[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

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

                                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

                                 ______
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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
                                 ------                                

               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

                              ----------                              


                      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.
---------------------------------------------------------------------------
    \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.

---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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\
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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\
---------------------------------------------------------------------------
    \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 
---------------------------------------------------------------------------
        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:
---------------------------------------------------------------------------
    \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).

---------------------------------------------------------------------------
          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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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 
---------------------------------------------------------------------------
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).
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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\
---------------------------------------------------------------------------
    \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).
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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




















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