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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

(II)

COMMITTEE ON SCIENCE AND TECHNOLOGY

HON. BART GORDON, Tennessee, Chair

JERRY F. COSTELLO, Illinois

EDDIE BERNICE JOHNSON, Texas

LYNN C. WOOLSEY, California

DAVID WU, Oregon

BRIAN BAIRD, Washington

BRAD MILLER, North Carolina

DANIEL LIPINSKI, Illinois

GABRIELLE GIFFORDS, Arizona

DONNA F. EDWARDS, Maryland

MARCIA L. FUDGE, Ohio

BEN R. LUJA ́ N, New Mexico

PAUL D. TONKO, New York

PARKER GRIFFITH, Alabama

STEVEN R. ROTHMAN, New Jersey

JIM MATHESON, Utah

LINCOLN DAVIS, Tennessee

BEN CHANDLER, Kentucky

RUSS CARNAHAN, Missouri

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

RALPH M. HALL, Texas

F. JAMES SENSENBRENNER JR.,

Wisconsin

LAMAR S. SMITH, Texas

DANA ROHRABACHER, California

ROSCOE G. BARTLETT, Maryland

VERNON J. EHLERS, Michigan

FRANK D. LUCAS, Oklahoma

JUDY BIGGERT, Illinois

W. TODD AKIN, Missouri

RANDY NEUGEBAUER, Texas

BOB INGLIS, South Carolina

MICHAEL T. MCCAUL, Texas

MARIO DIAZ-BALART, Florida

BRIAN P. BILBRAY, California

ADRIAN SMITH, Nebraska

PAUL C. BROUN, Georgia

PETE OLSON, Texas

SUBCOMMITTEE ON TECHNOLOGY AND INNOVATION

HON. DAVID WU, Oregon, Chair

DONNA F. EDWARDS, Maryland

BEN R. LUJA ́ N, New Mexico

PAUL D. TONKO, New York

DANIEL LIPINSKI, Illinois

HARRY E. MITCHELL, Arizona

GARY C. PETERS, Michigan

BART GORDON, Tennessee

ADRIAN SMITH, Nebraska

JUDY BIGGERT, Illinois

W. TODD AKIN, Missouri

PAUL C. BROUN, Georgia

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

(III)

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

Page

IV

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

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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.

2

1The terms ‘‘biologics’’ and ‘‘biologic drugs’’ refer to a class of medicinal products that are cre- ated 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. 2The 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. 3See, e.g., Medicines in Development, Biotechnology, 2006 Report; available at http://

www.phrma.org/files/Biotech%202006.pdf 4See 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-as- sociated pure red cell aplasia: past, present, and future considerations, Transfusion, Vol. 48 (August 2008), 1754–1762.

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.

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 Labora- tory at the National Institute of Standards and Technology.

III. Background

The use of biologics to treat complex diseases such as cancer, diabetes, and mul- tiple 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

If proper and accurate measurement standards, methods and tools had been available, the Eprex incident may have been avoided. Biotechnology companies, the Food

3

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, Congres- sional Budget Office (December, 2008), 126–128; Report to the Congress: Improving Incentives

in the Medicare Program, MedPac (June, 2009), 107. 7These 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. 8Testimony 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.

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 drugs5

and biosimilars.6

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 molecules7 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.

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 preclinical 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?

4

Chairman WU. The hearing will come to order. Good morning. I would like to welcome everyone to this sub- committee’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 Sub- committee 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.

5

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.

6

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.

7

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

8

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

9

1MEDTAP International, Inc., The Value of Investment in Health Care (Bethesda, MD: 2004)

at p. 12. 2 Id. at p. 10. 3PhRMA, ‘‘Medicines in Development: Biotechnology’’ (2008), at p. 1, available at http://

www.phrma.org/images/110308%20biotech%202008.pdf (last visited Sept. 21, 2009).

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

• 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:

• 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

10

4DiMasi, 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). 5Tufts Center for the Study of Drug Development, ‘‘Average Cost to Develop a New Bio- technology Product Is $1.2 Billion’’ (Nov. 9, 2006), available at http://csdd.tufts.edu/

NewsEvents/NewsArticle.asp?newsid=69 (last visited Sept. 19, 2009). 6PharmaProjects, ‘‘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. 7These 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.

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 bio- pharmaceuticals: 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

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 Bio- technology Medicines

Biotechnology medicines are complex molecules that require as thorough as pos- sible 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 methods7 to understand

11

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. 8For example, the United States Pharmacopeia (see http://www.usp.org/aboutUSP/), a nonprofit, 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/WorkProgrammeStatus-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).

their medicines and accurately identify which parts of the protein are most important, in order to ensure optimal product safety and efficacy.

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 pharmacopoeias8 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.

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

12

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 preapproval 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

13

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). 10The 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). 11The 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). 13For 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). 14The 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 16The 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

in the U.S. The House’s Innovation Agenda9 has also supported this new emphasis

on science, technology, engineering, and mathematics (‘‘STEM’’) education.

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

• 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 Foundation14 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 AcadVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00017 Fmt 6633 Sfmt 6621 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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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). 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). 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 employ- ment 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).

emy (co-founded with the National Science Teachers Association), and the AmgenBruce Wallace Biotechnology Lab Program.17

Continuing America’s Biotechnology Leadership Through Strong Intellec- tual Property Protection

Strong protection of intellectual property—both patents and data—is the corner- stone 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

Employment figures also reflect the U.S.’s dominance in biotech R&D: the Organi- zation 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

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, efVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00018 Fmt 6633 Sfmt 6621 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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21See 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).

fectiveness 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 legislation21 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.

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.

16

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 comVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00020 Fmt 6633 Sfmt 6601 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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parability 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

18

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, af- fordable 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 Com- pany 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

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1 It is worthwhile in this regard to consider the comparable gamesmanship that has been underway for some time with synthetically-manufactured drugs, which is mired in a Citizen Petition proceedings at FDA that seeks to indefinitely delay approval of applications. Such Petitions

are indicative of what the biosimilars industry is likely to confront in the years ahead in seeking

FDA approval for biosimilar that would compete with marketed PHS Act biologics. Reference

standards could ensure that such gaming of an otherwise-legitimate public petitioning process

is no longer incentivized.

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.

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.

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2 In implementing its biosimilars framework, Europe simultaneously implemented a new

8+2+1 data exclusivity regime. While that EU exclusivity can total up to 11 years, its implementation was dramatically different than that which is proposed for the 12-year biologics exclusivity in the U.S. Specifically, the EU exclusivity applied prospectively only to future products,

not to existing products, and it only went into effect for the first time for products first approved

several years after the pharmaceuticals legislation was adopted in Europe. Furthermore, extensive price control systems within the EU make that situation very different from the U.S.

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 unprece- dented, 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 exclu- sivity provision is simply a direct grant to the biotech industry without any giveback 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.

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 precondition 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 subVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00024 Fmt 6633 Sfmt 6621 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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committee’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 at- tached) 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 ref- erence 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 intercompany 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 prechange 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

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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.

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1See last page of testimony.

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.

69

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:]

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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

71

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

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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.

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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-byDesign 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 assessVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00078 Fmt 6633 Sfmt 6601 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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ment 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 factbased decision-making in research and development, manufacturing and the regulatory approval process for biologics.

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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 knowledgebased, 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:

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• 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 proVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00081 Fmt 6633 Sfmt 6621 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
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teins 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

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1McKoy, J.M., et. al., Epoetin-associated pure red cell aplasia: past, present, and future considerations, Transfusion, Vol. 48 (August 2008), pp. 1754–1762. 2FDA, 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).

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.

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 biologybased 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 riskbased 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.

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Viral clearance—Removal of potential viral contaminants by filtration is a key op- eration 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 devel- oping 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.

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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, prop- erties, 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.

82

Honors and Awards: Department of Commerce Bronze Medal Award, 1981; Na- tional 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

83

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.

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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

85

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. Luja ́n—oops. Mr. Luja ́n 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

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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.

87

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.]

(89)

Appendix 1:

ANSWERS TO POST-HEARING QUESTIONS

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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.

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 standard1 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.

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, deVerDate 11-MAY-2000 16:32 Dec 21, 2009 Jkt 052285 PO 00000 Frm 00094 Fmt 6601 Sfmt 6621 C:\DWORK\T&I09\092409\52285 SCIENCE1 PsN: SCIENCE1
91

pending 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.

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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

93

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

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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.

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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 devel- oping 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

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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.

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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

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1Shields, 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 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 bio- pharmaceutical manufacturing is the development of improved analytical tools used

to measure sugars attached to proteins. These sugars are a type of posttranslational 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 study1 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.

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

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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 posttranslational 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.

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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.

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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

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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.

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Appendix 2:

ADDITIONAL MATERIAL FOR THE RECORD

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