly after it's 
generated, allowing novel findings to be shared with cancer 
researchers around the world, and I think this has enabled the 
kind of contacts that were described in terms of sharing 
validation samples and other things to help people move their 
assays forward very quickly.
    Senator Cassidy. Is the path forward--actually, to ask you 
all--and I'm going to continue to use it, although, obviously, 
I'm not a millennial--is the path forward crowd sourcing with 
FDA or CLIA plugged into that which is taking place so that on 
a real-time basis, they have some scientists saying, ``Yes, 
this really works,'' but in the meantime, it's all of you 
plugging it in, and at the end, they put the FDA seal of 
approval, with a few caveats for the attorneys, but on the 
other hand, people can begin to use? Would that be a way 
forward?
    Dr. Allen, you're nodding your head.
    And, Mr. Spring, do you feel like that would be a way 
forward?
    Mr. Spring. I think there are elements of what you've 
mentioned, as well as what we've heard about New York State, 
that that can be adopted by FDA. I think the current framework 
can't exist as it is and get these unmet-need tests out as 
quickly as possible. What you're suggesting is certainly one 
option I think we should look at.
    Senator Cassidy. Thank you all--very provocative. Thank you 
all.
    The Chairman. Thanks, Dr. Cassidy.
    As far as the data sharing goes, that's one more reason why 
we need to pass the 21st Century Cures legislation that we've 
been working on for 2 years and that the President is 
interested in. The Vice President is interested in it, and it's 
part of Speaker Ryan's agenda, and Senator McConnell said it's 
the most important bill of the year, if we pass it. It includes 
a requirement that NIH researchers must publicize their data, 
and the Vice President has made that point.
    Dr. Allen, what did you think of that crowd sourcing 
exchange?
    Mr. Allen. I think there are some elements of that that 
have been captured in even some of the things that the FDA is 
working on in a couple of guidance documents that they put out 
recently. Everyone is progressing in this direction, and it 
could be a very worthwhile exercise to discuss what different 
pathways could be made available, particularly for these 
different tests that may be developed in different places that 
are intended to do the same thing. We wouldn't want necessarily 
every single test to have to start completely from scratch if 
there's a way for them to collaborate better.
    The Chairman. There are 60,000 existing laboratory-
developed tests, none of which are regulated by the FDA, 
correct?
    Mr. Allen. Correct.
    The Chairman. What do we do with those? Stop them until 
they spend $30 million or $75 million and get each one 
approved? What do we do about that?
    Mr. Allen. One, I think we certainly have to start with 
those that are presenting the highest risk to patients as the 
priority ones. And while the discussion most recently was about 
more advanced technology and large-scale genomic screening, a 
similar pathway could be constructed for older tests that 
potentially are reported to do the same thing. Not to say that 
60,000 tests are going to be required to have a full FDA PMA in 
order to be used, but could they show that they are 
analytically equivalent to something that has already 
demonstrated clinical validity or an accurate reference 
material that they could compare back to and make that be a 
much faster process that labs could--that some labs are already 
doing, but perhaps not all labs are doing, as a way to validate 
those tests.
    The Chairman. Let me ask this question while Senator 
Cassidy is here. Sometimes, if you own an old house and you 
invite the contractor in, he looks the house over and says, 
``You know, it would be easier and cheaper and quicker to tear 
it down and start over than it would be to try to remodel it.'' 
So you've got Sloan Kettering going to CLIA, then going to New 
York, and now the FDA says ``Come to us as well,'' and Dr. 
Klimstra says, ``If that happens, we'll close down our lab.''
    If I have lymphoma, and I want to check myself into Sloan 
Kettering, that's not a result I really want to happen. I'd 
like to trust the doctors there to take their experience with 
whatever test they've cooked up, and I wouldn't know anything 
about the test, even if you told me, but I would like for them 
to know about the test, and I would assume they did, and I 
agree it's an unusual place, but, still, we don't want that 
result.
    How much regulation is enough regulation? Do we want to 
have CLIA plus the FDA plus a State regulation? Or do we want 
to create a new regulatory agency and phase it in over time so 
that we meet all of our objectives of patient access, safe, and 
effective?
    Let me add that CMS is already so busy that it has no 
business making all the decisions it makes today. I do not see 
how anybody does that job. I've told them all that. We have far 
too many decisions made at CMS that need to be decentralized in 
this country. FDA is literally overwhelmed. They'll be asking 
us to appropriate billions of dollars next year to help them 
meet the existing responsibilities they have.
    In this really exciting area that affects so many people, 
why not start from scratch and create the ideal regulatory 
framework and phase it in over time so we meet those three 
objectives?
    Mr. Allen. I'm not a lawyer, and I'm not sure I can 
advocate for tearing down the existing laws that have been in 
place for many years. Having said that, I completely agree that 
we should look at efficiencies and processes and limit to the 
extent possible any duplication. We should start from the core 
tenet of what type of oversight do we need for these tests so 
that we can reasonably assure that they're safe and clinically 
valid as they go into use.
    Personally, I would advocate that the FDA have a critical 
role in these tests, because they do have the medical personnel 
there that have an understanding of the underlying disease. For 
example, both in the Cancer Moonshot and through the work of 
this committee, there's been steps that have been taken to 
direct the FDA to move toward a direction of establishing an 
FDA Oncology Center of Excellence to try and align the clinical 
expertise and the communication across that agency around all 
cancer products, including therapeutics and diagnostics, so 
compared to some of these other agencies----
    The Chairman. Why wouldn't that be a new regulatory agency 
if it's an independent Center of Excellence?
    Mr. Allen. Within--separate from the FDA?
    The Chairman. Maybe it is. Maybe it isn't. Dr. Califf says 
his biggest problem is he doesn't have the medical personnel. 
He has wonderful people, but what he has asked us for is more 
authority to pay more money to more talented people because he 
has so many vacancies and they can't get their work done.
    Here we give them 60,000 laboratory-developed tests and 
say, ``OK. Everybody stop while the FDA makes it way through 
60,000 laboratory-developed tests,'' at a time we're hearing 
from Sloan Kettering that it would close their laboratory, and 
Vanderbilt--that 95 percent of its personalized medicine is 
conducted by its own laboratory-developed tests. We don't want 
that result, I don't think, do we?
    Mr. Allen. We absolutely don't want that result.
    The Chairman. But you've been a leader, actually, in 
speeding things up with your breakthrough--I'm not picking on 
you. I'm really trying to take advantage of the work you've 
done with this committee to help us find ways to mobilize broad 
public support for getting these tests in the hands of doctors 
and patients more rapidly at a lower cost.
    Mr. Allen. And I don't want to speak for everyone here, but 
I hope we all can continue to work with this committee, who 
also has taken a leadership role in expediting access, 
accelerating innovation, and protecting safety around this 
topic.
    The Chairman. Let me ask any of you--could you give Senator 
Cassidy and me an update on private discussions that are going 
on about how to solve this challenge? Is there some consensus 
developing? Is there an organization that is working on this? 
Or is everybody just spouting off ideas and waiting for us to 
come up with some solution?
    Dr. Klimstra.
    Dr. Klimstra. Of course, there's been a lot of discussion 
since the release of the draft guidance a couple of years ago 
among individual institutions, local regulatory groups, and 
professional organizations. The Association for Molecular 
Pathology and the College of American Pathologists have been 
working hard on developing validation guidelines for next-
generation sequencing assays, for instance, that would allow 
prospective labs developing these LDTs to follow a very 
standardized process and to meet very specific analytic 
requirements for the test to be validated.
    I think that there is an enormous amount of expertise 
vested in the academic institutions and the commercial 
laboratories in doing this, and we really need to pull all of 
that together. I like your idea to develop something novel, 
whether it's put on top of the FDA or put on top of CLIA or 
even New York State. But I think we need to start from scratch 
in a sense and reevaluate this entire new climate using the 
experience of people who have been in the field for a long 
time.
    The Chairman. Mr. Spring, any concluding remarks?
    Mr. Spring. Yes. To answer your earlier question, we have, 
and I've been part of, discussions with the laboratories, 
academic institutions, and other manufacturers. To answer your 
earlier question about these 60,000 tests out there, we have to 
have some sort of grandfathering involved in that. You can't 
just automatically take them off the market.
    I think what we'd be looking at is--Dr. Allen mentioned 
some sort of--what are the higher risk tests, how do we address 
those, and then looking forward to the future tests and how we 
bring these products to market as quickly as possible. I think 
FDA has come up with some innovative ideas, as an example, 
relying on analytical bench testing, releasing the product 
while you gather the clinical evidence, and that depends on the 
risk of the test. There's some innovation out there and some 
recent guidance that will help us get there.
    To conclude, I won't re-read all seven principles that I 
spoke to, but I think these principles work for all 
stakeholders, the patients, the labs, industry, and others that 
may be involved in this. I think as we continue to look at 
these principles and use them in our discussions, we will find 
a path forward. But I do agree that FDA should be the body 
regulating these LDTs, just not under the current framework. We 
have to change it.
    The Chairman. That means CMS would be out of the business. 
Is that right?
    Mr. Spring. No. There has to be a clear line of 
jurisdiction where CMS would still look at lab operations. Even 
if I make a test at BD and sell it, they have to ensure that 
the lab is using that test appropriately.
    The Chairman. You'd still have CMS, New York State, and 
FDA?
    Mr. Spring. Not necessarily New York State.
    The Chairman. You would in New York.
    Mr. Spring. If you look at the Wadsworth Center and the 
role they play today, under new construct, they can still play 
a role that's not duplicative. They could assist either CMS or 
FDA in their roles. But lab operations is different, in my 
view, than developing a test. Lab operations is implementing 
the test.
    The Chairman. I see what you're saying.
    I see Senator Warren has arrived, and we'll go to her. But 
Dr. Allen and Dr. Kaul, I'll let you make a comment on that 
question, although you may have already done that, Dr. Allen.
    Dr. Kaul. Thank you again for the opportunity. I think a 
number of key points just bear reiterating. The labs are not 
boxing and shipping kits out for others to be running. I think 
that's a key difference between what Mr. Spring and many of us 
in the clinical laboratories are doing.
    Yes, CLIA addresses lab operations, safety, refrigerators, 
all those sorts of things that are part of operations. But 
they're also collecting a great deal of quality data, and this 
is inspected and reviewed at the time we have an onsite 
inspection. I think that this mechanism can be expanded. We've 
heard a variety of proposals that I think about today that have 
gone forward calling for CLIA modernization, and I think for 
the laboratory perspective, it fits more nicely into CLIA than 
into FDA, because we're already collecting a lot of this 
information already.
    The Chairman. Thanks, Dr. Kaul.
    Senator Warren.

                      Statement of Senator Warren

    Senator Warren. Thank you very much, Mr. Chairman, and I 
apologize. We're trying to cover multiple hearings here all at 
once.
    Lab tests are a cornerstone of precision medicine, and 
there's been a lot of innovation over the last several years. 
Most labs and most companies are doing amazing work that helps 
patients get diagnosed earlier and gets the best medications in 
at the right time.
    But, as you've noted, most tests aren't regulated by the 
FDA, and most tests aren't reviewed by any external party to 
make sure that their results are accurate. I'm concerned that 
that means a lot of uncertainty for patients and doctors who 
are making important decisions based on these test results. So 
let me start there.
    Dr. Allen, if a patient is offered a test to determine 
whether they are at a higher risk for cancer, can they be sure 
that the results they get are accurate?
    Mr. Allen. Unfortunately, currently, not in all cases.
    Senator Warren. The answer is no.
    Mr. Allen. The answer is no.
    Senator Warren. You can't know whether you're one of the--
yes, it was accurate, or, no, it's not. The answer is just no. 
You can't be sure of that.
    Mr. Allen. If the test has gone through FDA, I think you 
can have greater confidence in some of the information that has 
been provided in terms of evidence behind the test.
    Senator Warren. Do tests that haven't been demonstrated to 
be clinically valid come with some sort of disclosure so that 
patients and their doctors know--don't rely on these tests?
    Mr. Allen. Not that I'm aware of.
    Senator Warren. In other words, all the tests look the 
same.
    Mr. Allen. Correct.
    Senator Warren. The good ones and the ones that aren't so 
good. All right. It's great that our academic medical centers, 
like the ones in Massachusetts, are on the cutting edge, but 
not everyone can get to these centers. How do we ensure that 
you're getting the same results for a test done in Alaska as, 
say, a test done at Massachusetts General Hospital?
    Dr. Allen.
    Mr. Allen. That in some ways has been the subject of a 
discussion that we were just ending up--if there are processes 
that can be put in place rather than having every single test 
that is being offered have to go through their own individual 
pathway through the FDA in order to demonstrate validity, or is 
there a way for the different test manufacturers or the labs 
performing them to work together to demonstrate that there is 
some degree of concordance or at least understand the 
variability that may exist between different tests intended to 
do the same thing.
    Senator Warren. The best way I can understand this at this 
point is that we have identified a problem, and that is that 
we're not getting the same kind of results, they're not 
reliable, and that that means we have got to hammer out a way 
to make sure that if you get the test done in Alaska, the odds 
are at least above 99 percent that you're going to get the same 
kind of result if you had that test done in Massachusetts.
    I appreciate your doing this. I just want to make the point 
that the best personalized medicine in the world won't work if 
it's given to patients who are unlikely to benefit from it 
because the treatment was based on bad lab results. The best 
personalized therapies won't work if patients are skipped over 
for treatment based on bad lab results.
    Some of my Republican colleagues have suggested that we 
choose between innovation and verifying whether or not the 
tests are accurate. But innovation without proven accuracy is 
not a medical advance. I believe that we can have sensible 
oversight that will encourage more innovation, innovation that 
truly saves lives, and I look forward to working with you, 
Chairman Alexander, and with the committee to try to accomplish 
that goal.
    Thank you all very much.
    Thank you, Mr. Chairman. I appreciate you holding this 
open.
    The Chairman. Thank you, Senator Warren.
    Thank you to the witnesses. This has been very helpful. As 
I mentioned when we began, this is the 45th hearing we've had, 
and I think almost every single one has been bipartisan, as 
this one has been. I think every Senator who came learned 
something today from the four of you, so thank you for your 
time.
    The hearing record will remain open for 10 days. After you 
leave, if you think of points you wish you'd made or solutions 
that you think would be helpful to us, we'd like to have them. 
We'd like to have them. And despite our different points of 
view, we work together reasonably well here in this committee.
    The HELP Committee will meet again on Thursday for a 
hearing on the regulation of cosmetics, on the 22d.
    Thank you for being here today. The committee will stand 
adjourned.
    [Additional material follows.]

                          ADDITIONAL MATERIAL

  Response by David S. Klimstra, M.D. to Questions of Senator Murray, 
            Senator Enzi, Senator Isakson, and Senator Casey

                             senator murray
    Question. Your testimony discussed the close working relationship 
staff in your labs have with the healthcare providers within your 
institutions, such as an oncologists making treatment decisions for 
patients. That communication seems to be critical to making sure that 
doctors understand what tests mean and how they make treatment 
decisions. If a healthcare provider outside of your system orders that 
same test, what level of interaction do you have with those providers?
    Answer. It is indeed critical that ordering healthcare providers 
understand the indications for testing and the significance of results. 
Different tests provide different types of information, such as 
supporting a specific pathology diagnosis, predicting the clinical 
course of a disease, suggesting the use of a certain type of treatment, 
or raising the level of risk a patient may contract a specific 
condition. The last of these may not suggest that intervention is 
indicated but rather that other, more specific tests should be 
conducted. Direct communication with the professionals in the lab 
performing the test is essential to communicate the subtleties of test 
interpretation. In our department, the vast majority of molecular 
diagnostics tests are ordered by providers within our system, on 
patients under active treatment at our institution. There is close 
interaction between our molecular pathologists and the treating 
clinicians, including through tumor boards, conferences, and other 
meetings. Thus, our treating physicians are well aware of the 
indications for testing and the interpretation of the results. Unusual 
cases sent to us from outside institutions come as consultation cases, 
sent by physicians to one of our pathologists, who will convey the 
results along with information about their significance.
                              senator enzi
    Question 1a. In the hearing panelists testified that if the 
regulatory guidance concerning Laboratory Developed Tests (LDTs) is 
finalized many labs would be forced to close given a nearly impossible 
financial burden to meet compliance. Similarly, members of the panel 
also testified that a vast majority of their personalized medicine 
practices rely on in-house LDTs.
    Please describe what impact lab closures would have on availability 
of diagnostic tools for physicians, particularly those in highly 
specialized or rare diseases.
    Answer 1a. The majority of LDTs currently in use have been 
developed in not-for-profit academic centers, purely to support 
advances in patient care. If FDA premarket approval were to be required 
for all LDTs, under the current cost structure, the costs would quickly 
exceed what academic labs could afford, forcing the labs to stop 
developing LDTs. The impact would be twofold. Innovative research, 
bringing new tests quickly to clinical use, would stop in academic 
centers, delaying patient access to practice-changing test data. 
Testing would therefore be driven into large commercial laboratories, 
which would have the resources to maintain this new, considerably more 
burdensome and costly regulatory compliance. This would sever the 
interactions between the treating clinicians and their molecular 
pathologists, which are critical both to the proper use and 
interpretation of molecular tests and to the ongoing development of 
future tests tailored to meet the diagnostic needs defined by the 
clinical care team.

    Question 1b. In your view, would there be consolidation among 
commercial laboratories? If so, what would you anticipate repercussions 
of that change, specifically related to the availability of new or more 
specialized diagnostic tests?
    Answer 1b. In all likelihood, only the largest commercial labs 
would have the resources to function in a stringent and costly 
regulatory environment, forcing smaller operations (whether academic or 
commercial) out of the test development arena. This could limit the 
availability of tests for rare diseases or for uncommon alterations in 
common diseases, which lack the commercial market to justify the 
development costs involved.

    Question 2. What types of evidence or studies do your laboratories 
conduct and assemble to show both analytical validity and clinical 
validity for a new LDT?
    Answer 2. Details about our test development and validation process 
can be found in my previously submitted written testimony. Analytic 
validity (meaning accuracy, reproducibility, sensitivity and 
specificity or the test) is established via rigorous experiments, 
following guidelines established by the New York State Department of 
Health. Specifically for next-generation sequencing assays, our 
laboratory directors are also participating in the development of test 
validation guidelines being proposed by the College of American 
Pathologists and the Association of Molecular Pathologists. The 
analytic validation experiments vary depending on the test but 
generally involve repeated testing of control samples with known 
alterations, to demonstrate consistent test performance; verification 
of test results in another laboratory; and verification of test results 
using a different testing platform or technology. The results of these 
validation studies, including the raw data, are submitted to NYS as a 
premarket approval package, and the test is not offered to patients 
until approval is obtained. Prospective test performance after launch 
is assessed with quality control at every step of the procedure, by 
participating in proficiency testing of control samples provided by the 
College of American Pathologists, and by review of test results in the 
context of all relevant clinical findings for each patient.
    Clinical validity has been established for some tests by the 
performance of extensive peer-reviewed, published research, with 
recommendations incorporated into standard treatment guidelines such as 
those of the NCCN. For less well-established tests, the results are 
integrated into clinical management along with all other test results 
and other data. The utility of the results is the subject of ongoing 
outcomes research, generally conducted at the same academic 
institutions where the tests are performed. Indeed, these studies 
ultimately inform the standard treatment recommendations described 
above, as the data mature.

    Question 3. How frequently are human clinical trials utilized to 
prove clinical validity for an LDT? If utilized, please describe 
typical format for clinical validity clinical trials.
    Answer 3. Clinical trials are the best way to establish clinical 
validity for a biomarker detected by an LDT and should be performed 
before a molecular diagnostic biomarker is incorporated into routine 
use. Clinical trials are increasingly biomarker-driven and are designed 
in part to test the utility of the biomarker to guide therapy. As such, 
the size of the trial, outcome measures, and expectations from 
molecular diagnostic testing are determined during the development of 
the trial to ensure the clinical validity of the biomarker can be 
established once the research is conducted. However, it is important to 
note that several LDTs typically exist for a given biomarker. The 
analytical performance of individual LDTs can be readily validated 
against each other, and this occurs routinely in clinical practice. 
Requiring that every individual LDT (as opposed to the biomarker tested 
by the LDT) should undergo separate clinical validation in a separate 
clinical trial is simply unrealistic given the costs and the limited 
numbers of clinical trial patients available.

    Question 4. Would default requirements for clinical trials to prove 
clinical validity potentially create barriers to developing new LDTs?
    Answer 4. In short, yes. It is necessary to develop the new LDTs 
first to perform the trial testing their clinical validity. Without the 
laboratory test, clinical trial biomarker data cannot be generated. 
Establishment of clinical validity through clinical trials conducted 
primarily in academic institutions should be the first step before the 
novel test is offered generally to patients outside of the clinical 
trial setting.

    Question 5. Please describe the current approval standard your 
laboratory relies on for determining whether to widely offer a new LDT 
to patients. Does the standard originate from a government body or from 
a peer-review authority, such as the College of American Pathologists 
and what is the scope of that standard?
    Answer 5. See answer #2, above.

    Question 6. What portion of your laboratory's test menu are LDTs as 
compared to FDA approved or cleared IVD test kits?
    Answer 6. Over 99 percent of molecular diagnostics tests performed 
in Anatomic Pathology at MSKCC are LDTs. The Department of Laboratory 
Medicine at MSKCC uses mostly FDA-approved assays. The proportion of 
LDTs versus FDA-approved tests offered in other labs varies widely 
depending on the size of the lab, whether it is academic or commercial, 
and whether the focus is on innovative molecular diagnostics or more 
routine testing. The high proportion of LDTs used by the Molecular 
Diagnostics Service of the MSKCC Department of Pathology reflects its 
focus on being at the forefront of translating discoveries into cancer 
care by testing for critical new biomarkers, at the request of our 
oncologists, well before corresponding FDA-approved assays are 
available or in the continued absence of such assays.

    Question 7. What are the most common modifications made to an LDRT 
or FDA approved or cleared test kits?
    Answer 7. In Anatomic Pathology at MSKCC, we do not modify FDA-
approved tests when they are utilized. In Laboratory Medicine, and in 
diagnostic labs at other institutions, FDA-approved assays are modified 
usually to allow their use on a specimen type other than that approved 
on the FDA application. For example, testing for human papilloma virus 
on anal tissue, looking for circulating tumor cells in CSF, and testing 
amylase levels on pancreatic cyst fluid all involve using an FDA-
approved assay on a biospecimen not included in the approval 
application. These tests then become LDTs based on these modifications.

    Question 8. How many ``new'' LDTs are a result of modification 
within your laboratory?
    Answer 8. None in Anatomic Pathology; Laboratory Medicine at MSKCC 
has 20-30 LDTs based on modifications of FDA-approved assays.

    Question 9. How many modifications result in a significant clinical 
impact for a patient receiving the test?
    Answer 9. All modifications have a clinical impact, because the 
tests are modified to provide information requested by treating 
clinicians to help care for their patients.

    Question 10. How many modifications change or expand the intended 
use of an LDT?
    Answer 10. All modifications expand the use of the test. In New 
York State, any modifications to improve or expand an LDT trigger a 
round of analytical re-validation experiments to confirm that the 
changes have not altered the performance characteristics of the LDT, 
and a summary of these re-validation experiments must be submitted to 
the NYS DOH for approval prior to clinical use of the modified LDT. As 
FDA-approved tests are generally only intended to be used on a single 
or small subset of specimen types, the modifications that convert such 
assays to LDTs expand the range of specimen types that can be tested to 
help establish a diagnosis or guide treatment.
                            senator isakson
    Question. In your testimony, you explained that additional 
regulation of our LDTs would restrict availability of advanced 
diagnostic tests to patient and add significant cost. As you know, the 
Emory University Genetics Lab in Atlanta is at the forefront of 
diagnostic genetic testing. Many academic centers operate clinical 
laboratories to better serve their patients, but they are not large 
organizations and don't have the budget to handle mountains of 
regulatory red tape. I worry if we add too much regulatory burden, that 
we will create a backlog of applications at FDA that cannot be kept up 
with.
    What do you see as the unintended consequences on Emory and other 
academic medical centers if FDA takes a larger role in regulating LDTs?
    Answer. The answer to this question is detailed in my prior written 
testimony. In short, burdensome and costly regulation of LDTs will 
drive molecular testing out of the academic environment at leading 
centers such as Emory and our own, among many others, reducing 
innovation and slowing the delivery of novel diagnostic testing to 
patients, especially for rare diseases or rare alterations in common 
diseases. The cost of offering molecular testing to patients would 
likely rise in the end as well.
                             senator casey
    Question 1a. Under the current system, it's possible for both an 
FDA-approved diagnostic and one or more LDTs to be available to 
patients and providers at the same time. I have several questions about 
what happens in these situations. How does a health care provider or a 
patient know if the test being ordered is FDA-approved or if it's an 
LDT?
    Answer 1a. Since there is no current requirement for FDA approval 
for LDTs, it may not be necessary for laboratories to indicate that a 
given test is not FDA-approved. In our lab, however, we include a 
standard statement on all reports indicating that the test is not FDA-
approved, but that it has been performed in a CLIA-compliant laboratory 
and has been approved by the New York State Department of Health.

    Question 1b. Does the existence of an FDA-approved test raise 
questions about the validity or accuracy of other LDTs testing the same 
thing?
    Answer 1b. It is not necessarily true that an FDA-approved test is 
more accurate than an LDT testing the same thing; in fact, a number of 
FDA-approved tests are clearly inferior to LDTs. Examples include KRAS 
mutation testing, which only detects some of the currently recommended 
mutations, and BRAF mutation testing which is only approved for limited 
disease types. Given the long delay in developing FDA-approved assays, 
some have become obsolete by the time they are available, given the 
rapid pace of technological advancement now occurring in molecular 
diagnostics. Also, some FDA-approved tests are for a single analyte, or 
only to be used for limited indications (such as specific disease 
types). Contemporary multi-analyte tests allow much more comprehensive 
analysis of many genes at once, maximizing the use of patient biopsy 
tissue to obtain comprehensive molecular information.

    Question 1c. If you were a patient and were given the choice of 
either an FDA-approved test or a laboratory-developed test, with no 
difference in cost, which would you choose?
    Answer 1c. Depending upon the specific test result needed, current 
LDTs are superior to FDA-approved tests as discussed above. Only 
careful consideration of the testing options and indications would 
allow an informed choice.

         Response by Brad Spring to Questions of Senator Casey

    Under the current system, it's possible for both an FDA-approved 
diagnostic and one or more LDTs to be available to patients and 
providers at the same time. I have several questions about what happens 
in these situations.
    Response. Yes, it is true in the current system both FDA approved 
IVD's (manufacturer) and LDTs (labs) can be and are available at the 
same time. LDTs are currently regulated by CLIA and not by FDA. CLIA 
reviews the testing process that is used to perform the LDT on a 
biennial basis (not prior to the test being offered), but the LDT is 
never reviewed to determine whether it is clinically valid. The same 
test produced by an IVD must be reviewed and approved by FDA to 
establish analytical and clinical validity before it can be marketed.

    Question 1a. How does a health care provider or a patient know if 
the test being ordered is FDA-approved or if it's an LDT?
    Answer 1a. They don't. Patients or Healthcare Providers are not 
provided the FDA approval status of a test, unless they ask. A majority 
of patients either assume all tests are FDA approved or they don't even 
think to ask if the tests are an FDA approved or an LDT.

    Question 1b. Does the existence of an FDA-approved test raise 
questions about the validity or accuracy of other LDTs testing the same 
thing?
    Answer 1b. There is no transparency as to how LDTs are analytically 
or clinically validated whereas information on the validations 
conducted by diagnostic manufacturers is publicly available on the FDA 
website. The lack of transparency for LDTs raises questions on the 
level and rigor of testing conducted by the laboratory to demonstrate 
clinical and analytical validity.

    Question 1c. If you were a patient and were given the choice of 
either an FDA-approved test or a laboratory-developed test, with no 
difference in cost, which would you choose?
    Answer 1c. I would choose the FDA-approved test because it has been 
through rigorous testing. Also, I could look up the performance of such 
tests and if there are any adverse events associated with the test on 
the FDA's website.

    Question 2. The fact that some test developers have gone through 
the FDA approval or clearance process for their tests seems to indicate 
that they see a benefit to doing so. What is that benefit?
    Answer 2. A test that has gone through the FDA approval process 
provides the public with more confidence that the tests accurately 
identifies or predicts the target disease or condition.

Response by Jeff Allen, Ph.D. to Questions of Senator Enzi and Senator 
                                 Casey

                              senator enzi
    Question 1. In the hearing panelists testified that if the 
regulatory guidance concerning Laboratory Developed Tests (LDTs) is 
finalized many labs would be forced to close given a nearly impossible 
financial burden to meet compliance. Similarly, members of the panel 
also testified that a vast majority of their personalized medicine 
practices rely on in-house LDTs.
    Please describe what impact lab closures would have on availability 
of diagnostic tools for physicians, particularly those in highly 
specialized or rare diseases.
    In your view, would there be consolidation among commercial 
laboratories? If so, what would you anticipate repercussions of that 
change, specifically related to the availability of new or more 
specialized diagnostic tests?
    Answer 1. The primary goal for any new regulatory approaches for 
LDTs should be to ensure that patient safety is protected by 
understanding the characteristics of a test before it is widely 
administered. While access to tests is an important component of 
providing optimal care in many cases, access to an inaccurate test may 
be as harmful as providing a patient access to a drug that doesn't 
work. If laboratories that are unable to be compliant and demonstrate 
the clinical validity of the tests they are performing it would be in 
the best interest of the patients that could be exposed to misleading 
results for those labs not to be utilized.
    In oncology, labs that offer tests that have been approved by FDA 
could be relied upon by shipping tumor samples or other specimens to 
those facilities for analysis. This occurs frequently today. This may 
result in fewer hospitals or facilities having in-house departments 
that are performing certain tests, but patient safety can be protected 
by relying on tests that have been shown to work and access can be 
maintained through mechanisms that can support remote testing. If a 
clear regulatory approach is developed, there may be a consolidation of 
labs toward those that are able to maintain compliance, but this could 
help support a guaranteed high-quality industry which will lead to 
higher quality healthcare. And this will bolster innovation overall by 
ensuring patients, their physicians, and test developers are making 
decisions based on good information.

    Question 2. What types of evidence or studies do your laboratories 
conduct and assemble to show both analytical validity and clinical 
validity for a new LDT?
    Answer 2. Friends of Cancer Research is not a clinical laboratory, 
and I personally have never worked in a clinical laboratory performing 
or evaluating LDTs, so it would be difficult to answer several of these 
questions that quantify aspects of clinical lab processes with any 
direct relevant experience.

    Question 3. How frequently are human clinical trials utilized to 
prove clinical validity for an LDT? If utilized, please describe 
typical format for clinical validity clinical trials.
    Answer 3. Although I am not certain how often clinical trials are 
used to establish clinical validity for LDTs, laboratories have stated 
that a host of other forms of evidence have at times been used to 
establish clinical validity for LDTs. Owing to the expense of clinical 
trials and the less expensive nature of some of the other methods 
cited, it may be fair to assume that, in some circumstances, clinical 
trials are not the only source of evidence that can be used 
infrequently to establish clinical validity of LDTs.

    Question 4. Would default requirements for clinical trials to prove 
clinical validity potentially create barriers to developing new LDTs?
    Answer 4. Clinical trials could be one way to develop evidence to 
demonstrate clinical validity, but there may be situations for which a 
clinical trial may not be necessary and evidence from other types of 
analysis could be sufficient. For example, if a test exists that has 
been shown to be clinically valid (and approved by FDA) a subsequent 
diagnostic test for the same intended use may not need to repeat 
clinical trials if it shown to meet a determined level of equivalency. 
An abbreviated approach could be developed where a follow-on diagnostic 
test demonstrates a high level of analytical concordance (or 
improvement compared to validated reference material) to an approved 
diagnostic device. If analytical concordance is high, the clinical 
outcomes of the drug/diagnostic would be expected to be highly similar 
to the earlier approved device that was FDA approved to guide the use 
of the drug.

    Question 5. Please describe the current approval standard your 
laboratory relies on for determining whether to widely offer a new LDT 
to patients. Does the standard originate from a government body or from 
a peer-review authority, such as the College of American Pathologists 
and what is the scope of that standard?
    Answer 5. Many of the current oversight mechanisms, such as CLIA or 
peer-reviewed certifications, focus on laboratory processes rather than 
the clinical validity of the test itself. The College of American 
Pathologists (CAP) does conduct proficiency testing, wherein it 
provides individual laboratories with unknown specimens for testing and 
participating labs analyze the specimens and return the results to CAP 
for evaluation. However, this proficiency testing is not done prior to 
patients receiving the test. An important component of any new 
regulatory approach is the requirement for pre-market demonstration of 
analytical and clinical validity. If tests are being evaluated for the 
first time based upon their post-market use and outside of a research 
setting, it places patient safety at risk to inaccurate tests that 
could have been previously identified through sufficient pre-market 
review. This is one reason we support FDA premarket review for LDTs, as 
they are the only entity that assesses analytical and clinical validity 
before patients are exposed to tests.

    Question 6. What portion of your laboratory's test menu are LDTs as 
compared to FDA approved or cleared IVD test kits?
    Answer 6. While I can't comment on a specific laboratory, we 
recently published a study that explored the broad use of LDTs versus 
FDA-approved tests with the same intended use. For this research we 
audited hundreds of medical records from across the country to explore 
the use trends of molecular tests that assess two critical alterations 
in lung cancer, ALK and EGFR. The results of this audit showed that 49 
percent of patients tested for ALK alterations and 87 percent for EGFR 
mutations were evaluated with an LDT, despite the availability an FDA 
approved assay.\1\ Given the large number of tests currently in use, 
there exists the potential for wide variability in test performance and 
claims. Any test that produces a result intended to be used to guide 
medical decisionmaking should be evaluated in its clinical context for 
risks that may be incurred. For patients, consumers, and healthcare 
providers it's the result of the test that's important, not where it's 
manufactured.
---------------------------------------------------------------------------
    \1\ Audibert, CM, et al. Use of FDA-Approved and Laboratory-
Developed Tests in Advanced Non-Small Cell Lung Cancer: Results of a 
Retrospective Market Analysis. Personalized Medicine in Oncology. Vol. 
5 No. 7. 278-84. September 2016.

    7. What are the most common modifications made to an LDRT or FDA 
approved or cleared test kits?
    8. How many ``new'' LDTs are a result of modification within your 
laboratory?
    9. How many modifications result in a significant clinical impact 
for a patient receiving the test?
    10. How many modifications change or expand the intended use of an 
LDT?
    [Responses were not available for questions 7-10 above.]
                             senator casey
    Question 1a. Under the current system, it's possible for both an 
FDA-approved diagnostic and one or more LDTs to be available to 
patients and providers at the same time. I have several questions about 
what happens in these situations.
    How does a health care provider or a patient know if the test being 
ordered is FDA-approved or if it's an LDT?
    Answer 1a. In many cases, it is unlikely that the healthcare 
provider who orders a test for their patient is aware of whether the 
test performed is FDA-approved or an LDT, in instances where an FDA-
approved and LDT intended for the same use exists. In our research, we 
found that 21 percent of oncologists who had ordered tests used in 
determining treatment for lung cancer reported that they did not know 
what type of test was used when asked to identify whether the test was 
a single-gene assay or multi-gene panel. Moreover, when respondents 
were able to identify the brand name of the test or the name of the lab 
offering it, they often incorrectly reported labeled the tests they 
used as lab-developed or FDA-approved. If the healthcare provider isn't 
aware of the type of test being used it is of even greater likelihood 
that the patient doesn't know.

    Question 1b. Does the existence of an FDA-approved test raise 
questions about the validity or accuracy of other LDTs testing the same 
thing?
    Answer 1b. The existence of an FDA-approved test does raise 
questions about potential variability between LDTs and the approved 
version. The extent of that variability is usually unknown because the 
FDA-approved test and existing LDTs are typically not directly 
compared. However, they are held to different standards in terms of 
their performance. FDA-approved tests are subject to pre-market review 
of data demonstrating their analytical and clinical validity. LDTs are 
not. Yet, the only difference between the FDA approved tests and most 
LDTs is where they are manufactured. This presents the potential for 
wide variability in test performance and claims, and the reality that 
some patients making major medical decisions based on inaccurate test 
results as they may receive different information depending on if their 
hospital or doctor's office is using an FDA approved test, or not.

    Question 1c. If you were a patient and were given the choice of 
either an FDA-approved test or a laboratory-developed test, with no 
difference in cost, which would you choose?
    Answer 1c. If given the choice between an FDA-approved version of a 
test and an LDT alternative, I would opt for the test that had been 
reviewed and approved by the FDA. FDA pre-market review provides a 
greater assurance of the analytical and clinical validity of the test. 
Particularly for tests that measure relatively new markers, the 
clinical relevance and potential risks of an LDT may not be as well 
characterized as tests reviewed by the FDA.

Response by Karen L. Kaul, M.D., Ph.D. to Questions of Senator Murray, 
            Senator Enzi, Senator Isakson, and Senator Casey

                             senator murray
    Question 1. Your testimony discussed the close working relationship 
staff in your labs have with the healthcare providers within your 
institutions, such as an oncologist making treatment decisions for 
patients. That communication seems to be critical to making sure that 
doctors understand what tests mean and how they make treatment 
decisions. If a healthcare provider outside of your system orders that 
same test, what level of interaction do you have with those providers?
    Answer 1. Pathologists provide consultative services for health-
care providers who have privileges at our hospital, regardless of 
whether they are employed by the system, or are independent physicians 
associated with the hospital or system. All patients treated within our 
system are given the same level of care, which includes (for cancer 
patients) review of pathology, molecular findings, radiology and 
clinical details at multidisciplinary treatment conferences. Each 
hospital or system conducts its own series of such treatment planning 
conferences, which are based on published consensus treatment 
guidelines such as those from the NCCN; this provides continuity and 
consistency between treatment and care at different institutions. We 
generally would not provide consultative services for physicians who 
are not affiliated with our hospital or who do not use our laboratory 
services. Reference laboratories that test samples from physicians in a 
variety of settings may rarely provide limited consultation, but not at 
the level of hospital lab based pathologist who attends the 
multidisciplinary conferences, and is deeply involved in diagnosis and 
care.

    Question 2. Our country's public health labs play a key role in 
helping our communities deal with disease outbreaks, prepare for 
emerging infections like Zika, and screen our newborns. How do lab 
developed tests help meet these challenges? What do you think is the 
best way to balance the necessary rapid evolution of tests with 
assurances that the tests work as intended?
    Answer 2. Labs have historically developed many tests and 
procedures to provide diagnosis of emerging infections. Our lab 
successfully utilized an in-house influenza assay during the 2009 H1N1 
(swine pandemic), and again when certain commercially available assays 
were found to miss some cases of the virus as it underwent its usual 
seasonal DNA evolution. More recently a lab-developed assay for Zika 
virus was launched to provide much needed diagnosis in the Houston 
area. In many locations, patients are waiting weeks for test results, 
an unacceptable situation, especially for pregnant patients. Hospital 
laboratories are on the front lines of these epidemics and emerging 
infections, and need to be able to provide correct and timely diagnoses 
for patients, and also to limit the spread of infections. Better 
coordination with the public health system labs would be beneficial. 
Labs need access to tests early in an outbreak, either via access to 
the CDC test assays (because the public health labs capacity to test 
samples is rapidly overrun) or by a mechanism to utilize acceptable in-
house-developed tests that meet quality and performance standards. The 
FDA emergency use approval program is too slow to be effective in 
making test reagents available in outbreak situations.
                              senator enzi
    Question 1. In the hearing panelists testified that if the 
regulatory guidance concerning Laboratory Developed Tests (LDTs) is 
finalized many labs would be forced to close given a nearly impossible 
financial burden to meet compliance. Similarly, members of the panel 
also testified that a vast majority of their personalized medicine 
practices rely on in-house LDTs.
    Please describe what impact lab closures would have on availability 
of diagnostic tools for physicians, particularly those in highly 
specialized or rare diseases.
    In your view, would there be consolidation among commercial 
laboratories? If so, what would you anticipate repercussions of that 
change, specifically related to the availability of new or more 
specialized diagnostic tests?
    Answer 1. Labs develop test procedures to provide needed services 
to clinicians and patients, to maintain a level of care in keeping with 
consensus guidelines and the evolution of medicine. Hundreds of LDTs 
are performed across all divisions of the lab, and range from 
validating the use of a sample type or collection media that was not 
part of the FDA approval, to different diagnostic approaches that 
provide needed diagnostic information that is not otherwise available, 
or is more complete or faster than traditional approaches. The vast 
majority of lab testing needed to support personalized medicine falls 
into this LDT category.
    If labs were not able to offer such testing, there would be an 
enormous impact on patient care. In some cases, there would be simply 
no way to attain a diagnosis. In other cases, relying on older methods 
would be too slow, too insensitive, or would simply not provide the 
needed information for appropriate care. In general, only the largest 
commercial labs would be able to afford to submit LDTs to the FDA (and 
unlikely all LDTs: labs would be driven by commercial concerns rather 
than patient's needs), limiting patient access and slowing results, and 
preventing the local consultation that is so critical to patient care. 
Limiting provision of these tests to only reference labs would also 
impede education of pathologists as well as oncologists and other 
physicians, not to mention removing competition to lower charges. This 
would also create a significant barrier to the innovation arising from 
academic labs that has led to advances in patient care.

    Question 2. What types of evidence or studies do your laboratories 
conduct and assemble to show both analytical validity and clinical 
validity for a new LDT?
    Answer 2. Labs focus on analytic validity, and do examine clinical 
validity insofar as to prove correct identification of the clinical 
condition. Clinical utility is generally established in studies 
reported in the literature, with labs moving to establish the needed 
testing in-house as an LCT when it is not otherwise available. 
Extensive details for analytic and clinical validation is outlined by 
CLIA procedures, and labs are required to demonstrate accuracy, 
reproducibility, sensitivity and specificity, reportable range, 
reference intervals and interfering substances, and define calibration 
and control materials, as well as participate in ongoing proficiency 
testing programs to demonstrate quality.

    Question 3. How frequently are human clinical trials utilized to 
prove clinical validity for an LDT? If utilized, please describe 
typical format for clinical validity clinical trials.
    Answer 3. It is unusual for a lab to do a traditional clinical 
trial independently, as this is generally done to establish the need 
for the analyte. As part of a CLIA validation the lab will always 
examine a set of samples already with a diagnosis to demonstrate 
clinical validity of the test. There is a great need for more samples 
to aid in test validation, and high quality reference materials would 
be of great value in allowing to objectively assess the analytic and 
clinical validity and performance of their LDTs.

    Question 4. Would default requirements for clinical trials to prove 
clinical validity potentially create barriers to developing new LDTs?
    Answer 4. Clinical validity can be demonstrated with a set of well-
characterized blinded samples that labs would be able to access 
(purchase) for this purpose. Clinical trials are needed to demonstrate 
clinical utility--i.e., to establish the value of a new test to improve 
care. In many cases, labs are developing assays for assessment of gene 
mutations, markers, or analytes that are already known to be associated 
with a clinical condition, so a clinical trial is not needed.

    Question 5. Please describe the current approval standard your 
laboratory relies on for determining whether to widely offer a new LDT 
to patients. Does the standard originate from a government body or from 
a peer-review authority, such as the College of American Pathologists 
and what is the scope of that standard?
    Answer 5. Currently we watch medical literature, professional 
meetings, engage in discussion with colleagues to assess the need for a 
new LDT. When a new test is noted to offer an advantage, labs will 
develop an LDT if a high quality FDA approved assay is not available 
(note that the LDTS are most often developed years in advance of the 
FDA approved kit, to fill a clinical need). Often LDTs are developed to 
provide care consistent with national treatment guidelines. There is no 
formal national approval body. Many academic centers and laboratory 
departments have internal committees to review data and approve the 
assay (similar to institutional review boards for approving research 
studies). CAP does define in detail what data labs need to collect to 
validate a lab-developed test, and this data is reviewed by inspection 
teams at the time of onsite inspections. We carefully define 
performance requirements, collect data, do a statistical evaluation, 
and review with our lab and clinical colleagues prior to launching an 
LDT.

    Question 6. What portion of your laboratory's test menu are LDTs as 
compared to FDA approved or cleared IVD test kits?
    Answer 6. The proportion of LDTs on a lab's test menu varies 
widely: hospital labs offer a mix, with smaller community hospital labs 
offering primarily FDA approved testing and sending the more esoteric 
testing, such as that needed for personalized medicine, to an external 
lab. However, all but the smallest labs offer LDTs, many of which have 
been in use for decades, with extensive data to demonstrate their 
quality collected under CLIA. I would estimate that we run hundreds of 
LDTs.

    Question 7. What are the most common modifications made to an LDRT 
or FDA approved or cleared test kits?
    Answer 7. Modifications may be made to an FDA-approved test to 
accommodate specific sample types or tumors that must be tested but 
were not included in the original FDA approval. Similarly, use of new 
collection media, or other extensions of the clinical use of an FDA-
approved test are frequently needed, and are common reasons that cause 
a lab to collect additional validation data and essentially treat the 
FDA-approved test as an LDT.

    Question 8. How many ``new'' LDTs are a result of modification 
within your laboratory?
    Answer 8. It is difficult to accurately estimate how many FDA-
approved tests are modified. Some test kits in chemistry and hematology 
are likely to never be modified. However, with the speed with which 
DNA-based testing needed for personalized medicine is evolving and 
improving, most of the FDA-approved tests are behind the treatment 
standards and need modification, or are simply not adequate.

    Question 9. How many modifications result in a significant clinical 
impact for a patient receiving the test?
    Answer 9. Labs would not modify an FDA-approved test unless there 
was a significant clinical need, such as a sample type or collection 
media that was not covered by the FDA approval. However, this happens 
frequently, so labs are often faced with the need to modify or extend 
the intended use of an FDA approved assay. These actions would improve 
or broaden the impact of the test for patient care.

    Question 10. How many modifications change or expand the intended 
use of an LDT?
    Answer 10. Modifications to an FDA approved test are generally done 
to expand the intended use of the test to include needed new sample 
types or tumor types, and would require the lab to collect extensive 
additional data to demonstrate the performance of the assay for these 
purposes. This essentially converts the FDA test to an LDT, and is 
regulated by guidelines stipulated by CLIA. The same validation process 
and data collection would be done to extend the use of an assay that 
was originally classified as an LDT.
                            senator isakson
    Question. Knowing your background in infectious diseases and 
emerging threats, how do we ensure that innovation is not stifled at 
academic labs like Emory and at CDC who are both developing rapid 
responses to emergency situations like Zika and Ebola?
    Answer. Labs have historically developed many tests and procedures 
to provide diagnosis of emerging infections. Our lab successfully 
utilized an in house influenza assay during the 2009 H1N1 (swine 
pandemic), and again when certain commercially available assays were 
found to miss some cases of the virus as it underwent its usual 
seasonal DNA evolution. More recently a lab-developed assay for Zika 
virus was launched to provide much needed diagnosis in the Houston 
area. In many locations, patients are waiting weeks for test results, 
an unacceptable situation, especially for pregnant patients. Hospital 
laboratories are on the front lines of these epidemics and emerging 
infections, and need to be able to provide correct and timely diagnoses 
for patients, and also to limit the spread of infections. Better 
coordination with the public health system labs would be beneficial. 
Labs need access to tests early in an outbreak, either via access to 
the CDC test assays (because the public health labs capacity to test 
samples is rapidly overrun) or by a mechanism to utilize acceptable in-
house-developed tests that meet quality and performance standards; The 
FDA emergency use approval program is too slow to be effective in 
making test reagents available in outbreak situations.
                             senator casey
    Question 1a. Under the current system, it's possible for both an 
FDA-approved diagnostic and one or more LDTs to be available to 
patients and providers at the same time. I have several questions about 
what happens in these situations. How does a health care provider or a 
patient know if the test being ordered is FDA-approved or if it's an 
LDT?
    Answer 1a. Truly, if the goal is the best patient care possible, it 
would not matter if an FDA-approved test or lab-developed test is used. 
They are both maintained in the lab using the same standards for 
quality, which includes ongoing proficiency testing and review of data 
by external lab inspectors, regardless of which test is used. The 
initial approval process may differ, but it would be helpful for 
performance standards to be defined for all tests to meet prior to 
being placed into clinical service.

    Question 1b. Does the existence of an FDA-approved test raise 
questions about the validity or accuracy of other LDTs testing the same 
thing?
    Answer 1b. Currently, there are many examples of FDA-approved tests 
that do not satisfy needs of physicians and patients, and are not 
compliant with treatment guidelines. Many of the FDA-approved gene 
mutation tests in cancer are approved for one tumor but not another 
that needs that particular gene tested. Many FDA-approved tests don't 
cover the needed spectrum of gene mutations to be compliant with 
current consensus treatment guidelines.

    Question 1c. If you were a patient and were given the choice of 
either an FDA-approved test or a laboratory-developed test, with no 
difference in cost, which would you choose?
    Answer 1c. I have been a patient, and so have my family members. If 
I knew that both test types satisfied identical quality standards, and 
cost the same, I would not have a preference between an FDA approved 
test and an LDT. I would want the most complete and accurate test 
possible, and the reality is that in many cases, this will be an LDT. 
And in nearly every instance, the LDT will be the less costly 
alternative. In the end, quality, safety, and getting the information 
needed for the patient is most important.

    [Whereupon, at 11:49 a.m., the hearing was adjourned.]

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