[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
__________
Printed for the use of the Committee on Health, Education, Labor, and Pensions
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Available via the World Wide Web: http://www.gpo.gov/fdsys/
U.S. GOVERNMENT PUBLISHING OFFICE
21-906 PDF WASHINGTON : 2018
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
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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.
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\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.
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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\
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\2\ Allison, M. Is Personalized Medicine Finally Arriving? Nature
Biotech. Vol. 26 N. 5; May 2008.
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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\
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\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.
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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.
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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.
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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\
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\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.
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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.
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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.
pdf.
4. Hughes TP, Branford S. Molecular monitoring or BCR-ABL as a
guide to clinical management in chrominc myelogenous leukemia. Blood
reviews 2006;20:29-41.
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.
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\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.]