[House Hearing, 111 Congress]
[From the U.S. Government Publishing Office]
THE POTENTIAL NEED FOR MEASUREMENT
STANDARDS TO FACILITATE THE RESEARCH
AND DEVELOPMENT OF BIOLOGIC DRUGS
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HEARING
BEFORE THE
SUBCOMMITTEE ON TECHNOLOGY AND INNOVATION
COMMITTEE ON SCIENCE AND TECHNOLOGY
HOUSE OF REPRESENTATIVES
ONE HUNDRED ELEVENTH CONGRESS
FIRST SESSION
__________
SEPTEMBER 24, 2009
__________
Serial No. 111-53
__________
Printed for the use of the Committee on Science and Technology
Available via the World Wide Web: http://www.science.house.gov
______
U.S. GOVERNMENT PRINTING OFFICE
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COMMITTEE ON SCIENCE AND TECHNOLOGY
HON. BART GORDON, Tennessee, Chair
JERRY F. COSTELLO, Illinois RALPH M. HALL, Texas
EDDIE BERNICE JOHNSON, Texas F. JAMES SENSENBRENNER JR.,
LYNN C. WOOLSEY, California Wisconsin
DAVID WU, Oregon LAMAR S. SMITH, Texas
BRIAN BAIRD, Washington DANA ROHRABACHER, California
BRAD MILLER, North Carolina ROSCOE G. BARTLETT, Maryland
DANIEL LIPINSKI, Illinois VERNON J. EHLERS, Michigan
GABRIELLE GIFFORDS, Arizona FRANK D. LUCAS, Oklahoma
DONNA F. EDWARDS, Maryland JUDY BIGGERT, Illinois
MARCIA L. FUDGE, Ohio W. TODD AKIN, Missouri
BEN R. LUJAN, New Mexico RANDY NEUGEBAUER, Texas
PAUL D. TONKO, New York BOB INGLIS, South Carolina
PARKER GRIFFITH, Alabama MICHAEL T. MCCAUL, Texas
STEVEN R. ROTHMAN, New Jersey MARIO DIAZ-BALART, Florida
JIM MATHESON, Utah BRIAN P. BILBRAY, California
LINCOLN DAVIS, Tennessee ADRIAN SMITH, Nebraska
BEN CHANDLER, Kentucky PAUL C. BROUN, Georgia
RUSS CARNAHAN, Missouri PETE OLSON, Texas
BARON P. HILL, Indiana
HARRY E. MITCHELL, Arizona
CHARLES A. WILSON, Ohio
KATHLEEN DAHLKEMPER, Pennsylvania
ALAN GRAYSON, Florida
SUZANNE M. KOSMAS, Florida
GARY C. PETERS, Michigan
VACANCY
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Subcommittee on Technology and Innovation
HON. DAVID WU, Oregon, Chair
DONNA F. EDWARDS, Maryland ADRIAN SMITH, Nebraska
BEN R. LUJAN, New Mexico JUDY BIGGERT, Illinois
PAUL D. TONKO, New York W. TODD AKIN, Missouri
DANIEL LIPINSKI, Illinois PAUL C. BROUN, Georgia
HARRY E. MITCHELL, Arizona
GARY C. PETERS, Michigan
BART GORDON, Tennessee RALPH M. HALL, Texas
MIKE QUEAR Subcommittee Staff Director
MEGHAN HOUSEWRIGHT Democratic Professional Staff Member
TRAVIS HITE Democratic Professional Staff Member
HOLLY LOGUE Democratic Professional Staff Member
DAN BYERS Republican Professional Staff Member
VICTORIA JOHNSTON Research Assistant
C O N T E N T S
September 24, 2009
Page
Hearing Charter.................................................. 2
Opening Statements
Statement by Representative David Wu, Chairman, Subcommittee on
Technology and Innovation, Committee on Science and Technology,
U.S. House of Representatives.................................. 4
Written Statement............................................ 4
Statement by Representative Adrian Smith, Ranking Minority
Member, Subcommittee on Technology and Innovation, Committee on
Science and Technology, U.S. House of Representatives.......... 5
Written Statement............................................ 6
Prepared Statement by Representative Harry E. Mitchell, Member,
Subcommittee on Technology and Innovation, Committee on Science
and Technology, U.S. House of Representatives.................. 7
Witnesses:
Dr. Anthony Mire-Sluis, Executive Director, Global Product
Quality, Amgen Inc.
Oral Statement............................................... 7
Written Statement............................................ 8
Biography.................................................... 15
Dr. Patrick Vink, Senior Vice President and Global Head of
Biologics, Mylan Inc.
Oral Statement............................................... 16
Written Statement............................................ 18
Biography.................................................... 68
Dr. Steven Kozlowski, Director, Office of Biotechnology Products,
Office of Pharmaceutical Science, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration (FDA),
Department of Health and Human Services
Oral Statement............................................... 68
Written Statement............................................ 70
Biography.................................................... 74
Dr. Willie E. May, Director, Chemical Science and Technology
Laboratory, National Institute of Standards and Technology
(NIST)
Oral Statement............................................... 74
Written Statement............................................ 76
Biography.................................................... 81
Discussion....................................................... 82
Appendix 1: Answers to Post-Hearing Questions
Dr. Anthony Mire-Sluis, Executive Director, Global Product
Quality, Amgen Inc............................................. 90
Dr. Patrick Vink, Senior Vice President and Global Head of
Biologics, Mylan Inc........................................... 95
Dr. Steven Kozlowski, Director, Office of Biotechnology Products,
Office of Pharmaceutical Science, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration (FDA),
Department of Health and Human Services........................ 97
Dr. Willie E. May, Director, Chemical Science and Technology
Laboratory, National Institute of Standards and Technology
(NIST)......................................................... 101
Appendix 2: Additional Material for the Record
Letter to The Honorable Bart Gordon from Bruce A. Leicher, Senior
Vice President and General Counsel, Momenta, dated September
23, 2009....................................................... 104
THE POTENTIAL NEED FOR MEASUREMENT STANDARDS TO FACILITATE THE RESEARCH
AND DEVELOPMENT OF BIOLOGIC DRUGS
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THURSDAY, SEPTEMBER 24, 2009
House of Representatives,
Subcommittee on Technology and Innovation,
Committee on Science and Technology,
Washington, DC.
The Subcommittee met, pursuant to call, at 10:11 a.m., in
Room 2318 of the Rayburn House Office Building, Hon. David Wu
[Chairman of the Subcommittee] presiding.
hearing charter
SUBCOMMITTEE ON TECHNOLOGY AND INNOVATION
COMMITTEE ON SCIENCE AND TECHNOLOGY
U.S. HOUSE OF REPRESENTATIVES
The Potential Need for Measurement
Standards to Facilitate the Research
and Development of Biologic Drugs
thursday, september 24, 2009
10:00 a.m.-12:00 p.m.
2318 rayburn house office building
I. Purpose
On September 24, 2009, the Subcommittee on Technology and
Innovation will hold a hearing to discuss measurement science,
standards and technology that need to be developed in order to (a)
facilitate the discovery and development of biologics,\1\ including
biosimilars;\2\ (b) reduce manufacturing costs for biologics and
improve the ability to monitor quality during the manufacturing
process; (c) provide tools to shorten the amount of time needed for the
research, development and regulatory approval of biologics; and (d)
ensure that patients receive life saving medicines that are both safe
and effective.
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\1\ The terms ``biologics'' and ``biologic drugs'' refer to a class
of medicinal products that are created by a biological process, as
opposed to being chemically manufactured, or medicinal products that
include molecules created by a biological process. Examples include
vaccines, blood and blood components, allergenics, somatic cells, gene
therapy, tissues, and recombinant therapeutic proteins.
\2\ The terms ``biosimilars'' and ``follow-on biologics'' (FOBs)
are used interchangeably to describe biologic drugs that are similar
versions of approved biologic drugs and may be considered for expedited
regulatory approval.
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II. Witnesses
Dr. Anthony Mire-Sluis is the Executive Director of Global Product
Quality and Quality Compliance at Amgen, Inc.
Dr. Patrick VJJ Vink is the Senior Vice President and Global Head of
Biologics at Mylan GmbH.
Steven Kozlowski, M.D., is the Director of the Office of Biotechnology
Products and the Office of Pharmaceutical Science at the Center for
Drug Evaluation and Research at the U.S. Food and Drug Administration.
Willie May, Ph.D., is the Director of the Chemical Science and
Technology Laboratory at the National Institute of Standards and
Technology.
III. Background
The use of biologics to treat complex diseases such as cancer,
diabetes, and multiple sclerosis is a novel approach to modern medicine
that offers new hope for once incurable and life threatening
diseases.\3\ But the lack of scientific knowledge about biologics
presents risks to patient safety as their use may result in severe and
potentially life-threatening adverse reactions. As an example, between
1998 and 2004, nearly 200 patients taking Eprex, a genetically
engineered version of erythropoietin, or EPO, contracted a disease
called pure red cell aplasia that resulted in several of those patients
becoming chronically dependent on blood transfusions.\4\
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\3\ See, e.g., Medicines in Development, Biotechnology, 2006
Report; available at http://www.phrma.org/files/Biotech%202006.pdf
\4\ See Bennett, Charles L., et. al., Pure Red-Cell Aplasia and
Epoetin Therapy, N. Engl. J. Med., 351;1403-1408 (September 30, 2004),
www.nejm.org; McKoy, June M., et. al., Epoetin-associated pure red cell
aplasia: past, present, and future considerations, Transfusion, Vol. 48
(August 2008), 1754-1762.
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If proper and accurate measurement standards, methods and tools had
been available, the Eprex incident may have been avoided. Biotechnology
companies, the Food and Drug Administration (FDA) and academia have
suggested that proper measurement standards and reference materials may
reduce the need for clinical trials and provide a scientific basis in
support of a regulatory pathway for the expedited approval of
biosimilars. This would result in lower costs both for new biologic
drugs\5\ and biosimilars.\6\
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\5\ Although estimates vary, on average the research and
development costs for a new biologic drug are believed to be about
$1.2-$1.7 billion and it is estimated that it takes about eight to ten
years of pre-clinical and clinical testing to obtain federal regulatory
approval. See, e.g., DiMasi, Joseph A., et. al., The price of new
innovation: new estimates of drug development costs, J. Health Econ.
22(2003) 151-185; Drug Development Costs Hit $1.7 Billion,
DrugResearcher.com (December 8, 2003), http://www.drugresearcher.com/
Research-management/Drug-development-costs-hit-1.7-billion
\6\ According to the Congressional Budget Office, the Federal
Government could save between $9 and $12 billion in Medicare payments
over the next ten years with the expedited approval of biosimilars.
Budget Options, Vol. 1: Health Care, Congress of the United States,
Congressional Budget Office (December, 2008), 126-128; Report to the
Congress: Improving Incentives in the Medicare Program, MedPac (June,
2009), 107.
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As an example, if there were a standard and universally accepted
method to look at the three-dimensional structure of a protein, any
variation in that structure could be readily recognized and a
biotechnology company or the FDA could determine what tests may be
needed to show whether the variation impacted the quality of a biologic
drug based on that protein. As another example, standard reference
methods and materials that indicate a biological molecule's potential
to interact with other biological molecules\7\ or other substances in a
way that could be harmful to patients would help researchers and the
FDA determine whether that particular molecule may be harmful. In fact,
the FDA has expressed a need for the development of methods,
measurements and protein characterization tools to help them better
assess the ``sameness'' of two biological molecules, as well as examine
factors which may indicate the potential for a biologic drug to
interact with other materials in a way that can cause an immune
response in a patient.\8\ Development of these standard methods,
measurements and tools will allow biotech companies and the FDA to be
more flexible in developing and refining the manufacturing processes
for biologics.
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\7\ These interactions are called ``aggregation,'' which is the
process by which one or more proteins may ``clump'' together. If
proteins that make up a biologic drug show a tendency to aggregate,
this increases the likelihood of an immunogenic response in a patient
that receives the drug.
\8\ Testimony of Janet Woodcock, Safe and Affordable Biotech Drugs:
The Need for a Generic Pathway, Hearing before the Committee on
Oversight and Government Reform, House of Representatives, 110th
Congress, 1st Session, Ser. No. 110-43 (March 26, 2007), 19-55.
IV. Witness Questions
The witnesses were asked to provide their views on how research,
development and the regulatory approval process for biologic drugs
could be improved through the development of standard reference methods
and materials. In particular, the following questions were asked of
each witness:
Is there a need for measurements, reference
materials, reference standards, standard processes, and
validation procedures to improve the research, development or
regulatory approval of biologics?
If developed, how would these measurements, reference
materials, reference standards, standard processes, and
validation procedures: (a) reduce manufacturing costs or
improve safety monitoring during the manufacturing process for
biologics; and/or (b) reduce the need for or improve the
accuracy of pre-clinical and clinical trials for biologics and
biosimilars?
What are the current scientific challenges to
assessing the ``sameness'' of two biological molecules produced
by different processes, or to comparing different batches of
biologics produced by the same process? What measurements,
reference materials, reference standards, standard processes,
and validation procedures can be developed to address these
challenges and how would they benefit the biotech industry and
patients?
Chairman Wu. The hearing will come to order.
Good morning. I would like to welcome everyone to this
subcommittee's hearing on metrology, the measurement needs to
support the development of biologics and biosimilars.
While I am very, very aware that other policy issues
related to biologics and biosimilars are being considered by
Congress, today we are here to focus on the role that we can
play in helping develop the underlying science needed to
support the growing biologics industry in general.
As I have studied the challenges of developing biological
drugs, I realized that some of the issues facing researchers
may be addressed through the same paradigm used for traditional
pharmacologic drug development but in other arenas the
measurement tools to completely characterize relevant
pharmacological products do not exist for biologics today.
I have learned as a Member of this subcommittee and I have
frequently said that if you can't measure it, it doesn't really
exist for technologic or economic purposes. It could be an
important item of faith but it is not an item of economics or
technology. I do believe that this is the crux of the
inconclusive nature of the biologics debate, this difficulty in
characterization and measurement, which is why this
subcommittee has convened this hearing, and this is--at least
at this point--I view this as the beginning of a series of
hearings that we will hold on this and related biologics
topics.
This is not a new area of inquiry for the Science and
Technology Committee. This committee was the first in Congress
to hold hearings on the science and potential of other growing
scientific fields, such as recombinant DNA, cloning, genome
mapping and genetic testing. The Committee's emphasis has
always been focused on meeting the metrology needs that allow
these new technologies to move forward. I would like to think
that the Science and Technology Committee was successful in
realizing that goal in a number of other arenas.
In that line, today's hearing will focus on the metrology
needs of the biologics industry, and this will be the first in
a series of hearings surrounding potentially personalized
medicine and genetic diagnostics.
One additional issue I want to address today is the
interaction between the industry and the Federal Government to
date. I welcome the suggestions of our industry witnesses on
how the relationship between NIST [National Institute of
Standards and Technology] and industry might be enhanced to
ensure that NIST can fully anticipate the industry's metrology
needs. The thrust of these questions will not be to criticize,
but to learn how a better working relationship might be
created.
I want to thank our witnesses for appearing before the
Subcommittee and I look forward to your comments and
suggestions.
Now I would like to recognize my colleague, Representative
Smith, for his opening statement.
[The prepared statement of Chairman Wu follows:]
Prepared Statement of Chairman David Wu
I want to welcome everyone to this subcommittee's hearing on the
metrology--or measurement science--needs to support the development of
biologics and biosimilars.
While I am aware that other policy issues related to biologics and
biosimilars are being considered by Congress, today we are here to
focus on the role of the Federal Government in helping develop the
underlying science needed to support the growing biologics industry.
As I studied the challenges of developing biologic drugs, I
realized some of the issues facing researchers may be addressed through
the same paradigm used for traditional pharmaceutical drug development,
where measurement tools to completely characterize relevant
pharmacological products exist. At this point, methods to fully
characterize the complex molecules used in biologics have not yet been
developed.
I have learned as a Member of this subcommittee that if you can't
measure it, it doesn't exist. I believe this is the crux of the
inconclusive nature of the biologics debate, which is why the
Subcommittee has convened this hearing.
This is not a new area of inquiry for the Science and Technology
Committee. The S&T Committee was the first in Congress to hold hearings
on the science and potential of other growing scientific fields, such
as recombinant DNA, cloning, genome mapping, and genetic testing. The
Committee's emphasis has always been focused on meeting the metrology
needs that allow these new technologies to move forward. Given the
state of these fields today, I would like to think the S&T Committee
was successful in realizing that goal.
Along the same line, today's hearing will focus on the metrology
needs of the biologics industry. This is the first in a series of
hearings the Subcommittee will hold on the metrology issues surrounding
personalized medicine and genetic diagnostic testing.
One additional issue I want to address today is the interaction
between industry and the Federal Government to date. I welcome the
suggestions of our industry witnesses on how the relationship between
NIST and industry might be enhanced to ensure that NIST can fully
anticipating industry metrology needs. The thrust of these questions is
not to criticize, but to learn how a good working relationship might be
made better.
I thank our witnesses for appearing before the Subcommittee and I
look forward to their comments and suggestions.
Mr. Smith. Thank you, Mr. Chairman, for calling this
hearing today on the very important emerging issue of biologic
drugs and the associated standards and measurement science
necessary to facilitate their continued safe and effective
development.
On this committee, we regularly review and consider the
impact science and technology and related policies have on our
lives. Arguably, in no other area has this impact been so
direct and profound as in medical science where dramatic
technological advances have lengthened and improved countless
lives here in America and throughout the world.
At the heart of these advances are the continuous
revolutionary innovations of the pharmaceutical industry. We
have almost come to take new lifesaving drugs for granted,
expecting the arrival of new medications to continue quickly
without full appreciation of the complicated and sensitive
development system.
Central to this system, of course, are strong intellectual
property protections without which there would not be
incentives to enable the risk taking and investment of capital
necessary to foster new drugs throughout the long scientific
development and regulatory approval process. This is especially
important with respect to biologics where the enormous and
unique potential to combat major diseases is hindered by the
lack of a regulatory pathway for managing intellectual
property.
To this end, I am pleased to be a sponsor along with
Chairman Wu of the Pathway for Biosimilars Act, which would
provide the intellectual property protections and regulatory
clarity necessary for ensuring and accelerating continued
advances in biologics.
However, we are here this morning to focus on a separate
potentially limiting factor to biologic drug development, the
need for measurement science and standards development to
enable and leverage further advances in biologics. The FDA and
industry stakeholders have identified significant measurement
science needs to support the regulatory approval and
manufacturing processes associated with biopharmaceuticals, and
we know NIST has world-class measurement science capabilities
well suited to this task.
While there appears to be a good opportunity to leverage
NIST's capabilities to meet these needs, the details of what
exactly needs to be done and what the appropriate roles and
responsibilities of NIST, FDA, industry and other stakeholders
should be must be carefully considered. These are complicated
questions surrounding an incredibly complex issue. That is of
course why we are here today, and I certainly hope and expect
this hearing provides us a better understanding to this end.
I want to welcome the witnesses here today. Thank you for
your time out of busy schedules, and I look forward to a
productive discussion.
[The prepared statement of Mr. Smith follows:]
Prepared Statement of Representative Adrian Smith
Thank you, Mr. Chairman, for calling this hearing today on the very
important emerging issue of biologic drugs, and the associated
standards and measurement science necessary to facilitate their
continued safe and effective development.
On this committee we regularly review and consider the impact
science and technology and related policies have on our lives.
Arguably, in no other area has this impact been so direct and profound
as in medical science, where dramatic technological advances have
lengthened and improved countless lives here in America and throughout
the world.
At the heart of these advances are the continuous, revolutionary
innovations of the pharmaceutical industry. We have almost come to take
new lifesaving drugs for granted, expecting the arrival of new
medications to continue apace, without full appreciation of the
complicated and sensitive development system.
Central to this system, of course, are strong intellectual property
protections, without which there would not be incentives to enable the
risk-taking and investment of capital necessary to foster new drugs
through the long scientific development and regulatory approval
process. This is especially important with respect to biologics, where
the enormous and unique potential to combat major diseases is hindered
by the lack of a regulatory pathway for managing intellectual property.
To this end, I am pleased to be a sponsor, along with Chairman Wu,
of the Pathway for Biosimilars Act, which would provide the
intellectual property protections and regulatory clarity necessary for
ensuring and accelerating continued advances in biologics.
However, we are here this morning to focus on a separate,
potentially limiting factor to biologic drug development: the need for
measurement science and standards development to enable and leverage
further advances in biologics. The FDA and industry stakeholders have
identified significant measurement science needs to support the
regulatory approval and manufacturing processes associated with
biopharmaceuticals, and we know NIST has world-class measurement
science capabilities well-suited to this task.
While there appears to be a good opportunity to leverage NIST's
capabilities to meet these needs, the details of what exactly needs to
be done, and what the appropriate roles and responsibilities of NIST,
FDA, industry, and other stakeholders should be, must be carefully
considered. These are complicated questions surrounding an incredibly
complex issue. That is, of course, why we are here today, and I hope
and expect this hearing provides us a better understanding to this end.
I want to welcome the witnesses here today, and I look forward to a
productive discussion.
Chairman Wu. Thank you very much.
If there are any other Members who wish to submit
additional opening statements, your statements will be added to
the record at this point.
[The prepared statement of Mr. Mitchell follows:]
Prepared Statement of Representative Harry E. Mitchell
Thank you, Mr. Chairman.
I believe that it is critical to establish a system to bring low-
cost, generic forms of biologic medicines to the market. A pathway for
``follow-on'' biologics is important for treating various medical
conditions, including illnesses for which no other treatments are
currently available.
Today we will discuss the measurement science, standards, and
technology needed in order to facilitate the discovery and development
of biologics, including biosimilars.
We will also examine how to reduce manufacturing costs for
biologics, how to shorten the amount of time needed for the research,
development, and regulatory approval of biologics, and how to ensure
that biologics are both safe and effective.
I look forward to hearing from our witnesses.
I yield back.
Chairman Wu. I would like to introduce our witnesses. Dr.
Anthony Mire-Sluis is the Executive Director of Global Product
Quality and Quality Compliance at Amgen. Dr. Patrick Vink is
the Senior Vice President and Global Head of Biologics at Mylan
GmbH. Dr. Steven Kozlowski is the Director of the Office of
Biotechnology Products in the Office of Pharmaceutical Science
at the Center for Drug Evaluation and Research at the United
States Food and Drug Administration. We are just going to call
you czar of something. And our final witness is Dr. Willie May,
who is the Director of the Chemical Science and Technology
Laboratory at the National Institute of Standards and
Technology. You will each have five minutes for your spoken
testimony. Your written testimony will be included in the
record in their entirety, and when you complete all of your
testimony, we will begin with questions and each Member will
have five minutes to question the panel. Dr. Mire-Sluis, please
begin.
STATEMENT OF DR. ANTHONY MIRE-SLUIS, EXECUTIVE DIRECTOR, GLOBAL
PRODUCT QUALITY, AMGEN INC.
Dr. Mire-Sluis. Chairman Wu, Ranking Member Smith and
Members of the Subcommittee, I would like to thank you for the
opportunity to testify to you today. I have devoted much of my
career as a scientific researcher and regulator to the question
of how best to standardize and improve methods for
biotechnology medicinal products, so I am particularly grateful
for the change to weigh in on this topic.
There is a clear and pressing need for standards and
methods to better understand biotechnology medicines and their
manufacturing processes. First, although we need standards,
they should be the best standards, not just any standards. We
also need to understand that even the best standards can and
must evolve as science evolves. And finally, while having the
best standards possible is necessary, it is not sufficient to
assure safety and efficacy. Randomized clinical trials will be
needed in order to understand biotechnology medicines the best
that we can.
First, let us look at the impact of standards on patient
safety. One place where it is very critical to have the best
and most modern standards is when detecting and measuring
whether and how a patient's immune system is reacting to a
biological product, that is immunogenicity testing.
Immunogenicity happens when your body attacks the medicine that
it has been given. Consequences can be that the drug does not
work, or even worse, can result in severe side effects. In
testing immunogenicity, every company uses different tests and
internal standards which have different capabilities. Because
of this, we cannot compare the results that these tests
produce. Standardization would allow scientists and clinicians
to accurately and consistently measure the immune response
against biotechnology products, essentially allowing us to
speak the same language.
Second, let us look at the impact that standards could have
on testing biotechnology products themselves. It is essential
that we understand the structure of our biological products and
its impact on safety and efficacy and having the very best
standard methods and reference materials available will help us
to achieve this. They could also lead to reduced costs by
minimizing wasted time and effort and could facilitate greater
efficiencies of the FDA [Food and Drug Administration].
But measurement standards alone cannot ensure the continued
health of the biotech pipeline. It is essential that we
preserve the incentives that drive innovative research and
development and that we have a strong science-based FDA.
Companies must invest on average $1.25 billion to develop and
test a biological product and only seven percent of biotech
medicines that enter development ever reach the market. That is
why strong protection of intellectual property, both patents
and data, must remain the cornerstone of this research-
intensive innovation-driven industry. In addition, maintaining
the FDA as a world-class science-driven regulatory agency is
essential to public health and safety. Only vigilant government
oversight can sustain confidence in the safety and
effectiveness of biotechnology products taken by millions of
patients. Federal appropriations for FDA have increased in
recent years. However, more needs to be done to support the
agency's ability to recruit and retain the best and brightest
scientists and medical reviewers, modernize the agency's
information technology systems and enhance FDA's scientific
capacity. We commend the Science and Technology Committee and
the Subcommittee for your roles in passing the COMPETES Act,
which has provided a firm foundation for American scientific
innovation.
Over the past three decades, biotechnology products have
revolutionized the war against chronic and life-threatening
disease. The biotechnology industry, the FDA and, most of all,
patients are counting on policy-makers to continue to foster
biotechnology as our best hope against the devastating diseases
that face us today.
So thank you for inviting me to testify today and I will be
pleased to answer any questions you may have.
[The prepared statement of Dr. Mire-Sluis follows:]
Prepared Statement of Anthony Mire-Sluis
Chairman Wu, Ranking Member Smith and Members of the Subcommittee,
thank you for the opportunity to testify today. My name is Anthony
Mire-Sluis and I am the Executive Director of Global Product Quality at
Amgen, one of the world's leading health care biotechnology companies.
We are headquartered in Thousand Oaks, California and have a
significant presence in North America, Asia, and Europe, with research,
manufacturing, distribution and sales facilities worldwide. Amgen has
more than 17,000 employees.
Amgen's mission is to serve patients. We discover, develop,
manufacture and deliver innovative human therapeutics. A biotechnology
pioneer since 1980, Amgen was one of the first companies to realize the
new science's promise by bringing safe and effective medicines from
lab, to manufacturing plant, to patient. Amgen therapeutics have
changed the practice of medicine, helping millions of people around the
world in the fight against cancer, kidney disease, rheumatoid
arthritis, and other serious illnesses. With a deep and broad pipeline
of potential new medicines, Amgen remains committed to advancing
science to dramatically improve people's lives.
A Perspective on the Importance of Biotechnology Medicines
Biotechnology medicines are the new frontier in the fight against
illness. The first approved medicine manufactured by Amgen--Epogen--
revolutionized treatment for patients on dialysis. Kidney disease
hinders the production of red blood cells, causing severe and chronic
anemia in patients. Just 25 years ago, these patients would have to
receive regular blood transfusions, yet with the FDA approval of
Epogen, patients simply received an injection when they went for
dialysis and their bodies were able to produce red blood cells on their
own. This effectively eliminated the time-consuming and risky burden of
transfusions.
This is just one example of the way biotechnology is
revolutionizing the war against disease. Since the science of
biotechnology was first utilized to make medicines, more than 200
biologics have been approved, including Amgen therapeutics, and these
products have changed the practice of medicine, helping over 325
million people around the world in the fight against cancer, kidney
disease, rheumatoid arthritis, hemophilia, multiple sclerosis, and
other serious illnesses.
Enormous investments in biotechnology have made possible the
industry's medical breakthroughs, including:
new cancer medicines that take specific aim at tumor
cells;
``clot-buster'' medicines that dissolve clots that
cause heart attacks and strokes, thus dramatically reducing
disability and death from these health episodes. When patients
are treated a short time following a stroke, they are at least
30 percent more likely to have minimal or no disability three
months after the stroke,\1\ which was the third leading cause
of death in the U.S. and the leading cause of adult disability
in 2004;\2\
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\1\ MEDTAP International, Inc., The Value of Investment in Health
Care (Bethesda, MD: 2004) at p. 12.
\2\ Id. at p. 10.
a medicine that can help inhibit the progression of
joint damage and dramatically improve the health and well-being
of patients suffering from rheumatoid arthritis and juvenile
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rheumatoid arthritis; and
medicines that can alter the debilitating course of
multiple sclerosis.
Biotechnology holds the promise of other breakthrough solutions for
many devastating diseases and conditions for which there is currently
inadequate treatment or no treatment. There are scientific
breakthroughs taking place every day that will eventually have a
dramatic effect on our ability to treat and cure patients . . . from
therapies that may one day replace damaged tissue and organs, to cures
for sickle cell anemia and congenital blindness.
At present, more than 630 biotechnology medicines are in
development,\3\ including:
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\3\ PhRMA, ``Medicines in Development: Biotechnology'' (2008), at
p. 1, available at http://www.phrma.org/images/
110308%20biotech%202008.pdf (last visited Sept. 21, 2009).
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254 for cancer and related conditions
162 for infectious diseases
59 for autoimmune disorders
25 for cardiovascular disease
19 for diabetes and related conditions
These innovative treatments include:
monoclonal antibodies to treat asthma, Crohn's
disease, and lupus
therapeutic vaccines for AIDS
recombinant proteins to treat autoimmune disorders
Yet with all of the promise that biotechnology holds for modern
medicine, there are a number of very difficult hurdles that must be
overcome to bring that promise to fruition for patients. A recent peer-
reviewed study in the Journal of Managerial and Decision Economics
estimated the total capitalized cost per approved biopharmaceutical to
be $1.241 billion.\4\ Time is also a challenge for developers of
biopharmaceuticals: the Tufts Center for the Study of Drug Development
found that the a biotech medicine takes 97.7 months--more than eight
years--to progress through clinical development and FDA review.\5\ And
biotech drug development is not for the feint of heart. Only seven
percent of biotechnology medicines that enter the development stage
ever reach the market.\6\
---------------------------------------------------------------------------
\4\ DiMasi, Joseph A. and Henry G. Grabowski, ``The Cost of
Biopharmaceutical R&D: Is Biotech Different?'' Managerial & Decision
Economics, vol. 28, issue 4-5, pp. 469-479 (2007), at p. 475, available
at http://www.manhattan-institute.org/projectfda/wiley-inter
science-cost-of-biopharm.pdf (last
visited Sept. 19, 2009).
\5\ Tufts Center for the Study of Drug Development, ``Average Cost
to Develop a New Biotechnology Product Is $1.2 Billion'' (Nov. 9,
2006), available at http://csdd.tufts.edu/NewsEvents/
NewsArticle.asp?newsid=69 (last visited Sept. 19, 2009).
\6\ PharmaProjects, ``Biotech Marches On Despite Low Success Rates
and Faltering Investment'' (June 10, 2002), available at http://
www.pjbpubs.com/uploads/downloads/pharmaprojects/100602.doc (last
visited Sept. 19, 2009). As PharmaProjects points out, ``[o]nly
anticancer drugs, with a success rate of 4.6%, represent a more risky
prospect.'' Id.
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The importance of biotechnology medicines to the health of patients
in the U.S. and throughout the world is clear. We have some specific
comments in response to the questions you have raised about methods and
standards that are used to understand the structure, function and
safety of biotechnology medicines.
The Need for Improved Methods and Standards for Characterizing
Biotechnology Medicines
Biotechnology medicines are complex molecules that require as
thorough as possible an understanding of their structure and function
to ensure their safety and efficacy. In comparison to standard chemical
drugs, biotechnology medicines (proteins) are hundreds of times larger
and more complicated. They are a chain of building blocks (amino acids)
that are often folded in many ways and can have sugars attached to them
that make them even more complex.
Because biotechnology medicines are usually made using living
cells, each protein molecule can be slightly different, resulting in a
product that includes a mix of many different forms of a single
protein. Due to this potential variability, it is critical for
biotechnology companies to utilize the very best methods\7\ to
understand their medicines and accurately identify which parts of the
protein are most important, in order to ensure optimal product safety
and efficacy.
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\7\ These methods (often termed `assays') are laboratory procedures
using machines or devices that allow scientists to look at different
parts of the protein--its structure (physicochemical assays) and how it
works (biological assays). For example, one can develop an assay that
indicates whether a protein exists as a single chain or as two or more
chains stuck together, or even more. This is important to know because
the protein that is safe and efficacious could be the single chain,
whereas two or more chains stuck together in the medicine might not
have the same ability to work, or may even raise safety concerns.
Important things to understand about an assay include, for example, how
well it identifies its target(s) at the right level (sensitivity), how
well it provides the same result if the same sample is tested several
times (reproducibility), and the extent to which different laboratories
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are able to carry out the assay and achieve consistent results.
``Validation'' refers to the way that scientists ensure that they can
understand how well an assay works once it has been developed. This may
involve running an assay several times with different samples for which
the results are known, and then assessing the results achieved in the
real-world setting. If the expected results are achieved, scientists
can be confident that the assay can be used again and again and will
provide consistently reliable results.
One safety concern with biotechnology medicines--immunogenicity--
occurs when the body does not recognize the protein being administered,
triggering the immune system to produce antibodies, which are special
proteins that bind to the offending protein in an attempt to neutralize
it and clear it from the body. Depending on the nature of the protein
administered, immunogenicity can cause the medicine to be ineffectual,
or could result in adverse reactions ranging from mild to life-
threatening. Because of the potential for immunogenicity, it is
essential for patient safety that scientists and clinicians are able to
properly, accurately, and consistently measure antibodies that develop
in patients against biotechnology medicines.
It has been shown that subtle or even undetectable changes in the
structural properties of a biotechnology medicine can have an impact on
its safety, efficacy or immunogenicity. Therefore, the laboratory-based
analytical methods used to understand the structural characteristics of
biological medicines play a critical role in the product development
process.
The earlier on in development a company can develop sound and
rigorous measurement methods, the earlier it can alter the product or
the process as necessary to maximize the chance of success with a new
biologic--ideally, before expensive clinical studies are started and
patients given a medicine that may not work as expected. Having
standard methods and reference materials available as soon as product
development begins should give companies a head start in creating a
successful product. Furthermore, development costs may be minimized if
manufacturers don't have to `reinvent the wheel' of method development
and validation for each product. In addition, better understanding of
the product allows for development of more robust manufacturing
processes that in themselves lead to reduced manufacturing failures,
reduced wasted materials and rework, and cost containment.
The availability of standard methods, and of reference standards,
may also ease the burden on regulatory reviewers in verifying that the
methods used by product sponsors were appropriately developed and
validated and routinely run. This would reduce the need for continuous,
in-depth evaluation of methods from product to product and from company
to company. In fact, the pharmacopoeias\8\ represent such a precedent,
in that they have already developed some standard method protocols
(``monographs'') that are widely used in drug development and
regulatory review, freeing reviewers from the need to spend unnecessary
time verifying method development/performance.
---------------------------------------------------------------------------
\8\ For example, the United States Pharmacopeia (see http://
www.usp.org/aboutUSP/), a non-profit, non-governmental organization
that serves as an official public standards-setting authority for
prescription and OTC medicines and other health care products
manufactured or sold in the U.S.; and the European Pharmacopoeia
Commission (see http://www.edqm.eu/en/Work-ProgrammeStatus-607.html),
which promulgates European reference standards and is currently working
to advance a ``Biological Standardisation Programme'' (see http://
www.edqm.eu/site/BSP-Background-Missions-
60.html). (Sites last visited 9/19/2009).
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As described earlier, from the patient's perspective, one area of
testing that would most directly benefit from standardization is
detecting and measuring whether and how a patient's immune system is
reacting in response to administration of a biologic medicine--that is,
immunogenicity testing. This testing can only be carried out in
clinical studies because, simply put, this is the only way to really
understand what is happening inside the patient.
Biopharmaceutical developers use a number of different assays to
detect and measure immunogenicity. Each such assay is developed in
parallel to the medicinal product and is specific to that particular
product. Additionally, each such assay utilizes internally-produced,
custom-made materials to make it work. Because these assays and methods
are unique to each company and to each product, though, they are not
amenable to being standardized, and reference materials are not easily
available. Because of this, understanding exactly how sensitive or
accurate these methods are can be very challenging.
It takes a very substantial amount of work for a biotechnology
company to produce good immunogenicity assays that will ensure that any
signs of an immune response in patients are detected as early as
possible after administration of a biologic medicine. The future
availability of high-quality standard methods, validation techniques,
and reference standards will reduce the chance that immunogenicity
assays are not able to detect the antibodies that could expose patients
to risks to their health. The more sensitive the method, the more
likely it is that an immune response can be detected and stopped before
it has a chance to harm the patient.
To date, scientists have not been able to determine exactly what
can trigger the body to recognize a protein product as ``foreign'' and
try to stop the immune response and clear it from the body. Because of
this, clinical studies must be conducted, in order to determine what
will happen when a biologic medicine is administered to patients.
Scientists have been working tirelessly to develop ways to predict
patients' responses, in order to prevent the occurrence of adverse
events in clinical studies. Much work remains to be done. Developing
better ways to predict immunogenicity will be key to the biotech
industry's ability to create protein-based medicines that do not cause
unwanted side effects in patients, both during the pre-approval
clinical studies required to establish safety and efficacy, and in
studies conducted after product approval.
It is clear that the development of standard methods, validation
procedures, and reference materials for the variety of methods
described (i.e., to understand the structure of the protein product,
how it functions, whether and how it causes immune responses, and the
like) will be of direct benefit to patients as well as to the
biotechnology industry. But how they will be created and developed must
be carefully considered. If researchers working in federal agencies
such as NIST, government regulators, and industry scientists work
together in this effort, it is much more likely that the outcomes will
be successful--for government, for industry, and ultimately for the
benefit of patients.
Science, Regulation, and Intellectual Property--Needs Beyond
Measurements
As discussed, the development of good assays to understand the
structure, function, safety and efficacy of biotechnology medicines is
important, but it is also crucial to biotechnology and to U.S.
leadership in biotechnology innovation that we focus on the three-
legged stool that serves as the public policy foundation on which the
biotechnology industry stands.
First, it is essential to support the scientific component of
biotechnology. The U.S. Government has an important role to play in
ensuring that our students receive rigorous scientific education and
training in order to cultivate the next generation of scientists. It is
also important that Congress make a renewed commitment to supporting
the basic research that will fuel future scientific discoveries. These
foundational components benefit our society as a whole by creating the
capacity for scientific initiative. These scientific contributions of
government are absolutely necessary--but they are not sufficient to
foster a robust biotechnology industry.
We must also maintain and fully support a robust, science-based
regulatory system to ensure that patients and their physicians can be
confident that the biomedical innovations available to them are safe
and effective.
Finally, we must put in place strong intellectual property
protections that encourage the public and private investment needed to
advance scientific innovation.
The Science & Technology Committee has been a leader on many of
these foundational necessities of biotechnology. The Committee--under
Chairman Gordon's leadership--has demonstrated that it understands the
need to put in place all three ``legs'' to provide a firm foundation
for scientific innovation. We commend your work to date and ask that
you facilitate U.S. biotechnology--the future of medicine and an
economic engine of the U.S. innovation economy--by continuing your
efforts to support robust science and regulation.
Fostering Science, Technology, Engineering & Mathematics (``STEM'')
Education
The Members of the House Science & Technology Committee clearly
understand the important role that education plays in the future of our
innovation economy, and have led Congressional efforts to improve
science, math and technology education in the U.S. The House's
Innovation Agenda\9\ has also supported this new emphasis on science,
technology, engineering, and mathematics (``STEM'') education.
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\9\ ``In 2005, House Democrats, working with leaders from the
academic, high-technology, biotech, venture capital, and
telecommunications sectors, as well as with students and young
entrepreneurs, launched the Innovation Agenda, a Commitment to
Competitiveness.'' ``The Innovation Agenda: Creating a New Generation
of Innovators,'' available at http://speaker.house.gov/issues?id=0016
(last visited 9/10/2009).
---------------------------------------------------------------------------
In 2007 Congress, with the key involvement of the Science &
Technology Committee, passed the America COMPETES Act.\10\ This
landmark bipartisan legislation was enacted in response to concerns
identified by the National Academy of Sciences, the National Academy of
Engineering, and the Institute of Medicine in the 2007 report, ``Rising
Above the Gathering Storm: Energizing and Employing America for a
Brighter Economic Future.''\11\ The America COMPETES Act included many
provisions related to enhancing mathematics, science and technology
education and workforce development in the United States,
including:\12\
---------------------------------------------------------------------------
\10\ The America COMPETES Act (``America Creating Opportunities to
Meaningfully Promote Excellence in Technology, Education, and Science
Act''), Pub. Law 110-69 (121 Stat. 572, Aug. 9, 2007), available at
http://frwebgate.access.gpo.gov/cgi-bin/
getdoc.cgi?dbname=110-cong-
public-laws&docid=f:publ069.110.pdf (last visited 9/10/
2009).
\11\ The National Academies, Committee on Prospering in the Global
Economy of the 21st Century, ``Rising Above the Gathering Storm:
Energizing and Employing America for a Brighter Economic Future''
(Washington, D.C.: The National Academies Press, 2007), available at
http://books.nap.edu/openbook.php?record-id=11463&page=R1
(last visited 9/10/2009). The Committee was charged by the National
Academies to respond to a request by Senators Lamar Alexander and Jeff
Bingaman of the Senate Committee on Energy and Natural Resources, with
endorsement by Representatives Sherwood Boehlert and Bart Gordon of the
House Committee on Science (now the House Committee on Science &
Technology), to address the following questions: ``What are the top 10
actions, in priority order, that federal policy-makers could take to
enhance the science and technology enterprise so that the U.S. can
successfully compete, prosper, and be secure in the global community of
the 21st century? What strategy, with several concrete steps, could be
used to implement each of those actions?''
\12\ ``The Innovation Agenda: Creating a New Generation of
Innovators,'' available at http://speaker.house.gov/issues?id=0016
(last visited 9/10/2009).
Investing in 25,000 new teachers through professional
development, summer training institutes, graduate education
---------------------------------------------------------------------------
assistance, and scholarships;
Creating grant programs to allow prospective teachers
to earn undergraduate degrees in mathematics, science,
engineering, technology, and critical foreign languages, in
conjunction with teaching certifications;
Establishing new math-focused programs for elementary
and secondary schools, particularly high-needs schools; and
Working with the business community and academia,
creating public-private partnerships in mathematics education
and training.
Amgen shares Congress' and the Committee's concern and interest in
educating the next generation of American scientists. Amgen invests
millions in programs to advance science education, from the local
elementary school to the world's top universities.\13\ To date, the
Amgen Foundation\14\ has committed more than $45 million in science
education funding to non-profit organizations throughout the United
States, Puerto Rico, and Europe.\15\ Our signature programs in
advancing science education include the Amgen Scholars Program,\16\ the
New Science Teacher Academy (co-founded with the National Science
Teachers Association), and the Amgen-Bruce Wallace Biotechnology Lab
Program.\17\
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\13\ For example, the Amgen-Bruce Wallace Biotechnology Lab Program
(named in memory of one of Amgen's first staff members) provides high
school students with flexible hands-on, inquiry-based experience with
some of the same materials, tools, and techniques used by professional
scientists. The three-week program, funded by the Amgen Foundation,
allows teachers to introduce recombinant DNA technology, a fundamental
of biotechnology, into their science curriculum and provides all needed
equipment, supplies, and reagents at no cost to the teacher or school.
Miletich, Joseph P., ``Needed--One Giant Leap for Science Education''
(Sept. 2, 2009), available at http://www.genengnews.com/blog/
item.aspx?id=548 (last visited 9/10/2009).
\14\ The Amgen Foundation, established in 1991, seeks to advance
science education, improve quality of care and access for patients, and
support resources that create sound communities where Amgen staff
members live and work. Amgen Inc., ``Inspiring the Scientists of
Tomorrow,'' brochure available at www.amgen.com
\15\ Amgen Inc., ``Inspiring the Scientists of Tomorrow,'' brochure
available at www.amgen.com
\16\ The Amgen Scholars Program, launched in 2007, is a $27.5
million, eight-year program that provides undergraduate students with
the opportunity to engage in hands-on scientific research at some of
the world's top universities. The initiative is designed to advance
science education by inspiring college students to pursue graduate
training and, ultimately, research and scientific careers. Amgen Inc.,
``Inspiring the Scientists of Tomorrow,'' brochure available at
www.amgen.com
\17\ ``The Amgen-Bruce Wallace Biotechnology Lab Program is an
educational outreach program that provides equipment, curriculum
assistance and supplies to high schools and colleges. This molecular
biology curriculum is designed to introduce, with extensive teacher
support, the excitement of scientific discovery to students. Each year,
over 10,000 students and faculty participate in this laboratory
experience and have the opportunity to explore the steps involved in
creating biotechnology therapeutics. The reach of this program has been
extraordinary with over 100,000 students exposed to the fundamentals of
biotechnology across multiple states.'' See ``About the Amgen-Bruce
Wallace Biotechnology Lab Program,'' available at http://
bwbiotechprogram.com/aboutus.php (last visited 9/15/2009).
Continuing America's Biotechnology Leadership Through Strong
Intellectual Property Protection
Strong protection of intellectual property--both patents and data--
is the cornerstone of any research-intensive, innovation-driven
industry. Failure to ensure adequate intellectual property protection
will undermine investment in biotech innovation. Without it, venture
capital that is the lifeblood of startup companies will divert
resources to investments with more certain returns, regardless of their
social value.
Investment decisions by more mature biotech companies that are
self-funding are necessarily driven by the possibility of recovering
the cost of bringing a product to market because this funds the next
discovery. Without adequate intellectual property protection, research
and development will be greatly diminished. This is a very expensive
proposition for patients waiting for cures.
We know that incentives to invest can be successful. For example,
Congress has put in place incentives to encourage orphan drug
development. Moreover, partnerships with American universities in high-
risk early-stage research are extremely important and can only flourish
with a strong intellectual property base.
The respect for intellectual property in America is one of the
reasons that we, as a country, lead the world in biotechnology
innovation. The biotech medicines industry not only helps patients, it
is also a major economic and job-producing asset for the U.S. at a time
when concern about losing jobs to low-wage countries is growing.
The U.S. leads the world in biotechnology research and development.
In 2006, the U.S. biotech industry invested in R&D nearly four times
what the next largest market invested.\18\ Moreover, in 2003, the U.S.
biotechnology industry spent more than $14 billion on research and
development, more than double the amount of biotech industry R&D
spending in Germany, France, Canada, Denmark, Switzerland, Italy,
Australia, Israel, and Korea combined.\19\
---------------------------------------------------------------------------
\18\ Ernst & Young, ``Beyond Borders: The Global Biotechnology
Report 2007,'' at p. 7, available at http://www.ey.com/Global/
assets.nsf/International/
Industry-Biotechnology-Beyond-Bor
ders-2007-Full/$file/BeyondBorders2007.pdf (last
visited 9/15 2009).
\19\ Van Beuzekom, Brigitte and Anthony Arundel, ``OECD
Biotechnology Statistics--2006,'' at p. 41, available at http://
www.oecd.org/dataoecd/51/59/36760212.pdf (last visited 9/15/2009).
---------------------------------------------------------------------------
Employment figures also reflect the U.S.'s dominance in biotech
R&D: the Organization for Economic Cooperation and Development (OECD)
estimates that the U.S. biotech sector employed approximately 50
percent more people than the U.K., Germany, France, Canada, Denmark,
Switzerland, Israel, Spain, Sweden and Belgium combined.\20\
---------------------------------------------------------------------------
\20\ Employment figures also reflect the U.S.'s dominance in
biotech R+D: the Organization for Economic Co-operation and Development
estimates that the U.S. biotech sector employed about 73,000 people in
2003--compared to 46,000 biotech employees in the U.K., Germany,
France, Canada, Denmark, Switzerland, Israel, Spain, Sweden and Belgium
combined. These employment numbers are significantly lower than other
estimates, as noted above. Van Beuzekom, Brigitte and Anthony Arundel,
``OECD Biotechnology Statistics--2006,'' at p. 21, available at http://
www.oecd.org/dataoecd/51/59/36760212.pdf (last visited 9/15/2009).
---------------------------------------------------------------------------
U.S. leadership in this industry is second to none, but we must be
mindful that virtually every industrialized country in the world has on
its economic agenda the development of a biotech sector to take over
the U.S. lead in high-skilled, high-paying biotech jobs. In order to
maintain U.S. leadership in biotechnology, supportive government
infrastructure and strong intellectual property protections are
essential.
Science-Based, Transparent Regulation
It is also critical to scientific and biomedical innovation that
America has--in the FDA--a world-class, science-driven regulatory
agency. Ensuring a strong system of regulation is an absolute necessity
to get vital medicines to patients, because doctors and patients must
have confidence in the safety and effectiveness of biomedical
discoveries.
A strong, well-funded FDA is essential to the health and safety of
the American public. This agency carries the important charge of
helping to assure the safety, effectiveness and availability of
medicines taken by millions. While federal appropriations for the FDA
have increased over the last several years, more needs to be done to
support the Agency's critical work. Additional federal funding is
critical to FDA's ability to recruit and retain the best and brightest
scientists and medical reviewers, modernize the agency's information
technology systems, and restore FDA's scientific capacity.
The House and Senate each have approved legislation\21\ that would
provide more than $2.5 billion in appropriated funding for FDA salaries
and expenses in fiscal year 2010. This represents an increase of nearly
$299 million in discretionary funding over FY 2009, the fourth straight
increase in FDA appropriations since 2006, and the highest level of FDA
appropriations ever proposed to be enacted. We encourage Congress to
pass legislation providing this historic level of funding for FDA, the
world's standard-bearer for sound, science-based regulation.
---------------------------------------------------------------------------
\21\ See H.R. 2997, ``Agriculture, Rural Development, Food and Drug
Administration, and Related Agencies Appropriations Act, 2010,''
available at http://thomas.loc.gov/cgi-bin/query/z?c111:H.R.2997 (last
visited Sept. 21, 2009).
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We have been greatly encouraged not only by the recent increase in
resources that Congress has provided to the FDA but also in the public
comments by Commissioner Hamburg since her confirmation. We encourage
this committee to support Commissioner Hamburg's efforts to maintain
and improve the science base of the Agency and to establish Regulatory
Science as a discipline as well-regarded as basic research in the years
to come. Without a strong foundation of science in regulation, life-
saving therapies will be unnecessarily delayed.
Additionally, we wish to thank Commissioner Hamburg for her
emphasis on transparency in the regulatory process, communicating risk-
benefit to the public, and fostering scientific exchange. All of these
efforts will go a long way toward advancing biomedical therapies in the
years to come. Amgen takes this opportunity to applaud these efforts
and specifically to voice our firm commitment to open scientific
exchange with FDA scientists.
Conclusion
We thank the Subcommittee and the Science & Technology Committee as
a whole for your work to date, and we urge you to continue as the
Committee of ``good ideas and consensus'' in fostering innovation in
science and biotechnology and maintaining America's role as the global
leader in biomedical discovery, R&D, and regulation.
We encourage the Committee and Congress to continue to strengthen
the three essential components of biomedical innovation:
Education in mathematics, science and technology--and
basic scientific research;
Strong intellectual property protection; and
A robust, science-based regulatory system.
Amgen and other biotechnology innovators, the FDA, and--most of
all--patients, are counting on you as policy makers to continue to
support and foster biotechnology as our best hope for addressing the
most devastating diseases facing us today.
Biography for Anthony Mire-Sluis
Anthony Mire-Sluis, Ph.D., is currently Executive Director of
Global Product Quality and Quality Compliance at Amgen. In this role,
he is responsible for the scientific assurance of product quality for
Amgen's biotechnology products and leads the company's corporate
quality compliance organization, ensuring compliance to regulatory and
Good Manufacturing Practice (GMP) requirements.
Prior to joining Amgen, Dr. Mire-Sluis served as Principal Advisor
of Regulatory Science and Review in the Office of Pharmaceutical
Sciences at the U.S. Food & Drug Administration's (FDA) Center for Drug
Evaluation & Research (CDER) and as head of Analytical Sciences and
Standards in the Office of the Director at the FDA's Center for
Biologics Evaluation & Research (CBER). While at the FDA, he worked on
a variety of regulatory issues, including regulatory review best
practices, guidance on biosimilar characterization, biotechnology
product comparability and stability and published on the topic of
methodology to assess immunogenicity.
Dr. Mire-Sluis trained in Genetics and Biometry at University
College, London University in the United Kingdom and has a Ph.D. in
Cell Biology and Biochemistry from the Royal Free Hospital in London.
Dr. Mire-Sluis began his career as the head of the Cytokine Group
in the Division of Immunobiology at the National Institute for
Biological Standards and Control, a United Kingdom regulatory authority
and World Health Organization (WHO) laboratory. He specialized in the
development of assays for the characterization and quantitation of
biological products and for the creation of WHO International Standards
for Cytokines and Immunological Sera.
Dr. Mire-Sluis joined the biopharmaceutical industry when he became
Director of BioAnalytical Sciences at Genentech. He also served in the
industry as Executive Director of Analytical Sciences at CancerVax
Corporation in San Diego, Calif.
Dr. Mire-Sluis is an expert for The International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). He is on the editorial boards of
the Journal of Immunological Methods and the journal,
Biopharmaceuticals, and has over 100 scientific references in journals
and textbooks.
Chairman Wu. Thank you very much.
Dr. Vink, please proceed.
STATEMENT OF DR. PATRICK VINK, SENIOR VICE PRESIDENT AND GLOBAL
HEAD OF BIOLOGICS, MYLAN INC.
Dr. Vink. Good morning. Thank you, Chairman Wu, Ranking
Member Smith and the Members of the Subcommittee on Technology
and Innovation. My name is Patrick Vink and I am the Head of
Global Biologics at Mylan. I am privileged today to testify
before the Subcommittee on behalf of Mylan, which for over
almost half a century has established a solid reputation of
manufacturing high-quality, affordable pharmaceuticals. Mylan
is the largest U.S.-based generic-pharmaceutical manufacturer
with one out of every 13 prescriptions dispensed in the United
States, brand name or generic, being a Mylan product.
Today, Mr. Chairman, on the 25th anniversary of Hatch-
Waxman, we face a situation comparable to that of 1984 when
perpetual monopolies enjoyed by biologics under the PHS [Public
Health Service] Act ended. Unlike Europe, the United States
lacks a biosimilar pathway. A viable biosimilar pathway does
not require a competitor to re-establish de novo the safety and
efficacy of a legacy molecule. Instead, a biosimilar's pathway
recognizes how much is already known about legacy biologics and
enables both regulators and competing biologics manufacturers
to appropriately rely upon the prior knowledge and regulatory
conclusion flowing from the data. Specifically, this
information is the safety and efficacy of the underlying
molecule itself. It is that demonstration of comparability, Mr.
Chairman, where biologic reference standards could play a
crucial role. Comparability is an established scientific and
regulatory principle that the branded biopharma industry itself
developed with FDA in 1996 to alleviate regulatory burden on
the branded industry when they changed the manufacturing
process for biologics. An example of this is the product
Avonex, which paved the way for biosimilars and in many
important respects effectively constituted the first biosimilar
because its approval dispelled the age-old paradigm of the
product is the process and established a new biologics
regulatory paradigm premised on comparability. As a result of
subsequent regulatory developments, comparability was adopted
globally as the same standard for all biologics and yet every
time a brand biologic manufacturer has implemented the
manufacturing change, the change has result in a change in its
biologic. The evolutionary process of this comparability creep
among branded biologics means there are a number of brand
biologics on the market today that may have drifted
significantly or to a minor extent away from the original
versions of those biologics initially approved by the FDA
across the entire lineage of a brand biologic. There is
therefore a continuum of substitutability determinations that
have maintained the market acceptance and enhanced the abundant
market success of so many high-priced biologics in the U.S.
market today. It is time to recognize the implications of the
regulatory history, accept the scientific conclusions and
regulatory confidency supports and proceed to apply all logical
inferences across the regulatory framework for all biologics
going forward.
This is where reference biologic standards come in. With
the availability of appropriate reference standards, it should
be readily ascertainable just how much a branded biologic has
drifted between its original approval and FDA's approval of its
most recent manufacturing change. Originally approved biologics
and the most recent changed biologics enable a fair and readily
adoptable set of parameters. These essentially could serve as
the regulatory goal posts for approval of a generic biologic.
Thus, to be approved, a competing biologic manufacturing would
need to demonstrate comparability within that range. From
Mylan's perspective, a viable approach for this subcommittee is
to appropriately incentivize reference standards by creatively
linking them in a straightforward manner to existing and future
incentives benefiting brand biologics so as to provide a return
to American taxpayers, the U.S. health care system and patients
in need of these biologics. Specifically, we believe reference
standards should be linked directly to these incentives
including any exclusivity, if any.
While Mylan, like other key stakeholders, is very troubled
by the excessive exclusivity that is currently contemplated, we
have identified a constructive way to leverage exclusivity if
there needs to be any. This can be accomplished by simply
conditioning a brand biologic company's receipt of exclusivity
on the brand's voluntary provision of a reference monograph and
reference standard materials consisting of supplies of active
ingredient and the various iterations of finished products
approved by the FDA as comparable. The monograph would be
published as the reference materials are evaluated and sold on
a not-for-profit basis to companies and researchers for
analytical testing purposes. NIST certainly would be an
appropriate repository for such reference standard materials.
NIST could apply its in-house expertise and develop new
analytical tools for regulators and biologic developers and
characterizing those reference standards will be without
developing new standards or guidance which would become quite
problematic at the regulatory interface with FDA. Authorizing
NIST to implement such a system could put the United States
back in a leadership position and enable the United States to
begin catching up with Europe and other countries that are now
many years ahead in terms of enabling patients access to
generic biologics. The state-of-the-art analytical methods now
available to biologics competitors like Mylan, the operation of
a reference standard system would further enhance the global
nature of comparability and contribute to a single universal
set of tools by which FDA could assess comparability going
forward. Such a system would benefit all biologics
stakeholders. The approach is suitable and appropriate, I am
convinced about it, readily implementable and can enhance both
the quality and efficiency of all biologics while enhancing
patients' access to biologics that can help save lives.
In closing, Mr. Chairman, I again want to thank you and the
Subcommittee on behalf of Mylan for this opportunity to present
our perspective on the critical importance of establishing a
biologics reference standard system as Mylan has proposed.
Towards that end, Mr. Chairman, Mylan looks forward to working
with the Subcommittee to implement this approach, and I welcome
the opportunity to address your questions.
[The prepared statement of Dr. Vink follows:]
Prepared Statement of Patrick Vink
Good morning. Thank you, Chairman Wu, Ranking Member Smith, and
Members of the Committee on Science and Technology's Subcommittee on
Technology and Innovation. My name is Patrick Vink, and I am the head
of Global Biologics at Mylan Inc. (Mylan).
For nearly 50 years, Mylan has built a legacy of manufacturing
high-quality, affordable pharmaceuticals. We are the largest U.S.-based
generic pharmaceutical manufacturer and the third largest generics and
specialty pharmaceutical company in the world. One out of every 13
prescriptions dispensed in the U.S.--brand name or generic--is a Mylan
product. Additionally, Mylan has consistently been recognized by the
U.S. Food and Drug Administration (FDA) and by the pharmacy community
for excellence in quality and service.
Mylan's proven track record of U.S. and global leadership led me to
join the Company to lead its biologics business, having spent 20 years
in the pharmaceutical industry, including the past decade managing
various businesses across the breadth of the biopharmaceutical
industry. If the Subcommittee will indulge me, I would appreciate the
opportunity to review briefly that biologics' experience and how
directly relevant it is to the issues at hand during today's hearing.
After obtaining my academic degree as a medical doctor and holding
different positions in the Pharmaceutical industry, I was appointed
Vice President of International Sales at Biogen Idec in 2001, where I
managed the commercial activities of a product that not only paved the
pathway for biosimilars but that in many respects effectively
constituted the first biosimilar itself: Avonex (interferon beta 1a).
As has been well documented in court filings and public policy debates,
Biogen ``broke the mold'' by eliminating the age-old paradigm of ``the
product is the process,'' thereby forever changing the biologics world.
In the process, Biogen validated a scientific and regulatory science
principle that is the basis for all biologics today, including
biosimilars: comparability (to which I will return in a moment). Based
on that limited filing, FDA determined that Biogen had demonstrated
comparability of two biosimilar products from a different cell-line, a
different manufacturing facility with a different manufacturing
process-based solely on analytics--without a single comparative
clinical trial, let alone a head-to-head clinical trial--all the very
same ``differences'' that many opponents of biosimilars point to today
as purported rationales for continued regulatory blocks on FDA's
approval of true biosimilars. In 2002 I became Global Head of
Biopharmaceuticals for Sandoz, part of the Novartis Group of companies,
where I managed all facets of the business, including the R&D and
regulatory initiatives culminating in approval of the first biosimilar
in Europe, Omnitrope (somatropin), which became the first recombinant
follow-on product to a previously-approved recombinant drug approved by
FDA. As in the past, while working now with Mylan, I have been
extensively involved on an ongoing basis in policy discussions and
legal/regulatory dialogue around implementation of biosimilars
legislation in Europe and the U.S. and development of biosimilars
guidelines in Canada and Japan.
In a very short period of time, Mylan has built a robust biologics
business implementing a sound strategy that has positioned Mylan as a
future leader in the field.
Mylan's success in biologics will build on Mylan's proven track
record in developing generic versions of synthetically-manufactured
complex drugs that are regulated by FDA under the Federal Food, Drug,
and Cosmetics Act (FD&C Act).
Instead, it is biologics--like erythropoietins, beta-interferons,
anti-TNFs, monoclonal antibodies, and other biologics--FDA regulates
under the Public Health Service Act (PHS Act) that make today's
critically-important hearing so relevant and the Subcommittee's
consideration of biologics standards so timely. The regulatory history
and U.S. marketing experience of these and so many other PHS Act
biologics point to the very significant role that could be played by
the appropriate implementation of biologics' standards in enabling
biologics' R&D across the biopharma spectrum. As I will outline, with a
viable biologics' standards system in place, claims about biosimilars
having ``differences'' could be rapidly resolved from the outset on
technical scientific grounds, quite separate from the demonstration
that such claims lack merit as a legal/regulatory matter. That legal
conclusion about these and comparable arguments--all of which build on
the disingenuous theme that biosimilars are ``only similar'' but not
``the same''--could be buttressed by biologics' standards that
establish the inherent scientific flaws underlying such blockades to
generic biologics access.\1\ As has been demonstrated repeatedly, the
purported ``differences'' in generic biologics are, in reality, no more
significant and typically are much less significant than the
``differences'' that FDA so readily accepted when approving Avonex
based on its finding of analytical comparability. Similarly, an
appropriately-implemented system of biologics' standards would bring an
immediate halt to scare tactics--such as those that have been used for
years here on Capitol Hill to block viable generic biologics
legislation and that continue to be vocalized through heavy investments
across Europe to impede competition as more and more biosimilars enter
the European market. Such irresponsible fear-mongering has been the
strategic lynchpin of those who have expressly and/or implicitly
opposed constructive solutions to marketplace entry of competing
biosimilar products under the PHS Act. This subcommittee can help bring
those specious claims to a halt.
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\1\ It is worthwhile in this regard to consider the comparable
gamesmanship that has been underway for some time with synthetically-
manufactured drugs, which is mired in a Citizen Petition proceedings at
FDA that seeks to indefinitely delay approval of applications. Such
Petitions are indicative of what the biosimilars industry is likely to
confront in the years ahead in seeking FDA approval for biosimilar that
would compete with marketed PHS Act biologics. Reference standards
could ensure that such gaming of an otherwise-legitimate public
petitioning process is no longer incentivized.
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It is with this background in mind that I would like to take this
opportunity to outline for the Subcommittee in more concrete terms how
such an appropriate biologics' standards system can be viably
established--including through the use of creative incentives--and to
address the precise role of such standards at the regulatory interface
of FDA's evaluation of all biologics, both branded originator biologics
as well as biosimilars that compete against those biologics. As I trust
will become apparent, this is a true win:win opportunity for all
stakeholders if collectively we have the courage to seize the
opportunity.
As has been well-established over many decades of experience with
chemical drugs, reference standards play a critical role for all
stakeholders. At their core, reference standards provide a transparent
and global ``toolkit,'' if you will, that enables regulators,
manufacturers, researchers, and others to know whether a product is
what it purports to be. For chemical drugs, in the U.S., that process
has been and continues to be managed exceedingly well by the U.S.
Pharmacopeia (USP). USP develops and publishes drug monographs that
specify various tests, measurements, and methodologies for analyzing
products, and USP sells on a not-for-profit basis actual drug
ingredient reference standards for use in analytical testing. This
system has significantly advanced the pharmaceutical sciences, enhanced
drug development across the biopharma industry, and facilitated the
work of federal and State enforcement officials who can readily test
whether products meet established USP specifications. It also has
substantially added to patient confidence in the high quality of
medicines across the spectrum that are labeled ``USP,'' from over-the-
counter products to prescription drugs.
A comparable process does not exist today for biologics, of course,
which is precisely why this hearing has been convened. Both I and
others could delineate for the Committee at some length the actual and
supposed reasons for the absence of such a system, but that will not
significantly advance its establishment. From my perspective, based on
my global experience across the biopharma industry, I note that a key
driver to date has been the inability to compel the establishment of
reference standards due to Constitutional and other legal
considerations that could arise from compulsory mandates requiring
biologics manufacturers to publish monographs and make actual reference
biologic standards available. Today, however, it is apparent to me and
to Mylan that this barrier no longer exists, not because those legal
issues have been resolved, but simply because those issues can be
avoided through the use of some creative but also very straightforward
incentives.
As Members of the Subcommittee undoubtedly are aware, your
colleagues on the Energy and Commerce Committee reported a bill as part
of health care reform that includes various provisions on biosimilars
(many of which, in Mylan's view, build very effective and time-
consuming blockades to FDA review and approval of biosimilars under the
guise of enabling competition--a subject beyond the scope of this
hearing).
In addition, that Committee-reported bill grants a new, and
globally unprecedented, 12-year non-patent data exclusivity period to
all currently-marketed biologics as well as to all future biologics.\2\
As currently drafted, that 12-year exclusivity provision is simply a
direct grant to the biotech industry without any give-back in return by
the industry to American taxpayers and patients in need of access to
biologics. While Mylan, like many of our allies in the generics
industry, finds that 12-year exclusivity period to be highly
problematic--particularly in the context of legislation replete with a
myriad of roadblocks to biosimilars such as those in the Committee-
reported bill--I have been re-evaluating the role of that exclusivity
in the context of this hearing. In doing so, I would suggest that
perhaps there is a constructive manner in which to both consider and
leverage that generous exclusivity, even if it ends up being, as we
would cage, much shorter than 12 years, such that it provides a
meaningful return to U.S. taxpayers as well as the breadth of the
biopharmaceutical industry. This could be accomplished simply by
conditioning a brand biotech company's receipt and exercise of
exclusivity on the company's voluntary provision of a reference
monograph as well as reference standard materials (both active
ingredient and the various iterations of finished product) to a
centralized Federal Government repository, which could evaluate the
materials and also sell them on a not-for-profit basis to other
companies and researchers for their testing purposes.
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\2\ In implementing its biosimilars framework, Europe
simultaneously implemented a new 8+2+1 data exclusivity regime. While
that EU exclusivity can total up to 11 years, its implementation was
dramatically different than that which is proposed for the 12-year
biologics exclusivity in the U.S. Specifically, the EU exclusivity
applied prospectively only to future products, not to existing
products, and it only went into effect for the first time for products
first approved several years after the pharmaceuticals legislation was
adopted in Europe. Furthermore, extensive price control systems within
the EU make that situation very different from the U.S.
---------------------------------------------------------------------------
One appropriate repository for such reference standard materials
could be NIST, which, as such a repository, could apply its in-house
expertise to enhance existing and develop new analytical tools for
regulators and biologics developers in characterizing those reference
standards and comparable biologics. In that role, NIST also could
readily publish the manufacturer-provided monographs that would be a
pre-condition of receiving exclusivity. Enabling NIST to implement such
a system could allow the U.S. to regain some of the important
leadership in biologics and biosimilar regulation that it has lost to
Europe and other parts of the world, who are now many years ahead of
the U.S. While there is a great deal of lost time to be made up, taking
this significant step could bring the U.S. a long way forward in the
global regulatory community. Importantly, this system does not envision
NIST undertaking the de novo development of new standards and
monographs or the like, as such a step could be confounding not only to
industry in developing biologics but also become quite problematic at
the regulatory interface with FDA. To the extent there is guidance or
standards to be implemented, that authority should remain with FDA as
it continues its over 100-year-old role as the regulator of biologics.
There are many legislative precedents for a ``carrot'' approach
such as the one I am proposing here. Perhaps the most readily-
translatable one involves highway funding and the 55 mph speed limit.
Years ago, Congress conditioned states' receipt of Federal highway
funds on implementation of State laws imposing a 55 mph speed limit.
After much Congressional debate and Supreme Court argumentation about
states' rights and related Constitutional issues, the Supreme Court
confirmed the appropriateness of the legislative approach because it
was non-compulsory, and such ``voluntary'' contingencies on the receipt
of federal largess became engrained in the legislative process. The
biopharma industry is quite familiar with the reverse process, having
engrained the PDUFA process on FDA, with review timelines conditioned
on the payment of user fees. In many respects, the approach I have
outlined here would simply establish some degree of reciprocity from
the industry.
There is no reason that such an approach could not be implemented
here, and I would be happy to share some initial concepts for such a
system with the Subcommittee if that would be helpful. More to the
point, there are compelling rationales for adopting such an approach in
the context of biologics reference standards, because it would
immediately overcome the anticipated onslaught of objections and
demands for ``public participatory processes'' that could quickly mire
down this subcommittee's initiatives in the same type of never-ending
procedural hurdles that have kept biosimilars off the U.S. market for
10 years despite Biogen's establishment of the technical and regulatory
pathway for biosimilars through its and FDA's ratification of
comparability in 1996.
Importantly, it is likely to be that comparability context in which
the greatest value of biologics' standards will be realized.
Ever since FDA's adoption of the comparability standard in 1996
(guidance attached) and the courts' ratification of that comparability
standard in Biogen's defense of its Avonex approval in 1997 (judicial
opinion attached), its ensuing history--including the International
Conference on Harmonization's adoption of the comparability standard on
a global basis in 2005 (guidance attached), and Europe's adoption of it
as the basis of its biosimilars framework (guideline attached)--has
resulted in its establishment and global recognition as the
``sameness'' standard for all biologics. And yet, there is no
universally-accepted set of analytical tools by which comparability is
judged. Instead, each biologics manufacturer adopts and applies its own
tools and methodologies and pre-clears them with FDA as the bases for
their individual comparability protocol. That said, the current state-
of-the-art methods and technologies for characterizing biologics and
assessing comparability are significantly improved in comparison to
those used initially (and still maintained today for some biologics)
when the first biologics were approved. We are nowadays able to
establish comparability between biologics from different manufacturer
and confirm this with abbreviated clinical trials. Further improvement
of these characterization tools will further help in avoiding
unnecessary clinical trials.
The adoption of even more sophisticated analytical methods and
consistent reference standards, particularly utilizing an approach such
as the one I have outlined here, would further enhance the universal
nature of comparability and could enable a single, universal set of
tools by which FDA could assess comparability going forward. Such a
system would benefit all biologics stakeholders, originators and
biosimilar manufacturers alike. In the pre-approval phase, this system
could enhance batch-to-batch consistency and enable greater certainty
before initiating human clinical trials. Post-approval, such a system
would establish a consistent approach to comparability assessments and
create a level playing field for all companies manufacturing biologics
and seeking to demonstrate comparability--whether on an inter-company
or an intracompany basis. Notably, Europe began applying comparability
across companies on an intracompany basis in 2003, which has benefited
all stakeholders tremendously.
The impact of biologics' reference standards would perhaps be felt
most directly, and most pro-competitively, in this latter context
involving biosimilars to PHS Act. This is because of the past
utilization of comparability by the branded manufacturers of such
products. Over the years, the Amgen's, the Genzyme's, and the
Genentech's of the world have run dozens and dozens of comparability
protocols for their marketed, and still-exclusive, biologics. While
there is no centralized repository of accessible data on the nature and
extent of the manufacturing changes implemented by branded biologics
manufacturers in connection with those comparability protocols, one can
readily anticipate based upon professional meeting presentations and
publications in the scientific literature that such manufacturing
changes have run the one gamut--from a piping modification, to a
manufacturing process change, from a building change on the same campus
to a cross-country or international facility change, from an inactive
ingredient change to a change in cell line. These and many other
manufacturing changes have been approved by FDA, and each time FDA has
determined--as it did 10 years ago with Avonex--that the ``changed''
biologic is comparable to the pre-changed biologic, thereby enabling
both biologics to be on the market and freely interchanged with one
another as supplies of the pre-change biologic are depleted and
supplies of the changed biologic come on-line. For many biologics, this
cycle has occurred on multiple occasions with the ``same'' biologic. In
the process, as a result of the cumulative effective of the full set of
manufacturing changes that have been implemented by the branded
manufacturer and approved by FDA, the currently marketed product has
evolved quite significantly from the one FDA approved originally. And
yet, all the way through, with each iteration of change, FDA has found
comparability, creating a situation in which the currently-marketed
product has to be considered comparable with the original one and thus
fully interchangeable regardless of the nature or extent of the
evolution.
In short, while FDA has at various points addressed concerns about
comparability ``drift'' between biosimilar products and the branded
biologic to which comparability has been established, there is a
longstanding history of Agency acceptance and indeed ratification of
that ``drift'' for branded biologics themselves. Scientifically, in the
absence of data to the contrary, neither should be a concern, as
reflected by FDA's continual approval of numerous manufacturing changes
for any individual biologic. Instead, we should collectively recognize
the implications of that regulatory history over the past decade,
accept the apparent scientific conclusions it supports, and proceed to
make it an established part of the regulatory framework for biologics
going forward.
This is where reference standards can play a critical role. With
the availability of reference standards as I have outlined here, it
could readily be determined just how much a branded biologic has
``drifted'' in terms of its specifications between the date of its
original licensure and the most recent manufacturing change approved by
FDA. Those specifications could then readily be adopted as the
regulatory ``goal posts'' that would need to be met by any other
sponsor seeking approval to market a comparable biologic. We therefore
support the current initiatives the National Institute for Science and
Technology wants to undertake.
The approach I am advocating is suitable and appropriate, readily
implementable, and can enhance both the quality and efficiency of
biologics' R&D while enhancing patients' access to the biologics that
can help save lives. It is for this reason, among many others, that as
a physician with my industry background, I am very comfortable with the
option of biosimilars being dispensed to patients, and adoption of this
reference standards system would only reinforce that comfort level.
Towards those ends, Mr. Chairman, I again want to thank you and the
Subcommittee on behalf of Mylan for this opportunity to present our
Company's perspective on these critically-important issues. I look
forward to addressing any questions that you and your colleagues on the
Subcommittee might have.
Biography for Patrick Vink
Patrick Vink, M.D., is Mylan's Senior Vice President, Global Head
of Biologics, a position he has held since March 2008. He is
responsible for developing and implementing the company's biologics
strategy.
Vink has 20 years of experience in the pharmaceutical industry.
Most recently, he was an independent consultant for life sciences
companies, venture capital firms, private equity investors and non-
governmental organizations. He also served as global head of business
unit biopharmaceuticals at Sandoz, leading the successful development
and registration of the first biosimilar pharmaceutical in the United
States and Europe, a landmark event for the industry. Prior to Sandoz,
Vink held leadership positions at Biogen and Sanofi-Synthelabo.
Vink earned his doctorate of medicine from the University of Leiden
in the Netherlands and an MBA from the University of Rochester in New
York.
Chairman Wu. Thank you very much.
Dr. Kozlowski.
STATEMENT OF DR. STEVEN KOZLOWSKI, DIRECTOR, OFFICE OF
BIOTECHNOLOGY PRODUCTS, OFFICE OF PHARMACEUTICAL SCIENCE,
CENTER FOR DRUG EVALUATION AND RESEARCH, U.S. FOOD AND DRUG
ADMINISTRATION (FDA), DEPARTMENT OF HEALTH AND HUMAN SERVICES
Dr. Kozlowski. Good morning, Chairman Wu, Ranking Member
Smith and Members of the Subcommittee. I am Dr. Steven
Kozlowski, Director of the Office of Biotechnology in the
Center for Drug Evaluation and Research at the FDA. Thank you
for this opportunity to discuss how the development of
measurement science standards and related technologies might
make it easier to understand the composition of FDA-regulated
biological products and the benefits that could be gained from
these advances.
The term ``biological product'' or ``biologic'' includes
products that have been manufactured using a biological process
such as a cell line with altered DNA to produce a monoclonal
antibody. There are different types of biologics presently on
the market but I will focus on one type today, therapeutic
proteins. As part of the FDA's responsibility of ensuring the
safety and effectiveness of drugs and biologics sold in the
United States, it is important that we be able to understand,
or to characterize, the composition of these products. We want
to know what materials they are made up of and how the
materials are arranged at a molecular level; that is, what is
the molecular structure. I will begin with a general
description of biologics with a focus on therapeutic proteins
and explain why they are so difficult to characterize. I will
then discuss potential benefits that could follow from improved
analytical methods and measurement standards.
Please take a look at the slide on the displays.\1\ This is
a graphic representation to scale of a single molecule of the
drug aspirin and a single molecule of the protein product human
growth hormone. You can see the relative size and complexity.
But in comparison to other biologics, human growth hormone is
actually simple and well characterized. I was initially going
to show a graphic comparing aspirin to a monoclonal antibody,
which is five times the molecular size of human growth hormone,
but then the aspirin would have been rather difficult to even
see.
---------------------------------------------------------------------------
\1\ See last page of testimony.
---------------------------------------------------------------------------
I would like to point out three specific limitations of our
current analytical methods. First, there are additional
components not shown on this graphic that we call post-
translational modifications. For monoclonal antibodies and many
other proteins, these modifications include sugar chains of
various sizes, and our current analytical methods are not
sufficient to fully assess these additions. Second, we are
unable to fully characterize the three-dimensional structure of
a biologic, and third, we currently lack methods to measure and
quantify the aggregation or the clumping together of protein
molecules.
I will now turn to three specific benefits we might see
from improved analytical methods and measurement standards.
Improved analytical methods would enable quicker and more
confident assessments of the potential effects of manufacturing
changes in process, equipment or raw materials. This could
reduce the requirements for animal or human studies for
evaluating these manufacturing changes. In addition, for
products that have abbreviated pathways for approval, improved
analytical methods could facilitate comparison of products and
detection of differences between different manufacturers.
Number two, the development of analytical methods would
evaluate the quality of a biologic throughout the manufacturing
process and that could provide a superior system for ensuring
product quality in the manufacture of all biologics. Improved
analytical methods would increase general knowledge in the
field of biopharmaceuticals. The FDA can use this knowledge
from improved analytical methods to inform our regulatory
decisions and industry can use this knowledge to design even
better products. With the development of new analytical methods
comes the need for new standards to evaluate them. The term
``standard'' can apply to measurements or processes, and
although process standards are valuable in ensuring effective
manufacturing process operation and validation, today I will
focus on measurement standards.
A measurement standard can be a standardized test or
standardized materials used to evaluate the performance of a
measurement method. Standardized test materials can be used to
evaluate the precision and accuracy of many different types of
analytical technologies and thus, are more likely to foster
competition and development of new and improved analytical
methods by industry and academia. The development of such
measurement standards would also be extremely valuable for
ensuring both current and future methods are working properly
and provide consistent results from assay to assay and from
laboratory to laboratory.
In conclusion, the field of biopharmaceuticals is advancing
rapidly, in many ways more rapidly than analytical
technologies. We have identified three specific properties of
biologics that we cannot sufficiently measure but that are very
important to medicinal activity: post-translational
modifications, three-dimensional structure, and protein
aggregation. Furthermore, reliable and discriminating material
standards would enhance use of current technologies and
encourage new technologies to fill current gaps.
Thank you for the opportunity to testify today. I am happy
to address any questions you may have.
[The prepared statement of Dr. Kozlowski follows:]
Prepared Statement of Steven Kozlowski
INTRODUCTION
Mr. Chairman and Members of the Subcommittee, I am Dr. Steven
Kozlowski, Director of Biotechnology Products in the Center for Drug
Evaluation and Research at the Food and Drug Administration (FDA or the
Agency). I very much appreciate this opportunity to discuss how the
development of measurement science, standards, and related technologies
might make it easier to characterize FDA-regulated biological products.
I will begin with a general description of one type of biological
product--therapeutic proteins--and explain some of the difficulties we
face in characterizing these products. I will then discuss potential
benefits that could follow from improved analytical methods and
measurement standards. Finally, I would like to describe three specific
properties of biological products that we cannot sufficiently measure,
but that are very important for understanding the behavior of
biological protein products. Better analytical methods to measure these
three properties would be extremely helpful in determining the
similarity of similar biological protein products.
Congress has charged FDA with ensuring the safety and effectiveness
of drug and biological products sold in the United States. As part of
fulfilling this responsibility, it is important that FDA be able to
understand, or characterize, the composition of these products. We want
to know:
what materials they are made up of, and
how the materials are arranged (i.e., the structure)
at a molecular level.
For some medical products, characterization is relatively
straightforward. Non-biological, often called small-molecule, drugs are
typically of low molecular size and are manufactured in chemical
reactors rather than biological systems. The structure of small-
molecule drugs can be verified through established analytical testing.
However, we are now in the era of molecular biology where many new
therapies are manufactured by inserting novel genes into living cells
so as to produce therapeutic proteins by biologic processes. For
example, many therapeutic monoclonal antibodies are produced using cell
lines with manipulated DNA.
Size and Complexity of Biologics: Protein Therapeutics
Compared to assessing the structure of small-molecule drugs, which
generally have fewer than 100 atoms, assessing the structure of
biologics is a formidable task. Therapeutic proteins are much larger
than typical small-molecule drugs. Using molecular weight as a measure
of size, human growth hormone is more than 150 times larger than
aspirin and a monoclonal antibody is more than five times larger still
than human growth hormone. Therapeutic proteins are also much more
complex than typical small-molecule drugs. Attached is a graphic
depiction of human growth hormone and aspirin, which illustrates the
differences in size and complexity.
The manufacture of biologics is also quite complex. Most biologics
are composed of many thousands of atoms linked together in a precise
arrangement (called the primary structure). This organization of atoms
is further organized into a three-dimensional higher order structure by
the folding of the linked atoms into a specific pattern that is held
together by relatively unstable connections. A protein molecule
consists of a long chain of building blocks called amino acids, of
which there are 20 types--a single protein chain can be made up of
hundreds of amino acids. The sequential order of these building blocks
in the chain can be critical for medicinal activity. Protein chains
with the same sequence of amino acids can fold in different ways--much
like a single piece of rope can be tied into a variety of different
knots. The specific folding of these chains is also very important in
carrying out their therapeutic functions.
In addition, many of the linked amino acids can have modifications
attached. These attachments can be small (only a few atoms) or very
large (similar in size to the rest of the protein). One commonly
observed attachment is the addition of complex groups of sugar
molecules, called oligosaccharides. Attachments occur at very specific
locations on the protein and, like folding, can have great impact on
the therapeutic function of the protein. A protein can thus be
represented as a long chain with 20 different types of links with
different possible attachments on the links.
To further complicate matters, biologics are not composed of
structurally identical units. Instead, they are a mixture of products
with slightly different features. This is referred to as micro
heterogeneity and can be represented as a mixture of very similar
chains that differ in a few links or in a few of the attachments. The
protein chains themselves can then be linked together or aggregated
(i.e., clumped). It is a challenge to analyze and characterize the
composition of such a mixture. Even with currently available analytical
technologies, some uncertainty regarding the actual structure of a
biologic usually remains. Simple measurements of biological activity,
such as enzyme activity, may provide additional information about a
product. But there is currently no way to, a priori, understand how the
product will perform in patients (e.g., distribution in the body,
immune responses against the product). As a result, nonclinical or
clinical studies are necessary to assess the safety and effectiveness
of the product.
Potential Benefits of Improved Analytical Methods
Advances in analytical tests during the last two decades have
driven progress in biopharmaceutical manufacturing, but there is still
room for significant improvement. New or enhanced analytical
technologies and measurement systems and standards that can more
accurately and precisely assess the higher order structure and
attachments of biologics would provide additional assurance of the
quality of biologics in at least three specific ways:
1. Improved analytical methods would enable quicker and more
confident assessments of the potential effects of changes in
the manufacturing process, equipment, or raw materials.
At present, manufacturers and FDA are hampered by the inability to
fully measure structural differences that could be caused by changes in
the manufacturing process. Since these unknown structural differences
could change the properties of the product, FDA might only approve a
manufacturing change after seeing the results of studies of the product
in animals or humans. This can significantly slow the implementation of
innovative process improvements and impede the manufacturer's ability
to react to changes in raw material supplies, which could reduce the
availability of the drug to patients who need it. Improved analytical
methods could reduce the requirements for animal and/or human studies
for evaluation of manufacturing changes. In addition, for products that
have abbreviated pathways for approval, improved analytical methods
could facilitate comparison of products and detection of differences
between manufacturers.
2. The development of analytical methods that can evaluate the
quality of the biologic throughout the manufacturing process
would provide a superior system for ensuring product quality.
This would enable increased productivity and improved quality
control during the manufacturing process.
3. Improved analytical methods would increase general
knowledge in the field of biopharmaceuticals.
FDA can use knowledge from improved analytical methods to inform
our regulatory decisions, and industry can use this knowledge to design
better products. Experience to date with certain monoclonal antibodies,
a type of therapeutic protein, illustrates how this increased knowledge
can inform both regulatory decision-making and product design. Some
monoclonal antibodies better direct a patient's immune system to kill
tumor cells, and some do not. One reason for this difference was only
discovered after the development of an analytical technique that
enabled scientists to characterize the structure of the sugar chains
attached to the antibodies. It was discovered that antibodies with
certain sugar chains were more consistently able to direct an immune
system to kill tumor cells than antibodies with different sugar chains.
FDA initially used this knowledge to require monitoring and control of
these sugar chains to ensure consistent clinical benefit to patients.
But this knowledge has also enabled industry to design new monoclonal
antibody products with enhanced tumor-killing activity.
Potential Benefits of New Measurement Standards
With the development of new analytical methods comes the need for
new standards to evaluate them. The term standard can apply to
measurements or to processes, and although process standards are
valuable in ensuring effective manufacturing process operation and
validation, today, I will focus on measurement standards. A measurement
standard can be standardized test materials used to evaluate the
performance of a measurement method, or it can be a specific analytical
procedure used to take a measurement. Standardized test materials can
be used to evaluate the precision and accuracy of many different
analytical technologies and are, thus, more likely to foster
competition and development of new and improved analytical methods by
industry and academia. Standard test materials could be used to test
the ability of an analytical method to detect differences between
product batches from a single manufacturer or products from different
manufacturers. For example, if a method is being developed to assess
the sugars attached to a protein, the analytical method could be used
to test a set of related standard test materials in order to determine
the precision and accuracy of the method. In this way, a given
technology can be optimized or a variety of different technologies can
be compared for their ability to accurately and quantitatively assess
the quality of a product. The development of such measurement standards
would also be extremely valuable for ensuring that current and future
analytical methods are working properly and are providing consistent
results from assay to assay and from lab to lab.
Three Specific Properties Needing Improved Measurement
FDA has identified three properties of therapeutic proteins that
cannot be sufficiently measured at this time but that are very
important for understanding the behavior of protein drugs. Improved
analytical methods to measure these three properties would be
particularly useful in determining the extent of similarity of
biological protein products intended to be similar.
1. Post-translation Modifications
As indicated previously, proteins contain added structural
features, such as attached sugar chains, that may be critical for their
clinical activity. These attached modifications can be complex and
heterogeneous, and we currently lack standardized analytical methods to
qualitatively and quantitatively assess the structure as it relates to
the intact protein and understand the relationship of the modifications
to potency and clinical performance. We are particularly interested in
better methods for analyzing the sugars (glycosylation) and other
modifications known to affect the medicinal activity of these products.
2. Three-dimensional Structure
As described previously, proteins must be folded into a three-
dimensional structure to become functional (sometimes a three-
dimensional structure can be misfolded). The proteins within a biologic
will have one major three-dimensional structure along with a
distribution of other variants differing in three-dimensional
structure. Our current ability to predict the potency of biologics
would be enhanced if we had improved ability to measure and quantify
the correct (major) three-dimensional structure, aberrant three-
dimensional structures (misfolding), and the distribution of different
three-dimensional structures.
3. Protein Aggregation
Some biological products can stick to one another. When many
protein molecules stick together, they are referred to as aggregates
and have the potential to cause adverse immune responses in patients.
There are many forms and sizes of aggregates and many current
methodologies have gaps in their ability to detect different types of
aggregates. Our ability to minimize adverse immune reactions would be
enhanced if we had improved ability to measure and quantify different
types of aggregates.
CONCLUSION
The field of biopharmaceuticals is advancing rapidly--in many ways
more rapidly than analytical technologies. New measurement tools and
standards would be of value in all the areas I have discussed. In
particular, reliable and discriminating material standards would
enhance use of current methodologies and encourage new technologies to
fill current gaps. Moreover, as the field of biopharmaceuticals
continues to advance, there is the potential for greater research and
development in the evolving area of follow-on biologics, which could
provide significant savings for consumers and the Federal Government
over time.
Thank you again for the opportunity to testify today. I am happy to
address any questions you may have.
Biography for Steven Kozlowski
Steven Kozlowski is the Director of the Office of Biotechnology
Products (OBP), Office of Pharmaceutical Science, at the Center for
Drugs Evaluation and Research (CDER), Food and Drug Administration
(FDA). OBP is responsible for the quality review of monoclonal
antibodies and most therapeutic proteins at CDER. OBP also provides
expertise on immunologic responses to therapeutic proteins and performs
mission-related research. Dr. Kozlowski received his medical degree
from Northwestern University and trained in Pediatrics at the
University of Illinois. Prior to joining FDA, Dr. Kozlowski worked as a
staff fellow in the Molecular Biology Section of the Laboratory of
Immunology, National Institute of Allergy and Infectious Diseases at
the National Institutes of Health. He studied the immune responses to
proteins and peptides during his fellowship. Dr. Kozlowski joined the
Division of Monoclonal Antibodies in 1993 and was tenured as a Senior
Investigator in 2000. He has been involved in all phases of the
regulatory process as a reviewer, from pre-IND product development
through inspections, licensing and post-approval supplements. Dr.
Kozlowski served as the Acting Director of the Division of Monoclonal
Antibodies from 2004-2005. He has also served as an instructor and as
an adjunct clinical reviewer at FDA. Dr. Kozlowski's research interests
include the effects of drugs on the immune system. He has been very
involved in promoting Quality-by-Design approaches for the manufacture
of biopharmaceutical products.
Chairman Wu. Thank you, Dr. Kozlowski.
Dr. May, please proceed.
STATEMENT OF DR. WILLIE E. MAY, DIRECTOR, CHEMICAL SCIENCE AND
TECHNOLOGY LABORATORY, NATIONAL INSTITUTE OF STANDARDS AND
TECHNOLOGY (NIST)
Dr. May. Good morning, Chairman Wu, Ranking Member Smith
and Members of the Subcommittee. Thank you for the invitation
to testify today. I am Willie May, Director of the Chemical
Science and Technology Laboratory at the National Institute of
Standards and Technology. Additionally, for the past several
years, I have led a strategic planning effort for NIST program
growth in the biosciences.
The previous speakers have discussed the need for
additional measurement science and measurement standards to
improve the quality and efficiency and the development,
manufacture and regulatory approval of biologic drugs.
Therefore, I will focus my comments on our past experiences in
successfully responding to other health-related measurement
problems and our capabilities for addressing the measurement
and standards needs associated with biologic drugs.
We have used our expertise in measurement science and
standards to address important problems in health care since
the 1920s. Over the years our capabilities and our programs
have expanded and evolved in accordance with both societal and
industry needs. The primary focus of our current program in
health care is on the provision of reference methods and human
serum-based standards for clinical diagnostics and on standards
for medical imaging. In both these areas, NIST-traceable
measurement standards and calibrations are reducing
misdiagnoses, wasteful repeat testing and treatment decisions
based on inaccurate measurement results.
NIST can also make critical contributions to underpin the
development and the regulatory approval process for biologic
drugs. NIST brings to the table our unique combination of
expertise in the physical, chemical and biological measurement
sciences. These along with our expertise in statistics and
information science provide us with the tools required to
support: more accurate assessment of the sameness of biologic
drugs made by different manufacturers and/or by differing
manufacturing processes, improved safety and efficacy, and
improved efficiency and reliability in the manufacturing
processes.
Based on extensive discussions with our colleagues at FDA
and the pharmaceutical industry, we have identified five
critical areas where improved measurement methods and standards
would benefit both FDA and companies that produce innovator as
well as generic biologic drugs.
First, the assessment of structural sameness. In this area,
NIST expertise in the determination of protein structure and
function and protein measurement science could be used to
develop quality assurance standards for the measurement methods
used to compare post-translational modifications and three-
dimensional structure.
In predicting adverse immune response in patients, in
addition to developing reference methods and standards for
protein aggregation, our expertise in protein measurement
science and cell system science can be expanded and applied to
support a better understanding of the protein aggregation
process and its induction of adverse human responses to
biologic drugs.
Developing a comprehensive understanding of the inner
complex workings of production cells, NIST's expertise can
enable a better understanding of the genetics and complex
biochemical networks of cells used in bioreactors. This would
support industry efforts to optimize the production of drugs
with desired features, namely low immunogenicity and the
appropriate post-translational modifications and three-
dimensional structure to facilitate efficacy.
Predicting drug function and toxicity--NIST's expertise in
cellular and protein measurement science, genetic testing and
bioinformatics could be used to support more accurate
characterizations of the human cell types most often used in
toxicity assays. This would in turn support development of more
accurate measurement systems and modeling tools for predicting
therapeutic function and adverse human reactions to candidate
drugs.
And finally, contamination from the manufacturing process
and packaging. In this area NIST expertise in analytical
chemistry and protein chemistry can provide the reference
methods and quality assurance standards for measurements used
to detect and quantify potential contaminants such as unwanted
proteins from production cells, viruses, metals and various
organic compounds.
NIST has already begun to act on some of these needs. We
have started a pilot effort focused on improved measurement
methods and standards for glycosylation and aggregation.
However, NIST, and I am sure my colleagues from FDA and
industry, would agree that there is much more to be done.
We at NIST will continue our outreach to stakeholders and
determine and refine the best path forward for addressing the
critical measurement and standard challenges associated with
biologic drugs.
So in summary, measurement science and measurement
standards for biologic drugs would facilitate scientifically
sound and fact-based decision-making in research and
development, manufacturing and the regulatory approval process
for biologics.
Mr. Chairman, thank you for this opportunity to testify
today. This completes my statement and I too will be happy to
answer questions.
[The prepared statement of Dr. May follows:]
Prepared Statement of Willie E. May
Chairman Wu, Ranking Member Smith, and Members of the Subcommittee,
thank you for the invitation to testify today. I am Willie E. May,
Director of the National Institute of Standards and Technology's (NIST)
Chemical Science and Technology Laboratory (CSTL). Additionally, for
the past four years, I have been responsible for assessing, developing
and coordinating NIST programs in the Biosciences. I am pleased to be
offered the opportunity to participate in this morning's discussion
regarding the ``Potential Need for Measurement Standards to Facilitate
Research and Development of Biologic Drugs.'' My testimony will explain
NIST's role in this area and some of the critical measurement
challenges that we have identified.
The Need for Additional Measurement Science and Measurement Standards
to Improve the Quality and Efficiency of Health
Care
The rising cost of health care and increased prevalence of chronic
diseases, such as heart disease and diabetes, are having a significant
impact on the economy and quality of life for many in the United
States. The Obama Administration is committed to improving quality and
enhancing the efficiency and delivery of health care. The provision of
the necessary measurement science and standards potentially can drive
innovation and make the drug and biologics development process more
efficient. NIST's unique mission, core competencies in measurement
science and standards, and history of relevantly addressing such needs
in other areas, provide strong evidence that NIST can help accelerate
this innovation.
NIST's Historical and Current Role
NIST's mission is to promote U.S. innovation and industrial
competitiveness by advancing measurement science, standards, and
technology in ways that enhance economic security and improve our
quality of life. Over the years, NIST traditionally has focused its
research and measurement service activities on the physical science and
engineering disciplines--and become internationally renowned in that
regard as demonstrated by our world-premier measurement and standards
program and many internationally-recognized awards in measurement
science, including three Nobel Prizes in Physics since 1997.
In keeping with the spirit of our mission to address the
measurement barriers to innovation that are the highest risk to U.S.
economic security and quality of life, the biosciences have been
identified as a new area for significant emphasis at NIST, with health
care being our initial area of focus. To help define our efforts, NIST
has engaged in extensive outreach to the Food and Drug Administration
(FDA), National Institutes of Health (NIH), US Pharmacopeia, and the
medical diagnostic and pharmaceutical industries over the last five
years. The consistent feedback from those efforts have indicated that
major improvements are needed in the measurement science and
measurement technologies that support efforts to predict, diagnose and
manage disease, as well as for those used to discover and develop safe
and effective medical therapies. The lack of adequate standards to
ensure accurate and comparable measurements is an issue that must be
addressed to fully realize the potential impacts of new innovations in
health care and its delivery, whether it be for in vitro diagnostic and
medical imaging biomarkers, predictive toxicology for drug safety,
medical device materials biocompatibility, genetic testing, or
biopharmaceutical manufacturing. Whether quantifying the amount of
protein in a cancer cell or determining which drug will be most
efficacious with minimal side-effects on an individual basis,
measurements are the foundation for improving our understanding of
biological systems. This is critical to guide and support the efficient
knowledge-based, development of new tools for meeting next generation
of health care needs. NIST's FY 2010 budget request includes $14
million to support new initiatives in health care, including standards
and measurement work to address the information technology and medical
diagnostic issues mentioned here.
NIST is not a new player in the health care arena. Improvement in
measurement science, our foundational role and area of expertise, is
and has always been critical to technological innovation in the health
sciences. For example, we have:
a collaborative program with the American Dental
Association begun in the late 1920's which has led to, among
other things, the development of polymer composite dental
fillings and the air-driven turbine drill now found in
virtually all dentist offices;
a program in Radiation Physics begun in the 1920's
that is responsible for the standards used in the calibration
of X-rays, mammography, and other radiotherapies like those
used in the treatment of prostate cancer; and
a program in Clinical Diagnostics begun in the 1970's
that initially focused on high purity primary references for
electrolytes (e.g., sodium, potassium, calcium), and
metabolites (e.g., cholesterol, creatinine, glucose, uric acid,
urea).
NIST's current efforts are focused on improving quality and
reducing the cost of health care by targeting the measurement and
standards needs associated with clinical diagnostics and medical
imaging. The typical patient is often unaware of the inaccuracies
associated with most medical testing that contribute to the high cost
and sub-optimal quality of health care. For example, standards exist
for only about 10 percent of the 700 most commonly ordered clinical
tests, and there are no traceable, quantitative standards for MRIs, CT
scans, ultrasounds, and other medical imaging technologies, even though
such images account for $50 billion in annual health care spending.
Lack of traceable measurement references and the resulting lack of
demonstrable accuracy and comparability of results in clinical testing
and medical imaging contributes to misdiagnosis and/or wasteful repeat
testing, and treatment decisions based on inaccurate information.
NIST works closely with industry, academia, and other government
agencies to identify the measurement and standards tools required to
improve the quality of laboratory medical tests and medical imaging.
Our efforts have resulted in significant breakthroughs such as the
development of calibrations for radiotherapies and mammography that led
to reduced exposure to radiation and made treatments safer; and
identification of potential new biomarkers associated with the onset of
Type 2 diabetes, metabolic syndrome and cancer. We have also expanded
our program in clinical diagnostics to include blood serum-based
standards to reduce measurement errors and associated costs of clinical
testing to support early cancer diagnosis and treatment.
NIST could potentially impact yet another area associated with the
increasing cost of health care: the growing use of biologics to treat
disease. These therapies can substantially improve patients' health and
quality of life, but also can be very expensive. To help bring down
costs for both patients and the Federal Government, the President has
proposed to establish a pathway for FDA approval of ``generic''
biologics that would provide seven years of data exclusivity for
innovator products. We can contribute to the President's proposal by
leveraging our expertise in measurement science and measurement
standards to:
improve efficiency and reliability of the
manufacturing processes involved in the production of biologics
; and
put in place the measurement tools to facilitate the
approval of such drugs, such as measurement methods or
reference materials that would allow the FDA to accurately
assess the ``sameness'' of a biologic made by different
manufacturers.
A discussion of the measurement challenges that we have identified
in this area will be the focus of the remainder of my testimony.
Measurement and standards barriers for the efficient manufacturing and
characterization of safe and effective
biopharmaceuticals
Based on input from the FDA and biopharmaceutical manufacturers,
NIST has identified a number of measurement and standards challenges
that, if addressed, will enable:
a more complete understanding of the
biopharmaceutical manufacturing process;
better control over the chemical, physical, and
biological processes involved in manufacturing complex protein
pharmaceuticals; and
improved methods for physical, chemical and
biological characterization of the finished product.
A key measurement need, whether for manufacturing process scale-up,
process changes or for the regulatory approval of generic biologics (or
``biosimilars''), is the ability to measure the ``sameness'' between
different batches of manufactured proteins and to gain a better
understanding of the variations that are critical to the efficacy and
safety of the drug.
Working with stakeholders, NIST has identified the following
critical phenomena and measurement barriers as areas where the
development of improved measurement technologies and methods would have
great potential to positively impact the biopharmaceutical
manufacturing industry and improve the ability of FDA to regulate
``generic biologics'' as proposed by the President.
Immunogenicity--There is currently no measurement infrastructure in
place to ensure the accuracy and comparability of the various methods
used to measure key attributes of protein biologics that cause
immunogenicity. Immunogenicity is the ability of a protein therapeutic
to provoke an immune response in a patient. An immune response may
range from neutralization of the drug rendering it ineffective to a
life-threatening allergic reaction. A key attribute of protein
biologics linked to immunogenicity is aggregation. Aggregation is the
process by which one or more proteins may ``clump'' together to form
visible or invisible particles. For regulatory approval, all protein
therapeutics must be carefully examined for the presence of aggregates;
however, detecting and measuring the wide size range of possible
protein aggregates remains difficult. Manufacturers often use different
measurement tools and protocols that can lead to contradictory results.
Improving the measurement science for protein aggregates would
benefit manufacturers and patients in several ways. For example,
development of protein particulate standards would support
harmonization of results across different measurement platforms used by
manufacturers and provide a better scientific framework for regulatory
requirements and decisions. These standards would also facilitate the
development and acceptance of improved tools for measuring protein
aggregates during manufacturing and in final products. Improved
measurement of aggregation would ultimately lead to better
understanding and prediction of protein aggregation and immunogenicity.
The ability to predict immunogenicity of new biopharmaceuticals would,
in turn, increase the probability for their successful development.
Three-dimensional (3-D) protein structure--Biopharmaceutical proteins
are synthesized in cells as linear chains of amino acids that must be
``folded'' into a three-dimensional shape that allows them to function
as intended. The improper folding of a biopharmaceutical affects
several aspects of how it functions as a drug once injected into the
patient. Potency, efficacy and safety can all be severely compromised
by misfolding events. At present there are no consistently reliable
physical or chemical characterization methods for determining the 3-D
structure of biologic drugs.
Standards and improved methods for the characterization of 3-D
structure would help biopharmaceutical manufacturers and instrument
vendors verify the accuracy and comparability of the structures of
manufactured biopharmaceuticals. These efforts would help to ensure
that the manufacturer is producing the same product from one batch to
the next and would also allow for direct structural comparison of the
new product to the original product form. Standards would also help
determine the relationship between the structure of a biopharmaceutical
and its function, which is critical to our understanding of how the
biopharmaceutical will act in the body. Standards for protein 3-D
structure would make the biopharmaceutical marketplace more efficient
in these key areas: authentification of identity, and determining the
inter-comparability of the drug from batch to batch.
Post-translational modification (PTM) of manufactured proteins--The
majority of approved protein therapeutics contain post-translational
modifications. PTMs are chemical modifications to the protein that
occur after it is synthesized such as the addition of sugar molecules,
lipids, or biochemical functional groups. Among these, the addition of
sugar molecules, or glycosylation, is the most important because over
half of all protein therapeutics are glycosylated. PTMs are known to be
critical to the safety and efficacy of many biopharmaceuticals and
consistent PTM profiles must be maintained for manufactured biologics.
There are multiple and varied methods for determining PTMs; however,
assessing the accuracy and comparability of results from different
methods remains difficult. In order to evaluate the sameness of protein
products, these modifications must be fully understood and
characterized. Due to the complex and varied nature of the
modifications, methods are currently lacking which quantitatively
assess the structure and how it impacts protein stability and
functionality.
Improved measurement methods and standards would enable instrument
vendors and biopharmaceutical manufacturers to develop measurement
systems for determining PTM of products. Characterizing the PTM
signature of products would enable more streamlined comparative
analysis, could also be used as a basis for the authentication of
manufactured products and help safeguard against counterfeit drugs, and
would reduce the cost of comparing the PTM of batches of
biopharmaceuticals produced by different methods or companies.
Contaminants in the manufacturing process--There is currently no
measurement infrastructure in place to help ensure the accuracy and
comparability of the methods needed by manufacturers, regulators, and
investigators to identify and protect the public from the intentional
and unintentional introduction of substances in pharmaceuticals and
biologic drugs. Chemical contaminants, such as heavy metals or organic
chemical compounds, can leach from the manufacturing vessels,
containment vials used in producing biologic drugs or packaging
materials. These contaminants can alter protein therapeutics in ways
that harm patients. For example, a major adverse clinical event
occurred when batches of erythropoietin (EPO, a glycoprotein hormone
that controls red cell production) were contaminated with leachable
chemicals from primary manufacturing containers. The unidentified
contamination caused aggregation of EPO, triggering an immune reaction
that destroyed the patients' abilities to regenerate red blood
cells.\1\ Contamination by proteins originating from the host cells
used to produce a protein therapeutic is also a concern. Additionally,
cellular contamination problems have occurred where the unknown
presence of a host cell enzyme destroyed the biopharmaceutical protein
once it was packaged, rendering the product useless.
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\1\ McKoy, J.M., et. al., Epoetin-associated pure red cell aplasia:
past, present, and future considerations, Transfusion, Vol. 48 (August
2008), pp. 1754-1762.
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Standards (reference measurement procedures, reference data and
certified reference materials) would enable regulators and
biopharmaceutical manufacturers to develop and critically evaluate
measurement systems for adulterant detection, which would improve the
safety of biopharmaceuticals and vaccines. For example, it might be
useful to develop certified reference materials for organic leachates
found in biopharmaceutical products and/or a reference data base of
process and packaging materials and their corresponding leachates.
Additionally methods for identifying host cell protein contaminants
would facilitate their removal, reducing the possibility of toxic or
immunogenic adverse drug events.
Production cell unpredictability--Biomanufacturing processes are highly
variable and unpredictable due to a lack of tools to measure the
internal workings of the cells that synthesize, modify and secrete the
desired biopharmaceutical product. Most protein therapeutics are
produced in Chinese Hamster Ovary (CHO) cells, but numerous problems
are routinely encountered where CHO cells, for unknown reasons, do not
perform appropriately. When this occurs, weeks or months of production
time are wasted. Industry has indicated to NIST a strong desire to have
available measurement tools to enable a more complete understanding of
the CHO cell system to a point where it can better be manipulated and
controlled. This would require the ability to identify, quantify and
measure the thousands of biomolecules and signaling pathways that
govern the inner working of these tiny biopharmaceutical factories.
Industry and academia would be better equipped to understand
changes in the cell function and the associated production capacity by
using a systems biology-based approach to monitor production cell
behavior. However, this would require greatly improved measurement
capabilities and a robust measurement infrastructure to support
analysis of cell behavior at this level, particularly in a
manufacturing environment. With such robust capabilities available, a
more fundamental understanding of bioprocessing would be possible,
enabling the agile, low cost manufacturing of safe and effective
protein- and cell-based products.
Quality-by-Design (QbD) Implementation--According to the FDA,\2\ under
a quality by design paradigm, biopharmaceutical manufacturing will
depend on a risk-based approach linking attributes and processes to
product performance, safety, and efficacy. QbD relies heavily on the
use of process measurement technology and process understanding.
Currently, there is no measurement science support in place to help
manufacturers develop and validate new process measurement tools and
improve biological manufacturing processes. Often when new measurement
tools are introduced, each manufacturer must expend considerable effort
and expense to validate their performance. As a result, there is much
duplication of effort, and manufacturers are often hesitant to accept
new tools. In addition, manufacturers are reluctant to adopt process
changes that might increase manufacturing efficiency for fear of
unpredictable changes to the product.
---------------------------------------------------------------------------
\2\ FDA, Submission of Quality Information for Biotechnology
Products in the Office of Biotechnology Products; Notice of Pilot,
Federal Register, Vol. 73, No. 128 (July 2, 2008).
Viral clearance--Removal of potential viral contaminants by filtration
is a key operation in the manufacture of biologic drugs. Both filter
vendors and biopharmaceutical manufacturers agree that standardized
test methods for classifying and identifying virus filters are needed
to better assess performance and comparability of different filters.
Establishing and understanding uncertainties in the measurements of
virus size using different methods, which often give conflicting
results, is the key to developing robust filter challenge protocols. In
addition, there is well known variability in virus preparations
obtained from different contract testing labs used to challenge
filters.
Improved viral size measurements and preparation methodologies
would enable manufacturers of biopharmaceuticals to better evaluate
filter performance and compare different filters. The development of
standard materials and methods to support the detection of viral
particles present at low levels in biologic drugs would support product
safety and quality assurance.
A longer range and broader challenge for the industry is the
unpredictable nature of biopharmaceutical function--Presently we do not
fully understand the interplay between all of the ongoing interactions
that take place in our bodies that ultimately define our health. This
incomplete understanding makes it difficult to completely predict the
effect of new drugs, as we do not know how the drug will impact other
parts of the biological system beyond the part it was designed to
address. This lack of understanding poses a challenge to the
development of new drugs and biologics because we are not able to
confidently measure or predict how effective the products under
development will be, or how toxic they might be. Multiple biologics
have been subject to market recalls and withdrawals due to unpredicted
side effects.
Addressing this challenge will take a significant multi-
disciplinary approach and a significant amount of fundamental research.
Critical to this effort is the development of improved measurement
capabilities that are essential to the creation and validation of
reliable new functional assays and predictive toxicology tools that
would help the biopharmaceutical and drug development industry
streamline drug development and approval processes.
NIST's Role in Biopharmaceutical Manufacturing
NIST has the unique Federal role of providing measurement science
and developing the measurement standards needed to help the American
economy innovate and compete. The biopharmaceutical industry (Companies
that innovate the original products and those that produce generic
products) faces many challenges to further grow and succeed in a
globally competitive marketplace. Biotechnology drugs, protein and
cell-based therapeutics, represent the fastest growing category of
therapeutic drugs in the United States. Improved characterization and
manufacturing of biologic drugs will support the growth of a new
industrial sector that could produce generic biologics eligible for FDA
approval, as proposed by the President, which would reduce the cost of
health care for patients and the Federal Government. We have developed
a comprehensive program plan that would broadly address critical
measurement and standards issues associated with the manufacturing of
both innovator and generic biopharmaceuticals such as:
The structural sameness of the manufactured
biopharmaceutical
The propensity of the biopharmaceutical to induce an
immune response in patients
The presence of contaminants coming from
manufacturing and packaging
The ability to better predict safety and efficacy of
candidate biopharmaceuticals
The comprehensive understanding of complex inner
workings of production cells
NIST already has begun a pilot intramural effort focused on
physico/chemical measurements of protein structure, glycosylation &
aggregation.
Summary
NIST has been, and continues to be, a critical resource for
addressing the measurement and standards challenges associated with
innovation in health care. The cost of developing new drugs (including
biologics) is certainly a contributor to health care costs. We look
forward to a successful partnership with key stakeholders in industry,
government and academia to address the measurement science and
measurement standards challenges associated with the cost-effective
production of both innovator and generic biologic drugs.
New measurement science and standards for biologic drugs will
facilitate fact-based decision-making regarding:
research and development, manufacturing and the
regulatory approval process;
reduced manufacturing costs and increased safety; and
the determination of ``sameness'' in the production
of both ``innovator'' and generic biologic drugs.
Mr. Chairman, thank you for the opportunity to testify today. This
completes my statement and I will be happy to entertain questions.
Biography for Willie E. May
Dr. Willie E. May is Director of the Chemical Science and
Technology Laboratory (CSTL), one of the ten technical operational
units within the National Institute of Standards and Technology (NIST)
and has 325 technical staff of and an annual Budget of approximately
$90M. The NIST Mission is to promote U.S. innovation and industrial
competitiveness by advancing measurement science, standards, and
technology in ways that enhance economic security and improve quality
of life. CSTL supports NIST's Mission by addressing customer needs for
measurements, standards, and data in the areas broadly encompassed by
chemistry, chemical engineering and the biosciences. Areas of growth
and/or increased emphasis include bioscience and health, nanometrology,
climate change science, and renewable energy technologies. CSTL is
organized into six Divisions along disciplinary lines:
Analytical Chemistry: Chemical measurements research
and services in: inorganic, organic and electroanalytical
chemistry; atomic, molecular and mass spectrometry; and
microanalytical technologies
Biochemical Science: DNA chemistry, sequencing;
Protein structure, properties, and modeling; Biomaterials;
Biocatalysis and bioprocessing measurements
Chemical and Biochemical Reference Data:
Experimental, theoretical, and computational research on the
identity and reactivity of chemical species, emphasizing data,
information, and protocols for the identification of chemical
and biochemical species
Process Measurements: Research, calibration services,
and provision of primary standards for temperature, pressure,
vacuum, humidity, fluid flow, air speed, liquid density and
volume, and gaseous leak-rate measurements; Sensor research
Surface and Microanalysis Science: Nanoscale chemical
characterization; Particle characterization and standards;
Electronic and advanced materials characterization; Surface and
interface chemistry; Advanced isotope metrology
Thermophysical Properties: Experimental, theoretical,
and simulation research on the properties of gases, liquids,
and solids, emphasizing thermophysical properties.
Prior to his current position, Dr. May led NIST's research and
measurement service programs in analytical chemistry for more than 20
years. His personal research activities were focused in the area of
trace organic analytical chemistry, with special emphasis on the
development of liquid chromatographic methods for the determination of
individual organic species in complex mixtures and the development of
liquid chromatographic methods for the determination of physico-
chemical properties such as aqueous solubilities, octanol/water
partition coefficients, and vapor pressures of organic compounds. This
work is described in more than 100 peer-reviewed publications. During
his 35+-year professional career, he has presented more than 300
invited lectures at U.S. industrial sites, colleges/universities and
technical meetings throughout the world.
Dr. May has several leadership responsibilities in addition to
those at NIST. He is a member of the 18-person International Committee
on Weights and Measures (CIPM), whose principal task is to promote
world-wide uniformity in units of measurement and oversee the
activities of the International Bureau of Weights and Measures in
Paris, France (BIPM); Chairs the CIPM Consultative Committee on
Metrology in Chemistry's Organic Analysis Working Group; Chairs the
Interamerican System for Metrology's Chemical Metrology Working Group,
Co-Chair's the Joint Committee on Traceability in Laboratory Medicine's
Working Group on Reference Materials and Reference Procedures; and
Chairs the Executive Board for the Hollings Marine Laboratory in
Charleston, SC.
Honors and Awards: Department of Commerce Bronze Medal Award, 1981;
National Bureau of Standards (NBS) Equal Employment Opportunity (EEO)
Award, 1982; Department of Commerce Silver Medal Award, 1985; Arthur
Flemming Award for Outstanding Federal Service, 1986; NOBCChE Percy
Julian Award for Outstanding Research in Organic Analytical Chemistry
and Presidential Rank Award of Meritorious Federal Executive, 1992;
Department of Commerce Gold Medal, 1992; American Chemical Society
Distinguished Service in the Advancement of Analytical Chemistry Award,
2001; Keynote Speaker for the 2002 Winter Commencement Ceremonies,
University of Maryland, College of Life Sciences; Council for Chemical
Research Diversity Award, the NOBCChE Henry Hill Award for exemplary
work and leadership in the field of chemistry, Science Spectrum
Magazine Emerald Award, in 2005, and the 2007 Distinguished Alumnus of
the Year Award from the College of Chemical and Life Sciences,
University of Maryland.
Discussion
Chairman Wu. I thank the panel, each and every witness. We
are now going to start questions from the panel and each Member
will have five minutes to ask questions, and I will begin with
myself.
It has been a while since I have been exposed to
biochemistry so please bear with me. When you all talk about
biologics and biosimilars and measurement, what you can measure
and what the need areas are, if you will, Dr. Kozlowski, you
seem to list a couple areas where we need work and I think that
that was implicit or explicit in each of your testimonies. Are
you saying that we can--well, what we have is the translation
process but that post-translation, whether it is glycosylation
or aggregation or the folding, the 3D structures that, you
know, beyond the translation stage, there is, shall we say, a
whole lot of wiggle in what the same translational product
ultimately becomes?
Dr. Kozlowski. There have been a lot of advances to date in
being able to characterize molecules and we do know a lot about
post-translational modifications with cutting-edge technologies
but we don't know everything. There are areas where we are
lacking the capabilities. Some of these capabilities are more
in academic labs and not necessarily translatable as well to
industry routine use, so I think we are much better at knowing
the very primary structure, the list of amino acids in sequence
in a protein, but our ability to account for all the different
ways they are modified is lacking. That is not to say we can't
do it at all, and I think that, you know, in terms of the
molecules that I showed in my slide, human growth hormone was
approved through an abbreviated pathway, both in the United
States and Europe, through the 505 pathway, and so we felt we
knew enough from the characterization of that molecule to make
some judgment about an abbreviated pathway. So I think we have
a lot of capabilities now. The question is how to make them
better because there is still a lot of uncertainty and gaps in
those areas.
Chairman Wu. So we are a lot better at the translational
end and improvements will be helpful in the other arenas?
Dr. Kozlowski. Yes.
Chairman Wu. Thank you for that, purely a curiosity
question, I guess, although hopefully it will be helpful to my
understanding going forward.
I would like to ask you about each of your companies'
interactions with NIST, your perception of NIST's attempts to
engage the biotech industry, what has been done well, what can
be improved.
Mr. Mire-Sluis. So I can speak from my personal experience
and Amgen's experience of working with NIST on this program.
Through the work that I have done at NIBSC [National Institute
for Biologic Standards and Control] and the World Health
Organization, I am very well versed in the mechanisms for
producing standard methods and reference standards. I have
collaborated very closely with NIST on this effort, providing
advice from an industry perspective as to our priorities.
Obviously there are multiple different areas that we could
explore from a scientific perspective. I mean, it is naive to
think that we can do them all in one go. There has to be some
form of prioritization. From our perspective, I think the
protection of patient safety obviously rises to the top of the
list, so the issues, for instance, of immunogenicity and
linking structure to those possible potential side effects I
think is of increased relevance.
I would also say that from a perspective of having worked
specifically for institutes whose role is to improve methods
and standards directly related to personal health, that I think
transparency is a big requirement for any institute working in
that manner. These methods and standards cannot be provided in
a vacuum. There has to be the highest scientific rigor
associated with these methods as described in our testimony.
Making a bad standard does not do anybody any good, and
therefore sharing industry and research expertise I think is
vital. So I feel that outreach from NIST should be increased
throughout the industry as well as the scientific community.
Chairman Wu. Thank you very much, Dr. Mire-Sluis.
Dr. Vink.
Dr. Vink. Yes. Mylan, as a generic manufacturer, has
interacted on several occasions with NIST, mainly via the work
for the U.S. Pharmaceutical [USP] and other areas. Being now
also entering into biologics as a generic manufacturer, we see
a big role for NIST as was laid out in my testimony. We see big
opportunity of laying down standards and making objective
comparability tools available so that everybody is helped
through the same standards. NIST can play a very big role in
creating that transparency, creating standards that are
applicable for everyone and we completely agree with what was
said at the table here. Every progress we make is another step
in better understanding biologics. We have come a long way in
the past 15 years. Every step, especially for our area of
biosimilars, will further help better characterizing these
drugs, reducing the burden of clinical trials, which are
currently still necessary.
Chairman Wu. Thank you very much. My time is expired. Dr.
May, since I have invited the other witnesses to comment about
how NIST--what things NIST can do, when it comes back to my
turn I plan to ask you about your views of how Congress can
enable you to do your job better.
With that, Mr. Smith, five minutes.
Mr. Smith. Thank you.
Dr. Kozlowski, could you tell us approximately how much
funding currently is spent at FDA on biologics research and
what the research really focuses on?
Dr. Kozlowski. I am not really prepared to provide the
exact funding for what happens with biologics at the FDA. I can
tell you that there are laboratories within the Office of
Biotechnology Products which look at the manufacturing of
biologics, including characterization, and we are in discussion
in fact with NIST on moving forward on some of those projects
together. We also look at biological assays that measure the
activity of molecules, which is another way of characterizing
them, and there are other labs within the Center for Drug
Evaluation and Research which characterize proteins using
current methods and may actually look at some samples that are
provided for them. So we have capabilities. Again, could we do
more with more capabilities? That is always true.
Mr. Smith. Could you speak to or share with us if you are
comfortable that there is not a lot of overlap between NIST and
FDA but yet still working together? I mean, that is sometimes a
very delicate balance, both Dr. Kozlowski and Dr. May.
Dr. Kozlowski. I think overlap is always a tricky question.
It is a value to have some core capabilities in an organization
simply so that they can communicate and work together, and so
some level of overlap in technology is good. I think, you know,
you need to be communicating and that is the way to leverage
the least overlap in big ways and to get the most benefit. And
for instance, the FDA and NIST just had a meeting a number of
years ago on the issue of characterizing proteins that they co-
sponsored and invited industry, and I think that was a great
opportunity for dialogue and further meetings like this that
involve both FDA, NIST and industry together may be good ways
of figuring out what our overlaps are, how to work best
together and how to do things in a way that as a combined group
makes the most progress.
Mr. May. As you know, NIST has absolutely no regulatory
authority. We are not lead agency on anything except
measurements and we focus on measurement science, technology
and standards that have impact across other areas where other
agencies in the Federal Government do have lead agencies that
have responsibility. So the only way for us to be successful is
to collaborate with both the industry and other federal
agencies in the areas where they have interest and lead agency
responsibility and we do the things that we do well, that is,
the underpinning measurement science, the technology and the
provision of standards.
Mr. Smith. Thank you.
And Dr. Vink, in your testimony you propose a repository
within NIST, Federal Government basically that would then sell
some of the information to other companies for testing and
research, and given the nature of biologic drugs, do you think
that such an arrangement might undermine the intellectual
property [IP], you know, the facets of intellectual property
and certainly the incentives to move forward in the future?
Dr. Vink. No, not per se. We believe that a repository is
actually part of what we all need to know as a service to
public health. This is the standard that we hold every product
to which is approved to so we believe this is more a tool to
guarantee for public health that there is a standard for every
product and that everybody who wants to compare itself to that
standard can be measured in an objective, transparent way, and
the IP is guaranteed by the IP legislation which is in place.
This will only allow regulatory authorities to hold the current
product comparable to the standard. Once the patent is expired,
it will open up everyone who wants to make a similar product
available and be measured to that standard. We don't believe
that there is an IP issue around it per se.
Mr. Smith. Thank you.
Thank you, Mr. Chairman.
Chairman Wu. Mr. Lujan--oops. Mr. Lujan has slipped away to
vote perhaps.
Ms. Biggert.
Ms. Biggert. Thank you, Mr. Chairman, and thank all of you
for being here. I would like to just follow up on what Mr.
Smith was talking about and find out what the other members of
the panel think about that, and before that, I just wanted to
ask one question. I think in your materials, Dr. Vink, you had
a case, Berlex Laboratory versus the FDA. Is that part of your
testimony or--I was concerned about the standards and the
conclusion of the case where the FDA allowed a new drug to go
on the market, which was never really tested but it was a test
of another similar drug that allowed that. So I would like to
know, you know, as far as intellectual property from the other
members but also is that the way our regulations work that a
drug really doesn't have to go through--what it says is, FDA
did not act unlawfully when it determined that Avonex is
clinically superior to Betaseron and to approve Avonex for use
by patients with M.S. without requiring clinical trials of
Avonex and issued its guidance document without notice and
comment rule-making. Dr. Sluis, could you comment on that?
Mr. Mire-Sluis. Comment on the Avonex experience or----
Ms. Biggert. Well, on that and also the intellectual
property question I think that Dr. Vink raises for allowing
other companies to test somebody else's drug even before it is
on the market.
Mr. Mire-Sluis. So I think as far as the intellectual
property issue goes, it is all down to the timing. This is
actually not a unique experience for the biotechnology
industry. The pharmacopoeias have been supplying reference
standards and monographs for products for many years and Amgen
itself is collaborating with both the European pharmacopoeia
and the U.S. pharmacopoeia to provide just that, reference
material and the description of a test we use for our products.
So I think this is nothing unusual. As I say, it is just a
matter of timing. What we don't want to do is to lose the
intellectual property that allows for innovation. I mean, the
innovative industry is the industry that is producing new and
novel drugs to benefit our patients.
Ms. Biggert. Do you think that we are losing the innovation
and creativity? Again, Dr. Vink's testimony talked about the
fact that we are behind the European countries and so many
other companies in our development of drugs.
Mr. Mire-Sluis. I am not sure that that perspective is
entirely correct in the sense that in Europe the regulations
for the pathway for biosimilars is somewhat more advanced than
it is in the United States. I think the standards that have
been created in Europe are those necessary to maintain the
safety and efficacy for patients and to include the requirement
for clinical studies for biosimilar products. So I think it is
a matter of the United States now has to develop similar
regulations that focus on patient safety, product efficacy
whilst retaining those incentives that are not going to damage
the innovative work that the innovation industry does or we
will lose the chance to create new and novel medicine for our
patients.
Ms. Biggert. Dr. Kozlowski, could you comment on that?
Dr. Kozlowski. So I think there is no technological
advantage that Europe has in considering these products. So
again, I think that there are technological issues for
everybody in terms of better methods to facilitate, you know,
how much clinical information is necessary, but I don't think
there is actually a scientific advantage. I think it is a
question of what pathways are available for what types of
products.
Ms. Biggert. Dr. Vink, maybe you can comment since you are
the one that raised the issue.
Dr. Vink. Commenting on the last part where I did not yet
comment on what is the difference between the different areas
of the world, which was actually the last part, I think as Dr.
Kozlowski and also Dr. Mire-Sluis said, the difference is that
there is a pathway. We believe that the pathway that is
actually present in Europe is working well. It leaves
scientific discretion with the regulatory authority. Not every
molecule is the same every time, and that is also why we
support so much NIST. The more--the better we characterize the
drug, the more we can shift the balance from actual
characterization of the drug to that part of establishing the
sameness and reducing the burden of unnecessary clinical
conformity trials. The better you know what you are talking
about, the less that is needed. But one thing is clear: safety
of patients is at the foremost important thing for everybody in
the industry.
Ms. Biggert. Thank you. I will yield back.
Chairman Wu. Thank you.
We have two votes called and they are approximately six
minutes. That is NBA time, six minutes, before the clock runs
out. It is my intention to try to get to everyone's questions
and then adjourn the hearing if possible, and if not, I will
ask the witnesses to kindly stay until we can return.
Dr. May, I promised to give you a shot at how Congress can
do a better job, so other than sending NIST more money, what
are some legislative improvements that would help NIST do its
job better?
Mr. May. Certainly providing legislation that authorized
more research in general or supported research in general on
the five critical areas that I mentioned, and those funds need
not necessarily come to NIST but certainly there needs to be a
lot of work on measurement science to understand the underlying
mechanisms and phenomena that are associated with things like
aggregation and many of the phenomena that we have all said are
critical to the regulatory approval of biologic drugs.
Obviously we would certainly be happy to see you support any
budget initiatives that come from the executive branch in this
area.
Chairman Wu. Thank you, Dr. May.
Dr. Vink, Mylan, you try to do or you do biosimilars. Since
a pathway exists in Europe and currently either does not exist
or is a very narrow pathway here in the United States, is your
biosimilars activity primarily in Europe and then you are
looking at the pipeline in the United States? I am just trying
to understand Mylan's business.
Dr. Vink. Mylan has recently entered the area of
biosimilars. After the integration of two companies, we became
a global company, and our activity is a global one. Our effort
is a global one. We believe that the biosimilar scientific
standards are the same or very much aligned between the
different continents so we aim at global product files and a
global strategy and we do believe that the United States will
also offer a tremendous opportunity for patients, health care
and companies to enter the area of biosimilars. So of course,
currently the market for us is open in Europe and has recently
opened in Japan. We have a strong belief that this will be also
soon in the United States, so we do not make any difference for
regions with respect to our strategy.
Chairman Wu. But your activity is a little bit higher in
those other areas right now and part of it is a biosimilars
pathway but further research and reference materials and
metrology would assist in those efforts?
Dr. Vink. Absolutely.
Chairman Wu. Well, we have a number of other questions.
This is the nature of this institution that you adjust upon
contact with reality. I thank the witnesses. We would like to
submit further questions in writing and perhaps you and the
organizations that you represent would be kind enough to
respond.
With that, again, I want to thank each and every one of you
for coming here, for testifying, and we will adjourn this
hearing. Thank you very much.
[Whereupon, at 11:01 a.m., the Subcommittee was adjourned.]
Appendix 1:
----------
Answers to Post-Hearing Questions
Responses by Anthony Mire-Sluis, Executive Director, Global Product
Quality, Amgen Inc.
Questions submitted by Chairman David Wu
Q1. To the best of your knowledge, do the seven areas of scientific
research identified by NIST in its testimony complement or overlap
research being conducted by the FDA, other federal agencies or the
private sector?
A1. The seven areas of scientific research identified by NIST
(immunogenicity, three-dimensional protein structure, post-
translational modification of manufactured proteins, contaminants in
the manufacturing process, production cell unpredictability, quality-
by-design implementation, and viral clearance) are currently being
conducted to varying degrees by FDA and other federal agencies and by
industry, although not specifically in the area of standardization.
Standard method development and reference standard\1\ preparation
is a very specific area of research that is usually conducted under the
auspices of specialized institutions such as the World Health
Organization, the National Institute for Biological Standards and
Control (``NIBSC,'' a center within the U.K. Health Protection Agency),
the pharmacopeias (e.g., the United States Pharmacopeia and the
European Pharmacopoeia), and the U.S. NIST. These seven areas
complement the basic research and general method development that are
being undertaken by other organizations. The reference materials will
help to compare between methods and to assure that methods are working
properly.
---------------------------------------------------------------------------
\1\ ``Reference standards'' are samples of material, the properties
of which are already known and carefully measured, that can be used to
compare results in order to ensure uniformity in measurement.
Q2. What are the potential benefits to innovation and encouraging the
growth of the biotech industry or other industries, such as biologics
manufacturing, if analytical tools in the seven areas of scientific
---------------------------------------------------------------------------
research identified by NIST in its testimony are developed?
A2. There are distinct benefits to developing standards in the seven
areas identified by NIST, so long as such development is carried out
properly.
For example, providing reference standards will allow each company
to evaluate its performance against expectations of how well their
methods are working. Better methods, in turn, will allow for a better
understanding of the way medicinal products in development work--what
makes them safe and efficacious--and therefore could increase the
success rate of getting safe and effective biotechnology products to
patients.
Improved methods and analytical tools will also allow for a better
understanding of how the manufacturing process works and may ultimately
result in lower manufacturing costs through increased yields and
reduced waste. Improved standards in the area of immunogenicity, for
example, would allow clinicians and regulators to better compare the
safety aspects of medicines in development and to ensure that the
methods used in conducting such comparisons are detecting the correct
safety signals with appropriate sensitivity.
Q3. As you stated in your testimony, key public/private partnerships
between federal agencies such as NIST, government regulatory bodies
such as the FDA, and industry scientists will greatly improve the
chances of successfully developing standard methods, validation
procedures and reference materials. What are your recommendations on
how these partnerships should be structured? What has been your
experience with these types of partnerships and what lessons have you
learned?
A3. In my experience, there should be one central coordinator
responsible for gathering the technical experts in each area of
standardization being considered, in order to develop the most
appropriate, state-of-the-art standard methods and/or reference
materials. At present, there are very few institutions capable of
creating, storing, and distributing reference materials--particularly
biological materials--so this must be taken into consideration in
assessing who should lead this effort.
The coordinating body should approach recognized experts in the
area and develop a plan on how a standard method or reference material
is going to be generated. It is best to have representation from
several organizations as this process begins--usually the coordinating
institution, regulators, industry, and research concerns, depending on
the topic. The parties typically would execute an agreement that would
govern, for example, how the materials will be used, the use of
confidential information, and publication obligations.
It is important that the coordinating institution is capable of
running the methods itself to assure that it has the technical
knowledge needed to balance any differing viewpoints expressed by
various stakeholders.
For a standard method and/or validation protocol, a draft would be
written by the selected group and published in a widely-available
journal for public comment. Transparency in the final approval of the
standard method and/or validation protocol is essential. Any comments
received would be incorporated--as appropriate--in a second draft.
Depending on the volume and nature of the comments received, the method
protocol could be sent out for a second round of comments, or could be
published as final and made freely available.
The development of a reference standard is more complex than
developing a method, and as such, requires careful consideration so as
not to cause chaos or disruption in the research and industrial
communities. In standards development, it would be desirable to obtain
several ``candidate'' preparations of the same material--from different
sources if at all possible--to ensure that the most appropriate
material can be selected. The preparations then would be filled into
containers in an amount that will be appropriate for its use in
checking and standardizing assays. The reference material must be
extremely stable, and because it should be made available around the
world, it must be in a form that can withstand transport. A standard
that loses its activity over time, or breaks down, could provide false
results in assays--which would be worse than having no standard at all,
since it would give users a false sense of security.
There are very few institutions capable of preparing reference
materials in this way, so the coordinating institution must be
carefully selected. Once materials are collected, a ``trial fill''
would be undertaken, usually with one or more different formulations,
to determine which formulation will make the most stable standard. The
coordinating institute would then provide the trial material to a
limited number of expert laboratories, recognized in the field, for
testing. If a formulation is proven to be stable, then a
``collaborative study'' would be organized.
A ``collaborative study'' is organized by a coordinating body that
has advertised (in widely-read scientific journals) for participants.
It is essential to have a good range of laboratories to test the
candidate reference materials, including laboratories associated with
regulatory agencies, industry, research entities, and the coordinating
body itself. The more laboratories testing the candidate materials, the
more likely it is that a successful candidate preparation will work in
every laboratory that requests it, once the reference materials are
established.
It is vital that the participants in the collaborative study are
provided guidance on how to store, open, and use the materials
provided. In addition, it is essential to involve statisticians during
the development of the study protocol, in order to ensure that the data
provided by the study participants is in a format that can be readily
analyzed when it is received.
Coded materials would then be sent out to the participating
laboratories, along with a protocol and results sheet. Each
collaborative study participant would then send its data back to the
coordinating body for analysis. A report would be written and
circulated to the participants for comment, including a recommendation
for the most appropriate reference material. A final report would then
be published, and the reference material would be made publicly
available.
Questions submitted by Representative Adrian Smith
Q1. Please provide your company's comment on and reaction to the broad
plan of work for biologics measurement and standards outlined by Dr.
May in his testimony. Do you support the identified research activities
or have any concerns or suggested modifications?
A1. Amgen commends NIST for the comprehensive program plan it has
developed for future work in biologics-related measurement science, as
described in the testimony that Dr. May presented to this subcommittee.
NIST's program plan is very extensive in scope, however--ranging from
developing better standards for characterizing proteins' three-
dimensional structure, to a deeper understanding of host cell systems
and behaviors, to analyzing the performance of filtration systems in
viral clearance, to Quality-by-Design initiatives. Given the broad
range--and necessarily deep scope--of the activities envisioned in Dr.
May's testimony, we believe that it will be essential for NIST's
biologics-related initiatives to be prioritized.
For more than 25 years, Amgen has been a leading human therapeutics
company in the biotechnology industry, and our mission, first and
foremost, is to serve patients. As such, Amgen believes that patient
safety and ensuring product quality must remain the primary concern for
both industry and government and a priority for the work that NIST
proposes to execute.
Immunogenicity-Related Measurement Standards. From a patient safety
perspective, the main area that would directly benefit from the
application of measurement science, standards and technology is in the
detection and measurement of immunogenicity towards a biologic.
Biologics raise immunogenicity concerns not implicated by small
molecule drugs. Due to the small size of drug products and the
extensive understanding of the mechanisms by which these products work,
drug products rarely elicit an immune response. In contrast, biologics
can trigger an unpredictable--and potentially catastrophic--immune
response in the human body.
There are a number of assays currently used to detect and measure
immunogenicity, but they are not well standardized--and reference
materials are not now available to assist in the understanding of the
sensitivity or accuracy of the measurement methods. Therefore, it
requires extremely diligent development and validation of such methods
by industry in order to produce meaningful results that can identify
the nature and extent of any immune response a patient may raise
against a biologic.
The future availability of standard methods, validation and
reference standards would reduce the risk that immunogenicity assays
would be unable to accurately detect antibodies that could expose
patients to avoidable risks to their health. Because of this,
government support of scientific research in developing improved
technologies for measuring the causes of immunogenicity reactions--
including standards for detecting and measuring protein particulate
aggregation--should be given high priority.
Methods and Standards for Characterizing Proteins. Biotechnology
medicines are complex molecules that require a thorough understanding
of their structure and function to ensure their safety and efficacy. In
comparison to standard chemical drugs, biotechnology medicines
(proteins) are hundreds of times bigger and more complicated. They are
a chain of building blocks (amino acids) that are often folded in many
ways and (as described by Dr. Kozlowski in his written testimony before
this subcommittee) they can have complex groups of sugar molecules or
additional moieties attached to them which, like folding, can greatly
impact the protein's therapeutic function. Because biotechnology
medicines are usually made using living cells, each protein molecule
can be slightly different, making a product a mix of many different
forms, or variants, of a single protein. Due to this potential
variability, it is extremely important that companies are able to use
the most rigorous and reliable methods in order to understand their
medicines and know what parts of the protein are important, to ensure
that patients receive the safest and most effective medicines.
Although a protein's primary structure (that is, its amino acid
sequence) can be characterized utilizing currently available analytical
techniques, the exact spatial location of every atom in a protein
cannot yet be determined--nor can all of the modifications that can
occur with respect to the amino acids. A greater understanding of the
structural characteristics of a biologic could be gained as a
consequence of improved method capability and standardization. This in
turn could result in the ability to focus clinical studies on quality
attribute differences that might have specific impact on safety or
efficacy. Patient safety would thus be served if the scientific
community works to develop better, and more standardized, methodologies
for characterizing proteins' complex three-dimensional structures.
Therefore, governmental initiatives in this area, such as those
described in Dr. May's testimony, should also be prioritized.
Amgen strives to serve patients by transforming the promise of
science and biotechnology into therapies that have the power to restore
health and save lives. As a pioneer in developing medicines to treat
serious illnesses, Amgen supports prioritization of future NIST work in
developing improved measurement technologies in the areas of
immunogenicity assessment and protein characterization. Amgen and other
innovator biotechnology companies have worked, and continue to work, in
collaboration with the World Health Organization, NIST and other
organizations in their efforts to develop robust biologics-related
reference standards, in order to ensure that safe and effective
biotechnology medicines will be available to patients around the world.
Q2. With respect to measurement science and standards, where should
the Federal Government role end, particularly with respect to NIST? How
do we ensure that the Federal Government's biologics research
activities are broad-based and foundational, rather than pertaining to
the interests of individual companies or products?
A2. The Federal Government can play a critical role in ensuring the
development of robust measurement standards, methods and tools in the
area of biologics science. NIST has played a unique role in this regard
as the preeminent U.S. agency for measurement science in support of
American innovation and industrial competitiveness.
As Dr. May recounted in his testimony before this subcommittee,
NIST's work over the last 90 years in establishing health care-related
reference standards has supported important innovation in clinical
diagnostics, the therapeutic and diagnostic use of radiation, and
dental care. We encourage continued support of NIST as it carries out
its current and planned programs in support of biologics-related
measurement science.
Amgen believes that NIST should continue to work closely with other
federal science agencies--especially FDA and the National Institutes of
Health--in developing biologics-related standards, methods, and tools.
In addition, other appropriate health-related institutions--including
the United States Pharmacopoeia--and the academic community should
continue to play a key role in these efforts. We also believe that NIST
and these other organizations and agencies should conduct this critical
work in close conjunction with biologics manufacturers, especially the
biotechnology pioneers such as Amgen, who have unique experience in
bringing safe and effective biotech medicines from the lab, to the
manufacturing plant, and ultimately to patients.
As a global biotechnology innovator, Amgen also believes that
cooperation with international standards-setting, scientific, health,
and regulatory bodies will be essential. These organizations include,
for example, the World Health Organization, the International Committee
on Harmonization, the U.K.'s National Institute for Biological
Standards and Control, and the European and other national and regional
pharmacopoeias.
Governmental involvement, along with other appropriate public
health related organizations, will be critical to ensure that
biologics-related measurement science is developed and established in a
broad-based, foundational manner, rather than pertaining to the
interests of any particular manufacturers, products, or product
classes. In this regard, an open, transparent process should be
followed, including all relevant stakeholders throughout the
international scientific and regulatory community.
Q3. Please characterize the impact of the current shortcomings in
measurement science and standards related to biologics. Is drug
development or regulatory approval being delayed or completely
sidetracked due to gaps in scientific understanding?
A3. The ability to characterize proteins to a very high level of
certainty and sensitivity is very important to how well we can ensure
that a biologics manufacturing process produces high quality medicine--
as pure, consistent and stable as possible--that is efficacious and
safe. In this way, rigorous characterization increases the chance that
the medicine will be successful in the clinic, thus making new and
novel medicines available to improve the health of the American people
and those around the world. Rigorous characterization of proteins will
thus also help prevent the enormous investment in product development
from going to waste. Robust manufacturing processes in themselves lead
to reduced failures, less wasted material and rework, and thus reduce
the associated costs.
The earlier on in development a biologics manufacturer can develop
and implement good methods, the earlier it can alter the product or the
process as necessary to ensure its success--before expensive clinical
studies are started and before patients are given a medicine that may
not work as expected. Having a standard method and reference materials
available as soon as product development begins would give
manufacturers a head start in creating a successful product.
The availability of standard methods and reference standards would
also ease the burden on regulatory reviewers to ensure that the methods
used by the manufacturer were appropriately developed, validated and
routinely run. This would reduce the need for continuous in-depth
evaluation of methods from product to product, and from company to
company.
As described above, the main area of testing from a patient
perspective that would directly benefit from standardization is
detecting and measuring whether, and how, a patient's immune system is
reacting towards a biologic medicine--that is, immunogenicity testing.
This testing has to be carried out in clinical studies because this is
the only way to really understand what is going on inside a patient.
There are a number of different assays used by companies to detect and
measure immunogenicity, and each one is developed in conjunction with a
particular medicinal product and is unique to that product--and each
such assay uses internally produced, custom made materials to make it
work. Because the methods are unique to each company and product, they
are not well standardized, and reference materials are not easily
available. This makes it very difficult to understand exactly how
sensitive or accurate these methods are.
It takes a large amount of work by any particular company to
produce good immunogenicity assays that will ensure that the sponsor is
able to pick up signs of an immune response as early in patients as
possible. The future availability of methods, validation and reference
standards would reduce the chance that immunogenicity assays are not
able to detect the antibodies that could expose patients to health
risks. The more sensitive the method, the more likely an immune
response can be picked up and stopped before it has a chance to harm a
patient.
At the moment, we are not exactly sure what makes the body
recognize a protein product as foreign and thus attempt to clear it
from the body, and no non-human animal model mimics the human immune
system adequately to replace human trials. Consequently, clinical
studies have to be used to determine what happens when you inject the
medicine into patients. Scientists have been working hard to develop
ways to predict what might happen in patients before we give a medicine
to them, in the hope we can prevent adverse events in clinical studies.
Developing better ways to predict immunogenicity will help to ensure
the continued discovery and availability of safe and effective protein-
based biotechnology medicines that do not cause unwanted side effects
for patients.
Answers to Post-Hearing Questions
Responses by Patrick Vink, Senior Vice President and Global Head of
Biologics, Mylan Inc.
Questions submitted by Chairman David Wu
Q1. To the best of your knowledge, do the seven areas of scientific
research identified by NIST in its testimony complement or overlap
research being conducted by the FDA, other federal agencies or the
private sector?
A1. We believe that NIST can play an important role in all seven areas
that were mentioned in the testimony of Dr. May. In all of these areas
extensive research is being conducted in the private as well as in the
public area but significant advances can still be made. NIST's
independence and ability to create standards, publicly available to
everyone can certainly enhance pharmaceutical science and the quality
of biologics research and developmente--specially further improvements
of the characterization of biologics that can advance patient safety
and reduce the burden of unnecessary clinical trials. The future
research agenda of NIST should be coordinated with FDA but we see an
important unmet research need that can be filled by the plans of NIST.
Q2. What are the potential benefits to innovation and encouraging the
growth of the biotech industry or other industries, such as biologics
manufacturing, if analytical tools in the seven areas of scientific
research identified by NIST in its testimony are developed?
A2. As mentioned in the answer to Question 1, we see significant
opportunities in improving patient safety when biologics (new entities
and biosimilars) can be held to the same standards. Furthermore, the
advancement of developing improved quality parameters to guarantee
manufacturing compliance will be very helpful.
Questions submitted by Representative Adrian Smith
Q1. Please provide your company's comment on and reaction to the broad
plan of work for biologics measurement and standards outlined by Dr.
May in his testimony. Do you support the identified research activities
or have any concerns or suggested modifications?
A1. We believe that the areas identified by NIST are very appropriate
areas and that science can be further advanced. For example,
immunogenicity is an area of concern for every biologic. Improving our
understanding of measurement standards of key attributes of a protein
could reduce clinical testing and safety risks to humans. The seven
areas identified by Dr. May offer a very comprehensive and meaningful
approach.
Q2. With respect to measurement science and standards, where should
the Federal Government role end, particularly with respect to NIST? How
do we ensure that the Federal Government's biologics research
activities are broad-based and foundational, rather than pertaining to
the interests of individual companies?
A2. As was outlined in my testimony, we see an important role for NIST
in developing measurement standards for biologics (and advancing the
science in the area). Biologics reference standards would improve
transparency, as all products would need to comply to these standards;
patient safety; and, most important, access to medicine would be
improved by avoiding unnecessary duplication of research and
development efforts.
Q3. Please characterize the impact of the current shortcoming in
measurement science and standards related to biologics. Is drug
development or regulatory approval being delayed or completely
sidetracked due to gaps in scientific understanding?
A3. We believe that the scientific understanding of biologics has
improved very significantly over the past decade. The evolution of the
biopharmaceutical industry has improved health care to a great extent,
providing patients and doctors with new therapeutic options. At this
moment we are able to characterize biopharmaceuticals far better than
we could 10 years ago. NIST's proposed program can help us all further
advance our knowledge and understanding of biologics. By doing so, it
will contribute in a very meaningful way to the improvement of health
care.
One of the key problems is that access to medicines and patient
choices has been limited by the absence of a pathway for the FDA to
approve biosimilar versions of existing products, based on an
abbreviated regulatory application. We strongly believe the science is
available and legislation would provide the FDA with the opportunity to
determine, based on prevailing science, the standards to be met for any
given submission of a biosimilar pharmaceutical.
Answers to Post-Hearing Questions
Responses by Steven Kozlowski, Director, Office of Biotechnology
Products, Office of Pharmaceutical Science, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration
(FDA), Department of Health and Human Services
Questions submitted by Chairman David Wu
Q1. To the best of your knowledge, do the seven areas of scientific
research identified by NIST in its testimony complement or overlap
research being conducted by the FDA, other federal agencies or the
private sector?
A1. The National Institute for Standards and Technology's (NIST)
testimony identified seven areas of scientific research that could
promote innovation and improve efficiency in the drug and biologic
development process: immunogenicity, 3-D structure, post-translational
modifications, contaminants, production cell behavior, viral clearance,
and biopharmaceutical function. Advances in these areas could also help
enhance FDA regulatory decision-making when evaluating the safety and
efficacy of drugs and biologics.
FDA performs research in these areas and actively participates in
standards development activities, including development and maintenance
of select material standards. However, we typically do not create and
maintain material standards in the seven areas identified. NIST has
expertise in creation and maintenance of such standards to ensure that
the analytical methodologies used across industry are performing
similarly.
In addition, the seven named categories are extremely broad,
encompassing multiple specific research activities. For example,
industry, NIH, FDA, and academia are all currently studying various
aspects of immunogenicity. In general, industry focuses on the
technology it needs to develop specific products and meet regulatory
requirements.
FDA generally focuses on areas and tools that will benefit a wide
range of products and/or enable informed decision-making and guidance.
Academia and NIH ordinarily focus on the biology necessary to enable
more meaningful research in these areas. Thus, there are multiple
questions within the topic of immunogenicity that different groups
could study without overlapping research efforts. For example:
a) Protein aggregation (clumping) can present one risk for
immunogenicity. Different groups could study how to better
detect aggregates without overlap; one group might look at
tools for large aggregate detection and another at tools
sensitive to small aggregates. Still other groups might
research how to improve manufacturing processes to decrease
aggregation or study the biological impact of different types
of aggregates on immune cells and in vivo models.
b) There are causes for immunogenicity other than aggregates.
Different groups can conduct studies to better understand how
the impurities that lead to immunogenicity can affect product
safety,
c) It is also important to understand the potential
consequences of immunogenicity. Groups who use animal models
might study the potential consequences of immune responses to a
particular therapeutic product through the use of animals
genetically engineered to better reflect human immune
responses.
d) Once immunogenicity does develop in patients, it would be
useful to have better ways to measure it. Industry often
develops assays for immunogenicity but it is difficult to
compare results from company to company. Groups can work to
develop improved detection methods and standards so we can
better compare immune responses.
e) It would be very useful to discover interventions to
prevent or alleviate problematic immune responses. Different
groups can work to develop and study potential interventions
that might accomplish this goal.
Interactions and communication between different groups can lead to
synergy and ensure that related efforts are complementary. Thus, if a
group develops a better way of separating out aggregates and
collaborates with a group that has an improved animal model, real
progress is possible. Research also needs some level of overlap to
reproduce, verify and generalize conclusions--if one research group has
an important result, it may be due to something specific to the exact
protocols and systems they are using. However, if other research groups
reach the same conclusion with slightly different approaches, the
result is likely to be generalizable across many laboratories. Although
many groups perform research on basic biological questions, there are
far fewer research groups that focus on issues directly related to
product quality and manufacturing.
Q2. Can you describe the interactions between NIST and the FDA that
have led to the development of the seven areas of scientific research
for improved measurement technologies and methods in the biologics
identified by NIST in this testimony? How do you see NIST working with
the FDA to facilitate development of these technologies and methods?
A2. NIST and FDA have met on a number of occasions to discuss ways in
which the research program at NIST could enhance FDA's ongoing
regulation of biopharmaceutical regulation. Representatives from FDA's
Center for Drug Evaluation and Research (CDER) and Center for Biologics
Evaluation and Research (CBER) met with NIST's Chemical Science and
Technology Laboratory (CSTL) on January 30, 2008, to discuss what
information, technologies, and standards are most needed for advancing
the development and regulation of biological products. FDA also sent a
representative to CSTL's strategic planning go-away at the end of July
2009 to provide input on general issues facing the pharmaceutical
industry and FDA. Further meetings and collaborative projects could
facilitate development of these technologies and standards.
Q3. You mentioned that advances in analytical tools during the past 20
years have driven progress in biopharmaceutical manufacturing. Could
you please provide some examples? Also, were these analytical tools
developed primarily by federal agencies, private industry or some
combination?
A3. One example where an advance in analytical tools has driven
progress in biopharmaceutical manufacturing is the development of
improved analytical tools used to measure sugars attached to proteins.
These sugars are a type of post-translational modification to a
protein. The importance of these sugars to the biological function of
proteins was not widely appreciated 20 years ago and the tools to
evaluate them were very limited. Early analyses focused only on the
amount of each sugar present in total but did not examine how the
sugars were attached to each other or to the protein. Academia,
government and industry all worked to learn more about the biological
impact of these sugars and their specific structures. As knowledge
improved and FDA began to require drug sponsors to submit information
regarding the structure of the sugars in their products, industry
continued to improve methodologies to detect sugars and their
structures. This information has proved useful in many settings.
In 2002, the Nobel Prize in Chemistry was awarded to scientists in
both academia and industry for the application of two techniques,
Nuclear Magnetic Resonance and Mass Spectrometry, to the study of large
molecule structures. FDA's own research on the use of Nuclear Magnetic
Resonance to evaluate complex sugars enhanced the development of
polysaccharide vaccines in addition to enhancing FDA regulation of
polysaccharide vaccine quality.
In 2002, a published industry study\1\ showed the importance of one
particular sugar called fucose. The absence of fucose was shown to
significantly enhance the ability of monoclonal antibodies to kill
tumor cells. Many other groups in both industry and academia verified
and extended this finding. Based on this knowledge, FDA now expects
applications for such anti-tumor antibodies to provide information
about fucose content. This knowledge has also enhanced industry's
development of improved products.
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\1\ Shields, R.L., J. Lai, R. Keck, L.Y. O'Connell, K. Hong, Y.G.
Meng, S.H. Weikert, and L.G. Presta, Lack of fucose on human IgGlN-
linked oligosaccharide improves binding to human Fegamma RIII and
antibody-dependent cellular toxicity. J Biol Chem, 2002. 277(30): pp.
26733-40.
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Many companies now engineer their antibodies to lack this sugar and
have more potent anti-tumor potential. The ability to measure fucose
thus led to an understanding of its biological effect, which, in turn,
allowed for progress in biopharmaceutical manufacturing.
This example also shows the need for robust standards and the
importance of NIST's involvement in this area. When FDA began requiring
companies to submit information relating to fucose, each company would
submit data using their own methods and standards for detecting this
sugar. Without standardization, it was difficult to compare these
results. However, FDA did not want to slow the development of new
methods by requiring that all companies use one particular method. NIST
has the necessary expertise to develop material standards that allow
for comparison of different methods being used. When NIST develops
material standards, FDA can improve our ability to ensure consistent
quality while allowing industry the freedom to develop innovative new
analytical methods.
With better standards, our current knowledge can be extended more
quickly and the remaining gaps can be more rapidly addressed. Just as
the impact of fucose was not known more than five years ago, there may
be other important post-translational modifications that we do not
understand today. Improved standards will accelerate this
understanding.
Questions submitted by Representative Adrian Smith
Q1. How much does FDA currently spend on biologics research? What is
this research focused on and under what programs is it carried out?
A1. For Fiscal Year (FY) 09, FDA Centers that regulate biological
products expended approximately $31 million on biologics research
(including salaries and benefits).
FDA's biologics research activities are focused on scientific
endeavors aimed at ensuring the safety, efficacy, and availability of
biological products that advance the public's health. FDA achieves
these goals through highly skilled scientific staff, modern
laboratories and up-to-date equipment, and ongoing scientific
collaborations with the Department of Health and Human Services (HHS)
operating divisions and other stakeholders. These research activities
support all biologics regulated by FDA, including vaccines, therapeutic
proteins, monoclonal antibodies, plasma derivatives, blood, cell,
tissues, and gene therapies. Research is conducted in such diverse
areas as adventitious agent detection, product characterization
(including understanding the mechanism of action and development of
biological assays), immunogenicity, and evaluating product toxicities.
In addition, FDA research is involved in facilitating the
development and application of analytical technologies by biologic
manufacturers and regulators in the development and manufacturing
control of biologics.
FDA research capabilities also facilitate Agency testing and
characterization of products. The research activities at FDA create new
knowledge that provides scientific expertise, new laboratory and
testing tools, and generate data that support science-based regulatory
decision-making and policy development and that facilitate regulation
of existing products and development of novel biologics. In addition,
by maintaining an active multi-disciplinary research program, FDA is
poised to respond to emerging issues relevant to the agency's
regulatory responsibilities.
Q2. Have the respective biologics research roles of FDA and NIST been
defined in any way? Where would NIST's role begin and end, and is there
an agreed upon ``division of labor'' to pursue the identified research
needs?
A2. Although there is no formal definition of the research roles of FDA
and NIST, each focuses on different types of research.
FDA's research staff performs research related to ensuring the
safety, efficacy, and availability of biological products that advance
the public's health. FDA research staff stays current with product
problems and new areas of product development. They are responsible for
testing products taken from the field and performing research on
development of analytics, bioassays and quality-by-design manufacturing
approaches, along with research on immunogenicity and adventitious
agents. However, FDA is not in a position to develop novel analytic
technologies. For example, FDA can use Nuclear Magnetic Resonance to
study and develop approaches to better regulate products, but we cannot
create a next generation Nuclear Magnetic Resonance instrument. Unless
there is an emergent need, FDA does not usually create and maintain
material standards that will ensure a particular analytical methodology
is performing appropriately. Such standards are of value to FDA and
across industry and academia.
If NIST performs related research in the same areas as FDA and the
agencies communicate with each other effectively, synergies will be
likely. As indicated above, there is no shortage of important topics in
the seven research areas indicated by NIST. If collaborating in these
areas facilitates NIST development of material or performance standards
that FDA, academia, and industry can use, that would be a tremendous
boon to the development of biopharmaceutical science. Additionally,
NIST possesses expertise in engineering, physics, and material
sciences, which FDA, industry, and academia could leverage to
streamline product development and review. When multiple groups with
different perspectives and expertise collaborate, they cannot only
focus on improving an existing method, but may develop truly novel
methods that no one group would have developed on its own.
For example, collaboration between FDA and NIST could be of value
in the development of analytic ``signatures.'' The 3-D structure of a
protein can be evaluated by actually measuring spatial coordinates (a
picture of the protein). For very large complex molecules and for the
routine quality control of all proteins, measuring 3-D structures by
using such methods may be onerous and challenging. An alternative
strategy is to measure only a defined number of important features of
3-D structures and extrapolate the rest. Extrapolating information from
a signature subset of the data is a powerful tool for analysis of very
complex proteins. But this only works if the signature is sufficient to
uniquely identify the structure. NIST expertise may be helpful in
developing standards for signature methodologies that ensure that the
signature used is sufficiently unique to identify the structure.
Q3. More generally, how are NIST and FDA working together on
biologics? Have coordination or research activities been formalized in
any way? Relatedly, please provide FDA's comment on and reaction to the
broad plan of work for biologics measurement and standards outlined by
Dr. May in his testimony. To what extent would this research support
and advance FDA's regulatory decision-making needs? To the extent it
would, should a joint FDA-NIST funding arrangement for such activities
be considered?
A3. FDA and NIST have met a number of times to discuss biologics. FDA
and NIST co-sponsored a valuable meeting with the New York Academy of
Sciences on protein characterization in 2005. At present, the
coordination of research activities has not been formalized.
All of the research areas in Dr. May's testimony are important, and
additional research in these areas would be of great benefit to FDA in
regulating drugs and biologics. Specifically, the collaborative
development of robust material standards and novel methodologies in
these areas would assist FDA and industry in biopharmaceutical
development, review, and regulation. FDA could contribute its
scientific knowledge and research on biological products and NIST could
contribute its extensive experience in setting standards and its multi-
disciplinary expertise in engineering, physics, and material sciences.
The example of the development of analytics to study sugars described
in Question 3 shows how research and standards development can benefit
FDA in our regulatory decision-making.
Any collaborative efforts could be funded through NIST and FDA
budgets. If additional joint funding is provided, clear accountability
and authority over such additional joint resources would need to be
established and detailed definition of the specific objectives of any
targeted joint funding would be advisable.
Q4. Please characterize the impact of the current shortcomings in
measurement science and standards related to biologics. Is drug
development or regulatory approval being delayed or completely
sidetracked due to gaps in scientific understanding?
A4. FDA is very capable of approving biologics and many manufacturing
changes with current technologies. However, as indicated above,
although analytical methods have advanced over time, there are areas
that are in need of further development. In particular, better
approaches to measurement of 3-D structure, post-translational
modifications, and aggregates would be very beneficial. With improved
methodologies and standards, manufacturing changes could be more
rapidly implemented, abbreviated pathway approvals facilitated (where
authorized by statute), and manufacturing efficiency improved.
Answers to Post-Hearing Questions
Responses by Willie E. May, Director, Chemical Science and Technology
Laboratory, National Institute of Standards and Technology
(NIST)
Questions submitted by Chairman David Wu
Q1. The NIST advisory committee, the Visiting Committee on Advanced
Technology (VCAT) provided recommendations to NIST for a program to
support the evolving field of biologics and the biotechnology industry
in general. How will NIST propose to incorporate those recommendations
into current plans for research in support of reference standards and
analytical methods for biologics?
A1. NIST values the advice of the VCAT and is systematically reviewing
and responding to their input. We have undertaken an internal strategic
planning process for bioprogram growth that has involved extensive
outreach, including the hosting of an international conference in
October of 2008 entitled ``Accelerating Innovation in 21st Century
Biosciences: Identifying the Measurement, Standards, and Technological
Challenges,'' to help identify and prioritize measurement standards and
technology barriers to new discoveries in agriculture, energy, the
environment, manufacturing, and medicine. The measurement and standards
needs identified through this and previous outreach efforts dating back
to 2005 have resulted in three documents:
1. The Report From the October 2008 Conference--which describes
critical measurement and standards needs that are being used to guide
research at both at NIST and throughout the measurement standards
community worldwide.
2. Measurement Challenges to Innovation in the Biosciences: Critical
Roles for NIST--a high level document outlining our strategic approach
for addressing the bioscience measurement barriers of the highest risk
to economic security and quality of life.
3. Measurement Science and Measurement Standards to Support Innovation
in Health Care--an internal planning document currently being vetted
with the health care community that catalogues measurement and
standards needs articulated to us by the medical professional
community, industry, FDA and NIH.
Standards for health care is our initial area of focus within the
biosciences. Programs for ``standards for biologic drugs,'' along with
clinical diagnostics, medical imaging and health-IT are included in
internal program planning documents that will feed into the annual
update to the NIST Three-Year Programmatic Plan and inform the budget
process.
Q2. What role has VCAT played in the development of the seven areas of
scientific research for improved measurement technologies and methods
in biologics identified by NIST in its testimony? Have they provided
comments or feedback?
A2. The critical needs for additional measurement science research and
standards identified in the written testimony were based on extensive
discussions with our colleagues at FDA and in the biopharmaceutical
industry.
The seven areas were taken from document #3 identified in the
response to the previous question. Document #3 has been shared with the
VCAT Subcommittee on Bioscience.
Q3. What additional consultation has NIST had with VCAT since the
March 6, 2007 meeting in which a strategic planning process for health
care, biotechnology and life science was presented? What efforts have
been made to incorporate VCAT's comments from that meeting?
A3. Discussions of NIST plans for bioprogram growth and implementation
have been discussed with VCAT on an ongoing basis since the March 2007
meeting. Presentations concerning our programs in bioscience and
progress on our strategic planning process have been made to VCAT in
August 2007, December 2007, June 2008 and October 2008. Dr. James
Serum, VCAT Chair, was a member of the Steering Committee and attended
the October 2008 Bioscience Conference.
While no formal presentations have occurred at the two VCAT
meetings in 2009, VCAT has been kept abreast with our activities
through e-mails and conversations during those meetings.
Q4. With whom did NIST consult to develop the seven areas of
scientific research identified in your testimony? What government
agencies and biotechnology and pharmaceutical companies have been
involved in the identification of these seven areas of research?
A4. See response to Question 2. More specifically, measurement and
standards needs for biopharmaceutical manufacturing have been discussed
with:
FDA
Amgen
Mylan Pharmaceuticals
Biogen Idec
Eli Lilly
Genentech
BIO (Biotechnology Industry Organization)
The Generic Pharmaceutical Association
Questions submitted by Representative Adrian Smith
Q1. Have the respective biologics research roles of FDA and NIST been
defined in any way? Where would NIST's role begin and end, and is there
an agreed upon ``division of labor'' to pursue the identified research
needs? More generally, how are NIST and FDA working together on
biologics? Have coordination or research activities been formalized in
any way?
A1. The FDA is responsible for protecting the public health by ensuring
the safety, effectiveness, and security of human and veterinary drugs,
biological products, and medical devices, and the safety and security
of our nation's food supply, cosmetics, and products that emit
radiation and by reducing mortality and morbidity associated with
tobacco use.
NIST's mission is to promote U.S. innovation and industrial
competitiveness by advancing measurement science, standards, and
technology in ways that enhance economic security and improve our
quality of life.
The need for measurement standards was clearly articulated in the
FDA testimony. Through our lead agency role in measurement science,
standards and technology, NIST is regularly called upon to provide
measurement and standards solutions to support other government
agencies in carrying out their missions.
The FDA has requested that NIST provide reference methods,
standards, and validated protocols to enable increased confidence in
measurement results used to evaluate biologic drugs.
NIST and FDA are beginning scientific collaborations concerning
critical measurement and standards needs for biologic drugs. Activities
are currently underway to address measurement and standards needs
associated with immunogenicity and viral clearance.
Q2. With respect to measurement science and standards, where does the
Federal Government role in supporting biologics end, particularly with
respect to NIST? How do we ensure that these research activities are
broad-based and foundational, rather than pertaining to the advancement
of individual companies or products?
A2. NIST research will address the broad based measurement science and
standards needs identified in the testimony that will be of benefit to
the producers of both innovator and generic biologic drugs, namely:
more accurate assessment of the ``sameness'' of a
biologic drug made by different manufacturers and/or different
manufacturing processes;
improved safety and efficacy; and
improved efficiency and reliability in manufacturing
processes.
Appendix 2:
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Additional Material for the Record