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S. HRG. 110–375 

FOLLOW-ON BIOLOGICS 

HEARING 

OF THE

COMMITTEE ON HEALTH, EDUCATION, 

LABOR, AND PENSIONS 

UNITED STATES SENATE 

ONE HUNDRED TENTH CONGRESS 

FIRST SESSION 

ON

EXAMINING FOOD AND DRUG ADMINISTRATION FOLLOW-ON BIOLOGICS, GENERALLY REFERRED TO AS A BIOTECHNOLOGY-DERIVED 

PROTEIN DRUG (OR BIOLOGIC) THAT IS COMPARABLE TO A NOVEL, 

PREVIOUSLY APPROVED BIOLOGIC AND THAT IS APPROVED WITH 

LESS SUPPORTING DATA THAN THE INNOVATOR BIOLOGIC 

MARCH 8, 2007 

Printed for the use of the Committee on Health, Education, Labor, and Pensions 

( 

Available via the World Wide Web: http://www.gpoaccess.gov/congress/senate 

COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS 

EDWARD M. KENNEDY, Massachusetts, Chairman 

CHRISTOPHER J. DODD, Connecticut 

TOM HARKIN, Iowa 

BARBARA A. MIKULSKI, Maryland 

JEFF BINGAMAN, New Mexico 

PATTY MURRAY, Washington 

JACK REED, Rhode Island 

HILLARY RODHAM CLINTON, New York 

BARACK OBAMA, Illinois 

BERNARD SANDERS (I), Vermont 

SHERROD BROWN, Ohio 

MICHAEL B. ENZI, Wyoming, 

JUDD GREGG, New Hampshire 

LAMAR ALEXANDER, Tennessee 

RICHARD BURR, North Carolina 

JOHNNY ISAKSON, Georgia 

LISA MURKOWSKI, Alaska 

ORRIN G. HATCH, Utah 

PAT ROBERTS, Kansas 

WAYNE ALLARD, Colorado 

TOM COBURN, M.D., Oklahoma 

J. MICHAEL MYERS, Staff Director and Chief Counsel 

KATHERINE BRUNETT MCGUIRE, Minority Staff Director 

(II) 

C O N T E N T S 

STATEMENTS 

THURSDAY, MARCH 8, 2007 

Page 

Kennedy, Hon. Edward M., Chairman, Committee on Health, Education, 

Labor, and Pensions, opening statement ........................................................... 1 

Enzi, Hon. Michael B., a U.S. Senator from the State of Wyoming, opening 

statement .............................................................................................................. 2 

Clinton, Hon. Hillary Rodham, a U.S. Senator from the State of New York, 

opening statement ................................................................................................ 4 

Hatch, Hon. Orrin G., a U.S. Senator form the State of Utah, opening statement ...................................................................................................................... 4 

Schumer, Hon. Charles E., a U.S. Senator from the State of New York, 

opening statement ................................................................................................ 5 

Prepared statement .......................................................................................... 8 

Banwart, Sid, Vice President of Human Services, Caterpillar, Peoria, Illinois . 10 

Prepared statement .......................................................................................... 12 

Siegel, M.D., Jay P., Group President, Biotechnology, Immunology and Oncology, Research and Development, Johnson & Johnson, Radnor, Pennsylvania ...................................................................................................................... 14 

Prepared statement .......................................................................................... 16 

Rossignol, Nicholas, Administrator, European Commission Pharmaceuticals 

Unit, Brussels, Belgium ....................................................................................... 26 

Prepared statement .......................................................................................... 28 

Hussain, Ph.D., Ajaz S., Vice President and Global Head of Biopharmaceutical Development, Novartis, Princeton, New Jersey .................................. 32 

Prepared statement .......................................................................................... 33 

ADDITIONAL MATERIAL 

Statements, articles, publications, letters, etc.: 

Prepared statements of: 

AARP .......................................................................................................... 56 

Coalition of State Rheumatology Organizations ..................................... 57 

Letters from: 

Interamerican College of Physicians & Surgeons ................................... 59 

Amyotrophic Lateral Sclerosis Association ............................................. 59 

Society for Women’s Health Research ..................................................... 60 

Biotechnology Industry Organization (BIO) ............................................ 61 

Response to questions of Senator Kennedy by: 

Jay P. Siegel, M.D. .................................................................................... 62 

Nicolas Rossignol ....................................................................................... 70 

Ajaz S. Hussain, Ph.D. .............................................................................. 73 

Response to questions of Senator Enzi by: 

Jay P. Siegel, M.D. .................................................................................... 64 

Nicolas Rossignol ....................................................................................... 71 

Ajaz S. Hussain, Ph.D. .............................................................................. 74 

Sid Banwart ............................................................................................... 77 

(III) 

(IV) 

Response to questions of Senator Bingaman by: 

Jay P. Siegel, M.D. .................................................................................... 66 

Nicolas Rossignol ....................................................................................... 71 

Response to questions of Senator Burr by: 

Jay P. Siegel, M.D. .................................................................................... 67 

Nicolas Rossignol ....................................................................................... 72 

Ajaz S. Hussain, Ph.D. .............................................................................. 76 

Sid Banwart ............................................................................................... 78 

(1) 

FOLLOW-ON BIOLOGICS 

THURSDAY, MARCH 8, 2007 

U.S. SENATE, COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS, Washington, DC. 

The committee met, pursuant to notice, at 10 a.m., in Room SD– 

430, Dirksen Senate Office Building, Hon. Edward Kennedy, chairman of the committee, presiding. 

Present: Senators Kennedy, Reed, Clinton, Brown, Enzi, Gregg, 

Alexander, Burr, Hatch, Allard, and Coburn. 

OPENING STATEMENT OF SENATOR KENNEDY

The CHAIRMAN. We’ll come to order. Whoever that wonderful person is—Dr. Rossignol from Brussels. Thank you very much. We 

want to thank our distinguished witnesses for joining today’s hearing on the important question of whether Congress should give 

FDA the authority to approve follow-on versions of biologic medicines. 

We are in a remarkable period of discovery in the life sciences. 

Unprecedented advances are taking place and patients have already begun to see the benefits of this new era through new wonder drugs that can make the difference between life and death for 

patients afflicted with serious illnesses. 

Patients with leukemia once faced a bleak future now have new 

hopes, thanks to an extraordinary new medicine that can slow or 

even halt the progression of the disease. 

Until recently, a diagnosis of Gaucher’s Disease meant a shorter 

life, full of disability and pain for the people it afflicted. Now, a remarkable breakthrough has produced drugs to treat this grave illness and extend life and reduce disability. Similarly, a drug to 

stimulate the production of new blood cells is helping patients 

counteract the severe anemia caused by chemotherapy or renal disease. 

These miracle medicines, called biologics, are complex molecules 

whose healing power has been brought to patients by dynamic 

biotech companies. Such drugs were once a rarity in the medical 

arsenal but each day seems to bring new hope from new breakthrough biologics. 

With this extraordinary progress comes a challenge to public policy. Due to the cost of developing and manufacturing new biologics, 

their price is often steep. They can cost patients tens or even hundreds of thousands of dollars a year, putting an extraordinary 

strain on the budgets of those who must pay the bills—patients, insurers and companies or government programs. 

2 

Congress has faced similar challenges before. In the early 1980’s, 

the cost of prescription drugs was spiraling upward. In response, 

Congress enacted legislation that balanced the need to reduce costs 

for consumers through increased competition with the requirement 

to promote innovation. That legislation is known universally by the 

names of its sponsors, Senator Orrin Hatch and Representative 

Henry Waxman. Our committee is honored that Senator Hatch is 

helping guide our deliberations. Congress and the American people 

are indebted to his leadership on these important issues. 

When the Hatch-Waxman law was enacted, Congress did not include biologics because at the time, such drugs were not providing 

the major innovations and advances in the biological sciences have 

brought over the past 20 years. 

Now Congress must consider whether to authorize FDA to accept 

applications for follow-on versions of these path-breaking medicines. The stakes riding on the answer to this question are enormous, both for patients and our economy and the interest among 

our committee colleagues in this question is intense. 

One of our colleagues, Senator Clinton, has a proposal to allow 

FDA to approve follow-on biologics. I look forward to hearing her 

views on this question and receiving the testimony of the legislation’s cosponsor, Senator Schumer. 

Many have recommended that the committee’s legislation on 

drug safety and user fees should include a proposal to allow followon biologics. Today’s hearings will help provide the information the 

committee needs to make the right decision on that important 

question. 

Our committee should be guided by three basic principles. First, 

we must be led by the science. Acceptable legislation on follow-on 

biologics must not pre-judge science but should enable the FDA to 

make the best decisions based on the most complete science reasonably available. 

Second, protecting patient safety is essential. Congress must 

make certain that any drug given to patients, whether a conventional drug, an innovative biologic or a follow-on-product is safe 

and effective. 

Third, innovation must be valued and promoted. Just as it is essential to help patients afford the medicines of today, so too it is 

vital to provide incentives for the innovations that will bring the 

medical miracles of tomorrow. 

I look forward to the recommendations and insights of our distinguished witnesses to provide guidance to our committee as we undertake these important deliberations. 

Senator Enzi. 

OPENING STATEMENT OF SENATOR ENZI

Senator ENZI. Thank you, Mr. Chairman, for holding this important hearing and beginning an important discussion regarding follow-on biologics. Part of the reason we need to have this hearing 

today is for us to understand the complex issues surrounding follow-on biologics. It’s also a good opportunity to educate the public 

about the critical and complex nature of the issue. 

Some will say that it is easy to think about providing a generic 

version of biologics, just like we provide generic versions of drugs. 

3 

However, that assumes that all drugs are just like biologics. They 

aren’t. Biologics are very complex molecules modeled after key 

processes occurring daily within the human body. If a drug was a 

3-bedroom, 2-bath starter home, a biologic would be a skyscraper. 

The size and complexity of the items are just that different. 

Unlike drugs, which we can describe the structure with a high 

degree of precision, follow-on biologics elude similar scientific description. 

So, if I was to try to build a skyscraper of a biologic without the 

blueprints, as any generic company would have to do to create a 

follow-on biologic, I would have to ensure that every copy was identical to the last or there could be fatal results. Thus, we must ensure that the science drives any sort of safety standard. One girder 

out of place could cause the entire structure to fall. 

For all of their complexity, we can only imagine the potential of 

some of these potential miracle biologics, such as AIDs vaccine or 

cell therapy to cure diabetes. Today, some biologics are making it 

possible for thousands of Americans to live productive lives while 

others are changing the way we treat deadly diseases like cancer 

and infectious diseases. In the last 20 years, complex diseases such 

as multiple sclerosis and heart disease have been converted from 

virtual death sentences to manageable chronic conditions with the 

help of biologic drugs. 

Over 20 years ago, Congress enacted legislation that provided a 

framework for the creation of generic drugs, generic versions of 

small molecules. In creating that initial framework, Senator Hatch 

and others crafted the watershed Hatch-Waxman legislation, which 

balanced innovation, safety, and incentives to create an abbreviated pathway for the approval for small molecule drugs. However, that legislation intentionally did not directly address followon biologics because they were too new and too complex to fit within that framework. 

Now we’re being asked to find an appropriate framework for the 

approval of follow-on biologics. In doing so, however, we must acknowledge the differences between drugs and biologics. In addition, 

any framework must acknowledge safety and preserve the fast pace 

of innovation. 

I urge my colleagues to consider the ramifications of the legislation. If we get this wrong, then we face two potential undesirable 

outcomes—either new biologics will not be available to provide the 

next cure for life-threatening diseases or individuals die as we rush 

products to market without considering the safety implications. 

We shouldn’t rush a solution through Congress. We must take 

the time to fully consider other framework options, such as the European model for follow-on biologics. Any time we start legislating 

on complex scientific issues and don’t know all the facts, we risk 

endangering lives. 

Again, I thank the Chairman for holding this hearing and the 

witnesses for agreeing to participate. I look forward to learning a 

lot today. Thank you. 

The CHAIRMAN. Thank you very much, Senator Enzi. I’m going 

to ask if Senator Clinton, prior to—she and Senator Schumer work 

very closely. She is a member of this committee and then perhaps 

if Senator Hatch, who’s got a long—wants to say a word. We want 

4 

to keep the hearing moving along but Senator Clinton, obviously, 

has been a leader in the Nation on healthcare, very much devoted 

not only to the broad healthcare policy issues but also healthcare 

in regard to children and is interested in the quality issues. We 

work with her on the issues on information technology and this 

area of biologics as well and if she’d be good enough to say a word 

and then I’ll introduce our first witness. 

STATEMENT OF SENATOR CLINTON

Senator CLINTON. Thank you very much, Mr. Chairman and I 

want to thank you and Ranking Member Enzi for holding this 

hearing and I want to welcome my friend and colleague on this important issue, Senator Schumer. We have recently introduced the 

Waxman-Schumer-Clinton legislation to create a legal pathway for 

the approval of safe and effective follow-on biologics. And I would 

certainly underscore the concerns that Senator Enzi just enumerated. This obviously has to be done with great care and thoughtfulness but as I read the testimony last evening, I was struck by how 

far the discussion has come. There is finally acknowledgement that 

the science supports an abbreviated pathway for follow-on biologics, 

something many experts have asserted for years. 

So, Mr. Chairman, we are finally at a place where we are debating how, not if and it will be up to this committee to decide when. 

Certainly the stakes are very high because the cost of biologics are 

a major and increasing proportion of our healthcare costs in America. 

I’m not suggesting that this will be easy but we know from the 

previous efforts of this committee, certainly the Hatch-Waxman effort, where many of the same concerns and complaints were raised 

that if we work together and we do follow the science, we can devise appropriate legislation. 

Our challenge is to sort through concerns with the Schumer-Clinton legislation, to separate those that are legitimate from those 

that are designed to erect barriers to the approval of safe and effective follow-on biologics. 

So Mr. Chairman, this hearing starts that process. Certainly 

Senator Schumer and I believe we can cut costs, cut red tape, cut 

down barriers between people and safe, life-saving medicines and 

we are determined to work with everyone on both sides of the isle 

to accomplish this critical goal. 

So I look forward to the hearing and I thank the Chairman and 

Ranking Member for holding it. 

The CHAIRMAN. Thank you very much, Senator Clinton. If it is 

agreeable with our colleagues, Senator Hatch has been a particular 

leader in this complex area that affects families to such a great degree and we appreciate both his presence here and his involvement 

on this issue. If he wanted to say a word, that would be great. 

STATEMENT OF SENATOR HATCH

Senator HATCH. Thank you, Mr. Chairman and also Senator 

Enzi. I appreciate being here. Senator Schumer, we appreciate the 

work you’re trying to do on this. This is a very important area. As 

5 

you know—as everybody knows, Hatch-Waxman, Waxman-Hatch— 

whatever you want to call it—— 

The CHAIRMAN. How do you call it? 

[Laughter.] 

Senator HATCH. I usually call it Hatch-Waxman. I noticed that 

Hillary calls it Waxman-Hatch but to make a long story short, it’s 

been a very important bill because it’s saved at least $10 billion for 

consumers every year since 1984 and today, scientists tell me it is 

saving much more than $10 billion a year. 

But we have do it right because follow-on biologics are a much 

more difficult thing to duplicate. And I think it is going to be very 

important—this hearing is a very important hearing to me and I 

think it is important to all of us. I personally appreciate the work 

that my friend, Henry Waxman and Senator Schumer and Senator 

Clinton have done. I don’t quite agree with what they’ve done so 

I haven’t agreed to sign on to that particular bill but I think they 

have brought everybody’s attention to how important this really is. 

I’m also very interested, Mr. Chairman, as you’ve made arrangements to talk about the European Union approach towards these 

issues. I think they have some very, very substantial ideas that we 

should certainly give every consideration to and we are giving consideration to and I, in particular, Mr. Chairman, and the Ranking 

Member, Senator Enzi, I am in particularly in your debt for taking 

this seriously and in meeting with you regularly, we’re finding that 

I think we can maybe do some things here that are going to be very 

important in pushing biologic work forward, especially follow-on 

biologics. So I’m grateful to you, I’m grateful for this hearing and 

I look forward to hearing our witnesses. 

The CHAIRMAN. Thank you very much. We welcome Senator 

Schumer, a long time champion of helping make breakthrough 

medicines more affordable for families, use the principle democratic 

sponsor of the Schumer-McCain legislation on generic drugs that 

was approved by this committee in the 107th Congress, today appears before the committee to speak on follow-on biologics. He and 

Senator Clinton and a bipartisan group of Senate colleagues have 

introduced legislation on this subject that is being studied closely 

by our committee. So we welcome him to our committee and thank 

him for taking the time to appear. We understand he’s got pressing 

business, so we can submit questions if we have questions to him. 

Wouldn’t you like to be able to question. 

[Laughter.] 

Senator SCHUMER. Why not? Everyone else does. 

The CHAIRMAN. Everybody else does. Senator Schumer, we’re delighted. This is very, very important and I know how interested 

you’ve been on this subject and we look forward to hearing from 

you. 

STATEMENT OF CHARLES E. SCHUMER, A U.S. SENATOR FROM 

THE STATE OF NEW YORK 

Senator SCHUMER. Well, thank you, Mr. Chairman and I want to 

thank you for not only being gracious as always in allowing me to 

testify here today but for holding a hearing on this issue. I thank 

the whole committee for your work, just for my colleagues on the 

Republican side. Senator Clinton, I believe, was there but in one 

6 

of our caucuses, Senator Kennedy was outlining the work that is 

just ahead in this committee over the next month or two and it 

seemed like about three quarters of the agenda that America faces. 

So I very much appreciate the work that the committee has done 

under your and Senator Enzi’s leadership, Mr. Chairman. 

I also want to, of course, thank my colleague, Senator Clinton. 

This is another issue where we’re working together and her intelligence and caring on so many issues in healthcare and across the 

spectrum once again, come through in this area and I thank you. 

And my good friend, particularly, Senator Hatch, who along with 

Senator Waxman in the Hatch-Waxman Act—I think it is probably 

one of the most important pieces of legislation passed in the last 

25 years of the previous century for the good it has done. It has 

saved countless lives because people could afford drugs that they 

might not have been able to. 

Anyway, just thinking back to Hatch-Waxman, if you look at the 

record, I was in the Congress then but not involved at all. I was 

a new Congress member but you look at all the objections that people raised when Senator Hatch and Congressman Waxman started 

their legislation. They were told the science wasn’t there. They 

were told generic drugs would put the safety of consumers at risk 

and other issues. But their opponents were wrong and are wrong 

today when they make the same arguments about follow-on biologics. 

As Senator Clinton has correctly outlined just a minute ago, the 

science is there now. We know how to do this. We can have discussions about when to do it and the way to do it but we know how 

to do it and we should. Biologics, of course, are a large and growing 

sector of the pharmaceutical market, provide treatments for devastating diseases, cancer and its complications. It provided some of 

the most important innovations in medicine in the last 100 years. 

But the innovations are only useful if there is competition in the 

market that lowers the price and makes them available to average 

folks, just as Hatch-Waxman did for chemical drugs. 

Treating the patient with a biologic drug can cost $100,000 a 

year, total cost to the nation, $32 billion. If introducing competition 

in this market lowers the price of biologics even by only 10 to 25 

percent, the savings are astronomical. Studies have estimated the 

potential savings for Waxman-Schumer-Clinton bill are tens of billions of dollars every year, similar to the savings that Hatch-Waxman now give us. 

And obviously the science, as Senator Enzi has mentioned, is 

complicated. Biologics are not chemical drugs. It’s much more complicated. We agree completely, we’re not going to see all the savings 

at once but currently, the FDA’s hands are tied. They don’t have 

statutory authority to approve a lower-cost biologic product even if 

all the evidence is there to show the product is just as safe, pure 

and potent as the innovator’s product. 

So to get the process started, we believe we must provide the 

FDA with authority to act and this is the first step long overdue 

and it’s what our bill does. Now there is a great deal of debate generated by our legislation. That’s good. Certainly none of us wants 

a new law that doesn’t adequately protect either the consumer or 

the health of the patient and we don’t want a law that stifles innoVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00010 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
7 

vation by making biologic drugs unprofitable. That would make no 

sense whatsoever. So there is a lot of balancing that has to be done 

here. 

Now my time is brief so I just want to make two points, one on 

the EU system and the other on patents. I want to welcome Mr. 

Rossignol from the EU to this hearing because the EU has already 

moved forward on approving what they refer to as biosimilars and 

I think their experience is valuable but I would urge the committee 

to consider this experience carefully. There may be valuable lessons 

to be learned from a system that is already in place but we must 

fully understand how that model might work in our own market. 

First, we should understand how the EU system came to be and 

how it worked in practice. As it stands today, the EU has a highly 

regulated process in place that has arguably, at least and unnecessarily burdensome to competitors and here’s the interesting fact. It 

has only resulted in two approvals to date. This process was not 

established by legislation that was passed by the European equivalent of Congress, however. The statute that created a pathway to 

biosimilars in the EU was written in broad language, which gave 

Europe’s equivalent of the FDA discretion to flesh out the details. 

So when I think about the EU model, I agree we should pass legislation that would give the FDA the discretion but why would the 

United States want to deprive the FDA of the ability to draft its 

own regulations and force them to swallow a complex set of regulations that has been created by another government, a system of 

government that has a different way than ours. It has price controls and the EU’s generic market is not as robust as the market 

that Senator Hatch and Congressman Waxman created. 

Finally, on patents—just for a moment. As I mentioned earlier, 

we have to strike a balance between rewarding innovation and increasing access to lower cost pharmaceuticals. Many people inside 

this room, outside this room have ideas about how that would happen. The only thing I want to point out before I conclude is that 

when Hatch-Waxman was passed, it struck a bit of balance between the innovators and the generics for traditional chemical 

changes but created an imbalance for biologics. It gave the biologic 

manufacturers the same 5-year patent extensions that chemical 

manufacturers received and gave them the same access to 7 years 

of exclusivity under the Orphan Drug Act but did not set up an abbreviated pathway for the approval of biologic competitors. 

Therefore, I would argue that Waxman-Schumer-Clinton is not 

imbalanced but rather is restoring a balance in a sector of the 

pharmaceutical market that has never faced competition. So I 

know that some colleagues think we’re moving too quickly. I think 

those of us on our bill think we haven’t moved quickly enough. 

We’ve waited years for the FDA to issue White Paper or guidelines. 

The science is there. The groundwork has been laid and of course, 

every day we deny the FDA this authority, it means more delay in 

savings on vital medicines and again, I thank the Chairman and 

would be happy to answer any questions in writing. 

[The prepared statement of Senator Schumer follows:] 

8 

PREPARED STATEMENT OF SENATOR SCHUMER

Thank you, Mr. Chairman, for allowing me to testify before the 

committee today, and for holding a hearing on this very important 

issue. 

I am the sponsor, along with my friend Senator Clinton here in 

this committee and with Congressman Waxman in the House, of 

the Access to Life-Saving Medicine Act, which would establish a 

pathway for competition in the market for biologic products. 

As I sit here today, I’m reminded of the laudable work of my colleague Senator Hatch here and of Congressman Waxman to establish the first pathway for competition in the chemical drug market 

over 20 years ago. 

Back then, they were told that the science wasn’t there. Back 

then, they were told that generic drugs would put the safety of consumers at risk. But their opponents were wrong then, and are still 

wrong today when they make the same arguments about follow-on 

biologics. 

Mr. Chairman, biologics are a large and growing sector of the 

pharmaceutical market. They provide treatments for devastating 

diseases such as cancer and its complications, and have provided 

some of the most important innovations in medicine in the last 100 

years. But these innovations are only useful to the public if there 

is competition in the market that lowers the price and makes the 

drugs available to everyday people. 

Treating a patient with a biologic drug can cost $100,000 per 

year, at a total cost to the Nation of $32 billion per year. Even if 

introducing competition to this market only lowers prices of biologic 

drugs by 10 percent to 25 percent, the savings on products this expensive will still be astronomical. Studies have estimated the potential savings of the Waxman-Schumer-Clinton bill at tens of billions of dollars every year. 

We know that this field of science is complicated. We know that 

we won’t see the savings all at once. But currently, FDA’s hands 

are tied, and they have no statutory authority to approve a lowercost biologic product even if all the evidence is there to show that 

the product is just as safe, pure, and potent as the innovator’s 

product. To get this process started, we must provide FDA with the 

authority to act, and this first step is long overdue. 

That’s exactly what our bill does. The Access to Life-Saving Medicine Act gives FDA the authority to approve follow-on biologics 

and the discretion to determine what kind of information is needed 

to ensure that they are safe and effective. 

I understand that a great deal of debate has been generated by 

this piece of legislation, and I welcome it. Certainly none of us 

wants a new law that does not adequately protect the consumer, 

or a law that stifles innovation by making biologic drugs unprofitable for the brand industry. 

So as we move forward with this debate, I would like to make 

two points, one on the EU system, and the other on patents. 

I’d like to welcome Mr. Rossignol from the European Union to 

this hearing, and since the EU has already moved forward on approving what they refer to as ‘‘biosimilars,’’ I think their experience 

is valuable. 

9 

But I would urge the committee to consider this experience carefully. There may be valuable lessons to be learned from a system 

that is already in place, but we must fully understand how that 

model might work in our own market. 

As it stands today, the EU has a highly-regulated process in 

place that has arguably been unnecessarily burdensome to competitors and has only resulted in two approvals to date. This process 

was not established by the legislation that was passed by the European equivalent of Congress, however. The statute that created a 

pathway to biosimilars in the EU was written in broad language 

which gave Europe’s equivalent of the FDA discretion to flesh out 

the details. 

So when we think about this model, I agree that we should pass 

legislation that would give the FDA the discretion to establish a 

scientific approval process as they see fit. But why would the 

United States of America deprive the FDA of the ability to draft 

its own regulations, and force them to swallow a complex set of regulations that has been created by another system of government? 

A system of government, I might add, that has price controls and 

a generic drug market that is not as robust as our own. 

And finally, I’ll spend a moment on patents. As I mentioned earlier, we need to strike a balance between rewarding innovation and 

increasing access to lower-cost pharmaceuticals. 

I’m sure many people in and out of this room have ideas on how 

they’d like that to happen. 

But let me just point out that in 1984, when the Hatch-Waxman 

law was passed, it struck a balance between the innovators and the 

generics for traditional chemical drugs, but also created an imbalance for biologic drugs. 

It gave biologic manufacturers the same 5-year patent extension 

that chemical manufacturers received, and also gave them the 

same access to 7 years of exclusivity under the Orphan Drug Act, 

but did not set up an abbreviated pathway for approval of biologic 

competitors. 

Therefore, I would argue that the Waxman-Schumer-Clinton bill 

is not imbalanced, but rather is restoring balance in a sector of the 

pharmaceutical market that has never faced competition. 

I know that some of my colleagues are concerned that we are 

moving too quickly. I am concerned that we have not moved quickly enough. We have already waited for years for the FDA to issue 

a white paper on follow-on biologics. The science is there, the 

groundwork has been laid, and every day that we deny the FDA 

this authority means more delay in savings on vital medicines for 

consumers. 

Thank you, Mr. Chairman. 

The CHAIRMAN. Seriously, we thank you for a very thoughtful 

presentation on a complex issue but one of enormous importance 

to people. We thank you very much. 

Senator SCHUMER. Thank you. 

The CHAIRMAN. We’ll have a panel now and ask Mr. Sid 

Banwart, Vice President of Human Services for Caterpillar and is 

responsible for the compensation benefit for Caterpillar’s 95,000 

employees worldwide. Mr. Banwart joined Caterpillar in 1968, 

served in numerous positions throughout the organization. Mr. 

10 

Banwart also chairs a National Coalition for the Human Resource 

Policy Association to create a new, transparent model for purchasing pharmaceutical drugs. 

Dr. Nicolas Rossignol is a Senior Administrator of the European 

Commission Unit responsible for the implementation of the EU 

pharmaceutical legislation. He is in charge of all issues related to 

the biological medicines and since 2003, has been responsible for 

the implementation of an EU regulatory framework on follow-on 

biologics. He also represents the European Commission in technical 

discussions on follow-on biologics held by the World Health Organization. We thank you very much for joining us from Brussels this 

morning. 

Dr. Jay Siegel is a Group President of Research and Development at Johnson and Johnson Pharmaceutical. He is responsible 

for the oversight of research and development in biotechnology, immunology and oncology. Prior to joining J&J in 2003, Dr. Siegel 

was at FDA Center for Biologics, the evaluation of research for 20 

years. Dr. Siegel also has a special connection to the Kennedy Office. He is married to Dr. Mona Safroty, who worked on my health 

staff for many, many, many years and is now serving with the station on the faculty of the George Washington University of Public 

Health. So we welcome Dr. Siegel once again to our committee 

room. 

Dr. Ajaz Hussain is Vice President and Global Head of Biopharmaceutical Development at Novartis with a responsibility for 

the development of follow-on biologics. Before joining Novartis, Dr. 

Hussain served as the Deputy Director of the Office of Pharmaceutical Science in FDA Center for drug evaluation and research, 

where he had oversight responsibility for the development of 

science-based regulatory policies. I’m very grateful to you. 

So Mr. Banwart, we’d be glad if you’d be good enough to start 

off. We welcome the opportunity—we thank all of you for joining 

with us. 

STATEMENT OF SID BANWART, VICE PRESIDENT OF HUMAN 

SERVICES, CATERPILLAR, PEORIA, ILLINOIS 

Mr. BANWART. Thank you, Chairman Kennedy, Senator Enzi and 

other members of the committee. I’m pleased to present testimony 

on behalf of Caterpillar regarding the need to establish an abbreviated science-based regulatory pathway for approval of biogeneric 

products within the FDA. 

We commend you for your swift action in holding this important 

hearing to begin the process to apply balance and competition in 

the biotechnology market. My name is Sid Banwart and I’m the 

Vice President at Caterpillar responsible for the Global Human 

Services Division, which does include compensation and benefits. 

As the world’s largest manufacturer of construction and mining 

equipment, engines and related services, Caterpillar has 95,000 

employees worldwide, is a major U.S. manufacturer and is a leading exporter, with some $10.5 billion worth of U.S. built products 

shipped around the world in 2006. Caterpillar’s ability to maintain 

our position of market leadership depends on our success in attracting and retaining top talent and we use our benefits package 

11 

to recruit the best and brightest from some of the top schools in 

the country, to assure the future of Team Caterpillar. 

We are continuing to take positive measures, many positive 

measures to keep our employees and retirees healthy while managing cost. Last year alone, we spent more than $600 million in the 

United States for comprehensive healthcare benefits for Team Caterpillar. We strongly encourage a vigorous and competitive prescription drug market, one in which innovation leads to new lifesaving medicines. We recognize that one important element of innovation is patent protection but at the end of the patent term, we 

welcome competition in the marketplace. 

Currently, there is no opportunity for competition once a patent 

has expired on brand biotech drugs because the FDA does not have 

clear authority to approve biogeneric products and—let me be clear 

here—by biogeneric, I mean a lower cost alternative, whether the 

industry parlances comparable or interchangeable or therapeutic 

equivalent or generic, we want an abbreviated process that results 

in biogenerics. 

So I appear before you today to urge this committee to find a bipartisan solution to create an appropriate regulatory route for FDA 

review of biogenerics. We believe any solution should grant the 

FDA authority to use its discretion and scientific expertise to 

evaluate interchangeable and comparable biogeneric products while 

ensuring patient safety. One of the most important healthcare laws 

enacted over the past 30 years was the Hatch-Waxman Act. This 

law saves patients, employees and payers billions of dollars every 

year and we thank you, Senator Hatch, for your leadership. 

Now it’s time for an important next step, to create a similar process to spur competition within the biotechnology market. In 2006, 

Caterpillar’s prescription drug costs were in excess of $151 million, 

accounting for more than 25 percent of our total healthcare spending and while biologics currently account only for 3 percent of the 

total drugs utilized, they account for 12 percent in terms of the dollars spent and these biologics have increased in cost 45 percent just 

since 2004. This is our single fastest growing category of health 

cost and the trend is simply not sustainable. 

Caterpillar encourages the committee to consider five key principles, which I’ve expanded upon in my written testimony, as you 

begin to develop legislation. Protect and promote fair and open 

competition. Two, provide a definitive pathway for the approval of 

biogenerics. Three, encourage consistent and uniform terminology. 

Four and this is very important in my mind, increase the resources 

for the FDA. Five, include new legal authority for a biogeneric 

pathway in your must-pass legislation this year. 

In conclusion, I’m pleased that the Senate HELP Committee is 

considering issues like biogenerics that can make a positive impact 

on our health care system and would provide public and private 

benefits in terms of additional certainty in forecasting for 

healthcare spending and as already has been said, overall cost savings. So thank you to the members of the committee who have 

taken an active interest in understanding the important role of the 

FDA to use its scientific judgment to approve biogeneric products. 

Chairman Kennedy, Senator Enzi, we appreciate your leadership 

and that of others on the committee who have been out front on 

12 

this issue. More Americans should be given access to these important innovations and we encourage you to support a marketplace 

that has fair and open competition. Thank you for this opportunity 

to testify today. 

[The prepared statement of Mr. Banwart follows:] 

PREPARED STATEMENT OF SID BANWART

INTRODUCTION

Chairman Kennedy, Senator Enzi and other members of the committee, I am 

pleased to present testimony on behalf of Caterpillar regarding the need to establish 

an abbreviated, science-based regulatory pathway for the approval of biogeneric 

products within the Food and Drug Administration. We commend you for your swift 

action in holding this important hearing to begin the process, launched by the bipartisan efforts of Senators Schumer, Clinton, Stabenow, Leahy, Vitter, and Collins, to 

apply balance and competition within the biotechnology market. 

CATERPILLAR BACKGROUND

My name is Sid Banwart. I’m vice president at Caterpillar where I have responsibility for the company’s Human Services Division, which includes Compensation and 

Benefits. 

As the world’s leading manufacturer of construction and mining equipment, diesel, natural gas and turbine engines, and related services, Caterpillar employs nearly 95,000 employees worldwide, is a major U.S. manufacturer and leading exporter 

with some $10.5 billion of U.S.-sourced product shipped around the world in 2006. 

Caterpillar is able to be a leader in the global marketplace utilizing its strong 

U.S. manufacturing base because we make competitive products that are known for 

their quality and durability. But our ability to remain a market leader depends on 

our success in attracting and retaining top talent. We use our benefits package to 

recruit the best and brightest from some of the top schools in the country and consider those new grads to be the future of Team Caterpillar. 

HEALTH CARE STORY

To ensure our company is well positioned in that future, we are continuing to take 

aggressive measures to keep our employees and retirees healthy, while managing 

cost. As you know, the escalation of health care costs is a top concern for U.S. business executives, and we at Caterpillar are no exception. Last year alone, we spent 

more than $600 million in the United States for comprehensive medical, dental, vision, and prescription benefits. 

To manage our costs, we’ve taken action on both the wellness and cost sides of 

the equation. On the wellness front, Caterpillar has in place an award winning 

health promotion program, disease management systems, and our 

Work.Life.Solutions program to promote a balanced lifestyle. On the cost side, we’ve 

established preferred hospital groups, physician networks and a pharmacy benefit 

management arrangement to ensure the best possible rates and enhanced transparency in pricing. 

VIEW ON PRESCRIPTION DRUG MARKETPLACE

Caterpillar strongly supports a vigorous and competitive prescription drug market, one in which innovation leads to new life-saving medicines. Currently there is 

no opportunity for competition in the marketplace once a patent has expired on 

brand biotech drug products because the Food and Drug Administration (FDA) does 

not have clear authority to approve biogeneric products. I appear before you today 

to urge this committee to find a bipartisan solution to create an appropriate regulatory route for FDA review of biogenerics. We believe the solution should grant the 

FDA the authority to use its discretion and scientific expertise to evaluate interchangeable and comparable biogeneric products while ensuring patient safety. 

HATCH-WAXMAN LAW

One of the most important health care laws enacted over the past 30 years was 

the ‘‘Drug Price Competition and Patent Term Restoration Act of 1984,’’ commonly 

known as the ‘‘Hatch-Waxman’’ law. As Senator Hatch knows so well, this landmark 

legislation broke important new ground in granting FDA the authority to approve 

generic versions of prescription products. Hatch-Waxman also gave FDA express authority to provide an abbreviated approval process for those products deemed equivVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00016 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
13 

1Poisal, J.A., et al., ‘‘Health Spending Projections Through 2016: Modest Changes Obscure 

Part D’s Impact,’’ Health Affairs 26, no. 2 (2007) Exhibit 6. 2MedAdNews, November 2006. 3 Engel & Novitt, LLP, ‘‘Potential Savings That Might Be Realized by the Medicare Program 

From Enactment of Legislation Such as The Access to Life-Savings Medicine Act (H.R. 6257/S. 

4016) That Establishes A New CBLA Pathway For Follow-On Biologics. Table 4a, January 2, 

2007. 

alent to the prior approved product. It is estimated that this law saves patients and 

payers billions per year—and we thank you, Senator Hatch, for your leadership in 

this important area, as well as your recent commitment to work to pass legislation 

this year to spur competition within the biotechnology market. 

CONSUMERS AND PURCHASERS WILL BENEFIT WITH GREATER INNOVATION

AND GREATER COMPETITION

Total spending on prescription drugs in 2006 is estimated at $213.7 billion and 

rising to $497.5 billion by 2016.1 The use of biopharmaceuticals is increasing at almost twice the rate of traditional medicines—accounting last year for approximately 

$30 billion in U.S. sales and 12 percent of total pharmaceutical usage.2 These medicines can and do improve the lives of millions of patients—but without generic 

versions, the costs may keep needed treatments out of the hands of consumers. 

Caterpillar is focused on drug issues because we expect prescription drug expenses to be among the most significant health care cost drivers for our company 

in the years ahead due to an aging workforce and increased rates of utilization. For 

2006, Caterpillar’s prescription drug cost were in excess of $151 million, accounting 

for more than 25 percent of our health care total spent. For our company, biologics 

currently account for 2.9 percent of the total drugs utilized but account for 12 percent in terms of spending. Most concerning is the financial trend Caterpillar has 

documented with biologic products . . . costs have increased 45 percent since 2004. 

This is our single fastest growing category of health cost, and the trend is simply 

not sustainable. 

CERTAINTY

Caterpillar, like other U.S. manufacturers, is very concerned about the implications of our health care expenses. For business planning purposes, it is critical for 

us to have certainty when forecasting spending . . . be it for commodities such as 

steel or for health care benefits like prescription drugs. Currently there is no certainty in our pharmaceutical spending because we do not know when or if there will 

be lower cost alternatives for biopharmaceuticals. Many of the biopharmaceuticals 

on the market today are ‘‘off-patent’’ and more than $10 billion worth of biopharmaceuticals are expected to come off patent by 2010.3 When exploring avenues to introduce competition into the marketplace, I ask Congress to clearly outline a reasonable process for early resolution of patent disputes to avoid any unintended loopholes and ensure certainty for the biogeneric marketplace. 

GUIDING PRINCIPLES FOR BIPARTISAN LEGISLATION

Caterpillar encourages the committee to consider five key principles as you begin 

to consider legislation: 

1. Protect and promote fair and open competition. As innovators, we respect 

and understand the development of innovation and need for patent protections. 

However, once a patent expires or is successfully challenged, biogeneric competition 

should be able to enter the market. 

2. Provide a definitive pathway for the approval of biogenerics. We believe 

there must be certainty in both timing and method of the biogeneric approval process. FDA needs the authority—to approve both comparable and interchangeable biogeneric products. Congressional deference to the FDA’s expert scientific judgment is 

appropriate. In addition, any action should permit prescribers to substitute one biologic for another when appropriate. 

3. Encourage consistent and uniform terminology. Whether the terms are 

‘‘comparable,’’ ‘‘interchangeable,’’ ‘‘therapeutic equivalent,’’ or ‘‘generic’’—we want an 

abbreviated process that results in a ‘‘biogeneric,’’ meaning a lower cost alternative 

to biologic pharmaceuticals. 

4. Increase resources for the Food and Drug Administration. In order to 

adequately assume these new responsibilities, the FDA will need adequate resources. We support additional resources for FDA to secure more staff to ensure the 

timely review of biogeneric applications and the safety of biogenerics for consumers. 

14 

5. Include the new legal authority for a biogeneric pathway in must-pass 

legislation this year. We encourage Congress to move quickly to establish a regulatory pathway for the approval of biogenerics. We are confident that this hearing 

will affirm that the science for comparable and interchangeable products has arrived. Once the FDA has the discretionary authority to begin this process, it will 

drive innovation that will assist in the identification of similar and substitutable 

methods for these off-patent products. Each day that passes without biogenerics is 

another day of limited options. No payer, whether individual or employer, public or 

private, can afford unlimited monopoly pricing. Caterpillar, therefore, is encouraged 

to hear reports that members are committed to including a workable pathway into 

the prescription drug reauthorization legislation—called PDUFA—and strongly supports you in this endeavor. 

CONCLUSION

In conclusion, I’m pleased that the Senate HELP Committee is considering issues 

like biogenerics that can make a positive impact on our health care system. Thank 

you to all the members of this committee who have taken an active interest in understanding the important role of the FDA to use its scientific judgment to approve 

biogeneric products. Chairman Kennedy and Senator Enzi, I appreciate your leadership and also that of others on the committee who understand and have taken leadership on these issues. A bipartisan bill that empowers the FDA to use the best 

science to encourage innovation and biogeneric competition should be passed this 

year. More Americans should be given access to these important innovations—we 

encourage you to support a marketplace that has fair and open competition. Thank 

you for this opportunity to testify today. 

The CHAIRMAN. Thank you very much. 

Dr. Siegel. 

STATEMENT OF JAY P. SIEGEL, M.D., GROUP PRESIDENT, BIOTECHNOLOGY, IMMUNOLOGY AND ONCOLOGY, RESEARCH 

AND DEVELOPMENT, JOHNSON & JOHNSON, RADNOR, PENNSYLVANIA 

Dr. SIEGEL. Good morning, Mr. Chairman and members of the 

committee. Thank you for your introduction. I’ll skip over my employment but I would like to note in the context of today’s hearing 

that in my 20 years in the public health service, I was responsible, 

entirely over that 20 years for regulation of biologics, over the final 

7 years for the review and approval of all biological therapeutics 

and led the review and approval of about 50 such products and particularly relevant to today’s hearing, played an essential role in setting scientific standards for ensuring the comparability of biological 

products after manufacturing changes. I am speaking on behalf of 

Johnson & Johnson and I thank you for the opportunity to be here 

today. 

My company and I appreciate and share the concern shown by 

Senators Clinton and Schumer and others here for expanding access to biologic therapies. I also appreciate the concern this committee and other members have repeatedly demonstrated for protection of patient safety and welfare. 

A concern we all share and that must guide us as we develop a 

statutory pathway for follow-on biologics. To that end, I will discuss 

several science-based principles that are critically important to address in any regulatory paradigm for follow-on biologics. 

First, there will always be a need for appropriate pre-marketing 

testing in humans to ensure that a follow-on biologic is safe and 

effective. In contrast to typical non-biologic drugs, biologics are 

often 100 to 1,000 fold larger or more complex. They are produced 

15 

by living cells in tissues and organisms and they are highly susceptible to changes. 

As is detailed in my written testimony, recent history is replete 

with examples of how seemingly minor manufacturing changes for 

biologics have led to inadvertent changes in the biologic product. 

Due to the complexity of biologics, these changes often are not detectable by laboratory testing but they can present significant risks 

for patients. 

The production of follow-on biologics will necessarily involve substantial changes in the manufacturing process and laboratory testing of follow-on biologics will be even more limited in its ability to 

detect resultant product differences because the manufacturers 

have incomplete access to knowledge and materials necessary for 

optimal testing. 

To ensure safety and efficacy, testing in humans will be needed. 

The types and extent of clinical testing required for follow-on biologics’ approval will need to be determined on a case by case basis, 

considering factors about the product, its laboratory testing and its 

potential effects in patients. 

The second principle is this: there need not and should not be allowance for determinations of comparability for products that are 

so different in structure that they should be considered different 

products entirely. While generic drugs have identical active ingredients, it is essentially impossible to make a follow-on biologic with 

an identical active ingredient. Thus, if we are to move forward with 

an abbreviated biologics application for follow-on biologics, they 

need to be based on biologics being highly similar rather than identical. 

But there is no need nor scientific basis to allow abbreviated applications despite differences so substantial they could readily be 

avoided by the manufacturer and that they present the significant 

likelihood of differences in the safety and efficacy of the biologic. 

Third, a follow-on biologic should not be considered interchangeable with its reference product. Within the limitations of science 

today and in the foreseeable future, there is no realistic potential 

for scientifically valid determination of interchangeability. Followon biologics can be shown to be similar but never identical to an 

innovator biologic. Application of interchangeability status to a follow-on could lead to inappropriate assumptions of sameness and 

substitution of one for the other. Such substitution could not only 

have potentially serious health consequences but could seriously 

impair the ability of post-marketing surveillance systems to detect 

new safety problems and to determine which biologic was responsible. Indeed, follow-on biologics policy should discourage inadvertent substitution. 

Fourth, FDA must be empowered to require post-marketing clinical studies and post-marketing safety surveillance needed to ensure safety. 

Fifth, any proposed pathway for follow-on biologics should not 

constrain the FDA’s ability to request data and studies in support 

of sound scientific decisions. 

In conclusion, it is my hope and that of Johnson & Johnson that 

a scientifically-based public process will provide a framework and 

pathway for follow-on biologics in the United States, a pathway 

16 

which reflects an overriding concern for patient safety and well 

being. It is also critical that this pathway provides appropriate incentives for innovation so that the promise of new and innovative 

biological therapies can continue to be realized for patients for generations to come. 

I thank you again for the opportunity to speak here today and 

look forward to answering questions you may have. 

[The prepared statement of Dr. Siegel follows:] 

PREPARED STATEMENT OF JAY P. SIEGEL, M.D. 

Good morning, Mr. Chairman and members of the committee. My name is Dr. Jay 

Siegel, and I am pleased to come before you today to offer a scientific perspective 

on the issues relevant to any proposed framework for the abbreviated approval of 

follow-on biologics. I will provide examples from my experience to illustrate the significance of these issues. I hope you will find my contribution to this discussion constructive and useful as you seek out a sound, science-based path forward for followon biologics. I particularly appreciate the concern shown by Senators Clinton and 

Schumer, the sponsors of S. 623, the Access to Life Saving Medicine Act, for patient 

access to biologic therapies. It is a concern that I share—as does my company, Johnson & Johnson. 

By way of introduction, I studied biology at the California Institute of Technology 

and received my medical degree from Stanford University. My post-doctoral training 

was in Internal Medicine at the University of California San Francisco and in Infectious Diseases and Immunology at Stanford. As a scientist with specific expertise 

in the fields of biotechnology, immunology, and clinical trial design, I have dedicated 

much of my life and career to public health, working 20 years regulating biologics 

at the Food and Drug Administration (FDA), including as the founding Director of 

the Division of Clinical Trial Design and Analysis and then as Director of the Office 

of Therapeutics Research and Review within the Center for Biologics Evaluation 

and Research (CBER, 1996–2002). 

In this role, I supervised the medical and scientific team responsible for the evaluation and approval of all biological therapeutics, including monoclonal antibodies, 

cytokines, growth factors, enzymes, cellular and gene therapies. I have led the review and approval of more than 50 new therapies. Particularly relevant to today’s 

hearing, I also led efforts to develop FDA policy regarding scientific standards for 

demonstrating the comparability of biological products after a manufacturing 

change. 

In the course of ensuring appropriate regulation of biologics, my associates at 

FDA and I worked closely with Members of Congress and testified before committees such as this one to communicate the complexities of biological therapeutics, 

their promise, and, at all times, our concern that they be as safe as possible for patients. I know that patient safety is a concern that we share and that it will be the 

guiding concern for you as you develop a statutory pathway for follow-on biologics. 

Presently, I am Group President of Research and Development for Biotechnology, 

Immunology, and Oncology for the Johnson & Johnson family of companies, one of 

the world’s largest producers of biotechnology-derived biologics, and today I am 

speaking on behalf of Johnson & Johnson. Having devoted decades of my life as a 

regulator and scientist working on biologics, I sincerely hope my experience will 

help you in the task ahead. 

While legislation on follow-on biologics has the potential to improve access to lifesaving medicines, that legislation should be well-founded in science and ensure that 

the lifesaving medicines to which access is provided are no less life-saving or safe 

than medicines already on the market. I believe that through the proper process, 

those critical ends can be met. 

There are many important examples from the recent past that should give rise 

to caution about the possibility that follow-on biologics could have important differences from their reference products. This concern results from the complexity of 

biologic products and the inability to fully characterize them. Experience has taught 

us that there is significant likelihood that differences in a product will result when 

it is made by a different manufacturer; that such differences cannot always be detected except through clinical testing; and that such differences can have potentially 

serious ramifications for the health and safety of the patients that we all serve. 

I would now like to focus my remarks on five principles that I feel are critical 

to address carefully in any follow-on biologics legislation: 

17 

• First, there will always be a need for appropriate pre-marketing clinical data 

to ensure that a follow-on biologic is safe and effective. 

• Second, there cannot be allowance for determinations of ‘‘comparability’’ for 

products that are so different in structure that they should be considered different 

products entirely. 

• Third, a follow-on biologic product should not be considered interchangeable 

with its reference product. 

• Fourth, FDA must be empowered to require post-marketing clinical studies and 

post-marketing safety surveillance to ensure safety. 

• Fifth, there should be no constraints placed on the FDA for ensuring the safety 

of follow-on products. 

I would now like to share with you my scientific perspectives on these key areas 

in more detail. 

1. ANY PATHWAY FOR FOLLOW-ON BIOLOGICS SHOULD REQUIRE PRE-MARKET CLINICAL

DATA FOR DEMONSTRATION OF SAFETY AND EFFICACY

To understand why we should always expect some need for pre-market clinical 

testing of follow-on biologics, it is important to understand the nature of biologics 

in general and how they differ from small molecule therapies. 

With small molecule drugs—for example, the conventional pills you see on pharmacy shelves and in medicine cabinets—you are working with substances that are 

relatively small, relatively simple in structure, and relatively easy to replicate using 

carefully controlled processes. Most importantly, their relatively small size and simple structure allow precise characterization and detection of even minor changes in 

the product. 

Biologics are vastly different from small molecules in all these aspects. In contrast 

to small molecules, biologics are very large—typically several hundred- or thousandfold larger. They are produced not by well-controlled chemical processes but by complex living cells and organisms. 

Minor differences in production conditions in these living ‘‘factories’’ can lead to 

important differences in their product. To a far greater extent than small molecules, 

biologics frequently can bind to themselves to form pairs or aggregates, can change 

their shape over time or with minor changes in conditions, and can interact with 

materials in their containers and packaging. They are relatively unstable and are 

sensitive to how they are handled, processed and stored as they have the ability to 

assume many forms and variants. They are typically not homogeneous in chemical 

structure; rather, they are a large family of molecules with related, but not identical, structures. They cannot be fully characterized, so not only are differences common, they can be extremely difficult to detect, and their effects on the product’s safety and efficacy are extremely difficult to predict. 

As a result, the regulation of biologics is strongly based upon strict control of the 

manufacturing process to minimize the likelihood of changes to safety and efficacy. 

And additional clinical testing is often required when substantial changes to the 

manufacturing process occur. 

It is true that the ability to characterize biological products using physical, chemical, and biological testing has improved as science has advanced. However, such 

laboratory testing, without testing in patients, is still very far from being able to 

ensure that a follow-on biologic is without differences from a reference product—differences that could adversely affect its safety or efficacy. 

When a biologics manufacturer makes a substantial change to its process (e.g., 

new cell line), given the incomplete ability of laboratory testing to identify or predict 

differences, FDA requires substantial testing in humans (clinical testing) to validate 

the comparability of the product. This was the case when I was at FDA and remains 

the case now. And that clinical testing not infrequently reveals differences (see some 

of the examples below). The manufacture of a follow-on will by definition involve 

very substantial changes—a new cell line, a new facility, and, to varying extents, 

a new process—raising the relatively high likelihood of clinically important differences. 

The manufacturer of a new follow-on biologic also faces several limitations in its 

ability to identify clinically important differences short of clinical testing. When a 

manufacturer makes substantial changes in its manufacturing process, that manufacturer is able to compare not only final product but also various components and 

intermediates that are produced during various stages of the new and old manufacturing process. For example, depending on the changes made, comparisons might be 

made of the unpurified biologic (made by the old and new processes), and/or of purified product prior to formulation. Such comparisons may detect important differences that remain in the final product, but at levels that make them undetectable 

18 

in the final product. Manufacturers of follow-on biologics will not have these materials for testing and will only have access to final, marketed reference product. 

Additionally, optimal comparisons of ‘‘before change’’ and ‘‘after change’’ materials 

require an understanding of which parameters are key to ensuring the safety and 

efficacy of the molecule and what the best approaches to assessing them are. This 

understanding comes from years of working with the reference product and is not 

available to manufacturers of follow-on biologics. Further, when differences are detected, the key question becomes whether the difference is clinically important. 

While manufacturers of innovator products have extensive experience which sometimes helps address this question, the manufacturer of a new follow-on biologic will 

have limited experience with the molecule. 

Thus, a manufacturer of a follow-on biologic will face significantly more limitations in demonstrating comparability than a manufacturer modifying its own process. At Centocor, a Johnson & Johnson company that develops biological therapies, 

when we make changes that might affect the clinical effects of a product, while we 

do extensive laboratory testing, we nonetheless also face an appropriate requirement 

for clinical studies to ensure safety and efficacy. How can we accept a lesser standard of evidence from the manufacturers of follow-on biologics, who face even greater 

limitations in laboratory testing, without significant concerns for safety? 

In light of these limitations, and based on my experience, I firmly believe that 

there will always be a need (in the foreseeable future) for some amount of clinical 

testing of a follow-on biologic to provide adequate assessment of potential changes. 

The amount and type of testing will depend on the specifics of the products and assessment of potential risks. While clinical trials may be abbreviated compared to 

those required of a new nonfollow-on product, clinical studies to address questions 

such as immunogenicity, pharmacokinetics, and common adverse events under controlled conditions will always be important before a product is marketed. I would 

never take a biologic that had not been tested in humans; the risks are too high. 

New legislation should not cause others, who may be less informed, to do so. Congress should not create two standards of medicine—those appropriately tested for 

safety and efficacy and those that are not. 

Examples 

There are many examples of how seemingly minor changes in a biologic’s manufacturing process have resulted in significant changes in the product. And while 

these changes sometimes are undetectable in laboratory testing or are ‘‘minor’’ 

enough to qualify under S. 623 as preserving ‘‘highly similar principal molecular features,’’ they can often trigger clinically important changes in the product’s safety 

and efficacy—changes that, at times, can be detected only through clinical testing. 

I would like to use some specific examples to ensure that this committee’s members understand that my concerns are not theoretical or alarmist in nature, but are 

in fact very real issues that need to be considered. 

In recent years, at Johnson & Johnson, we changed the cell line used to make 

an experimental biologic called CNT095. By physical and laboratory testing, the 

product made by the new cell line looked quite similar to the old product, so it 

would have passed a comparability determination were clinical testing not needed. 

But clinical testing revealed that the new product had different pharmacokinetics: 

that is, the drug levels in the body over time were different from those seen when 

the old cell line was used. This sort of change in pharmacokinetics, revealed only 

in clinical studies, was an extremely common occurrence observed during my time 

at the FDA. 

In my experience at the FDA, even seemingly innocuous manufacturing changes 

for a biologic product often led to significant differences—sometimes detected only 

through clinical testing. In another example, a manufacturer opened a new facility 

in Japan to treat patients in Japan. The process used at the new facility was made 

as similar as possible to that of the pre-existing facility. Laboratory testing of the 

physical and chemical properties and bioassays showed no differences between products made at the new and pre-existing facilities. But in clinical testing, blood levels 

of the biologic were 40 percent lower in patients taking the product manufactured 

in the new facility versus the old. Although it was initially suspected that this reflected a difference in the patient population, further studies indicated the difference 

was indeed in the drug itself. 

Sometimes, changes that seem not only innocuous but beneficial can create problems. Proleukin is a biologic for treatment of cancer that contains a detergent used 

in manufacturing. Prior to licensure, the manufacturer lowered the detergent levels 

in an attempt to make the product more pure. Product made by this new process 

passed routine testing. Highly specialized additional testing later found that the 

new product had increased microscopic clumping. This microscopic clumping reVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00022 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
19 

sulted in rapid clearance of the drug from the circulation. In yet other examples, 

a change as seemingly minor as placing a product in a pre-filled syringe instead of 

a vial has led to clinically meaningful changes to several biologic products: One 

interacted with silicone in the syringe, one interacted with trace metals in the needle, and, as discussed below, one interacted with the rubber stopper on the syringe 

plunger. 

Immunogenicity 

Special attention should be given to the problem of immunogenicity: i.e., the ability of most or all biologic products to stimulate an immune system response in the 

body, prompting the formation of antibodies. Immunogenicity is particularly important in the context of manufacturing changes for a biologics because (1) product differences that are difficult or impossible to detect can lead to changes in 

immunogenicity; (2) changes in immunogenicity can impact on safety and efficacy 

in many ways and (3) immunogenicity can be assessed only through clinical testing. 

The immune system evolved to distinguish foreign proteins (e.g., bacteria, viruses, 

proteins from other people) from its own proteins as a means of survival. This 

means that our immune systems can be exquisitely sensitive to differences in proteins. 

Thus, there is great potential for seemingly minor changes in therapeutic protein 

products, even those not detected by physical, chemical, and biological testing, to result in clinically significant changes in immunogenicity. 

Most biologic products have some degree of immunogenicity; that is, they will 

cause formation of antibodies in some patients. For vaccines, this is desirable. For 

therapeutic proteins, these antibodies can inactivate the protein or cause it to be 

cleared from the body, resulting in a loss of efficacy and the progression of the disease. Patients with hairy cell leukemia treated with interferon alfa, for example, 

have been reported to experience a relapse of disease when antibodies develop. Similarly, some patients receiving insulin and blood clotting Factors VIII and IX have 

been reported to lose responsiveness after developing antibodies. 

In addition to inactivating or clearing a drug, antibodies bound to a drug can also 

play a direct role in causing various adverse effects. Patients who have developed 

antibodies to experimental biologics have experienced consequences including joint 

swelling, fever, and encephalitis. Even for approved biologics, it is not uncommon 

that the development of antibodies during treatment increases the likelihood of having adverse reactions, sometimes even severe, at the site of subsequent injections 

or following subsequent infusion into the blood stream. 

In addition to these effects, and more serious still, for certain drugs, antibodies 

can also inactivate the body’s naturally occurring protein, resulting in adverse and 

even life-threatening side effects. Patients who received an experimental biologic 

version of thrombopoietin, a protein that stimulates production of platelets critical 

for blood clotting, developed antibodies which neutralized not only the biologic, but 

also their own naturally produced thrombopoietin, resulting in problems with bleeding. 

Avonex® is an interferon beta product used to treat multiple sclerosis. After clinical testing proved that interferon beta was safe and effective for this use, the manufacturer needed to develop a new cell line to make the biologic and manufactured 

it in a new facility. While the Agency would normally be quite reluctant to permit 

a change in cell lines at this late stage of development, there was a public health 

need for this treatment which had been shown in clinical studies to be effective in 

treating multiple sclerosis. However, the original cell line used to make the drug 

for clinical studies was no longer available to the manufacturer and it was necessary 

to use another cell line in order to bring this product to patients. 

Only after a couple of years of work using the new cell line was the manufacturer 

able to make an interferon beta product, Avonex, that appeared highly similar to 

the material used in the clinical trials that showed safety and efficacy. While the 

manufacturer was not required to repeat multi-year clinical testing, substantial clinical study was done before approval. Thereafter, post-marketing clinical experience 

showed that Avonex did indeed have clinically relevant differences from the earlier, 

clinically tested material. Fortunately for all, Avonex differed in that it had less 

immunogenicity. This example contributed to heightened awareness of the potential 

for manufacturing changes to lead to immunogenicity changes and of the importance 

of immunogenicity testing after many types of manufacturing changes. 

The case of EPREX®, a biologic product sold in Europe by Johnson & Johnson 

companies, illustrates how even a seemingly minor change can increase a product’s 

immunogenicity and cause harm to patients. In 1998, our company changed the stabilizer in its EPREX formulation at the request of European authorities because of 

concern in Europe that the human serum albumin stabilizer could theoretically 

20 

transmit Mad Cow Disease. The switch from the old stabilizer to another well-established one seemed simple enough and relatively benign. Indeed, it was intended to 

improve the safety profile. It was applied to a variety of product presentations, including single-use vials and pre-filled syringes with both Teflon-coated and uncoated 

rubber stoppers. 

However, shortly after this seemingly minor change, there was an increase in the 

incidence of antibody-mediated pure red cell aplasia (PRCA) among patients taking 

EPREX. Pure red cell aplasia is a serious condition in which the bone marrow 

ceases to produce red blood cells. It took 4 years of extensive investigations involving more than 100 experts from clinical, pre-clinical, manufacturing, process 

sciences, logistics, quality, analytical, and regulatory fields and in excess of $100 

million to identify the cause. The conclusion was something no one had expected: 

Uncoated rubber stoppers, when exposed to the new stabilizer, released substances 

called leachates into the EPREX formulation and that these substances were most 

likely responsible for the increase in the product’s immunogenicity and the resulting 

increase in patients developing pure red cell aplasia. 

It’s important to note that the several examples I have given are just some of the 

many cases in which immunogenicity concerns have arisen. Most biologics have 

some degree of immunogenicity; their immunogenicity levels can change with even 

slight changes in their manufacturing process, the consequences of which can be 

clinically important. And as stated above, immunogenicity can be detected only 

through clinical testing. 

Clinical Studies May Be Needed for New Uses Despite Same Mechanism of Action 

One significant concern about S. 623 is that it contains a provision stating, ‘‘If the 

applicant has demonstrated comparability for a single condition of use . . . the Secretary shall issue a comparable biological product license for all conditions of use 

of the reference product sharing the same mechanism or mechanisms of action.’’ 

This provision presumes that if the drug has the same mechanism in two conditions, 

evidence of safety in one condition can be used to establish comparable safety in the 

other. It is important to understand that this presumption is not scientifically correct and could lead to approvals of use in indications in which the follow-on biologic 

is not safe. While the mechanism of action may be the same for two indications, the 

patients, their co-morbidities and concomitant therapies may differ. 

Once again, the EPREX example is instructive: EPREX is used to correct anemia 

in patients with cancer and in patients with renal failure. In both patient populations, EPREX and other erythropoietins work to correct anemia through the same 

mechanism of action: by stimulating more blood cell production in the blood marrow. 

But PRCA is seen only in patients with renal failure and not in patients with cancer. So if a follow-on version of EPREX were studied only in patients with cancer 

and found to be ‘‘comparable’’ with an approved erythropoietin, this proposed legislation would allow its use in patients with kidney failure, notwithstanding the possibility that it might have unacceptable immunogenicity in those patients. A similar 

situation is observed with granulocyte-monocyte colony stimulating factor or GMCSF, a biologic that stimulates some bone marrow and blood cells. Like EPREX, 

GM-CSF is immunogenic when used in some diseases and not in others. 

These two examples call into serious question the wisdom of approval for all indications with the same mechanism of action after demonstration of comparability in 

just one indication. Simply stated, if a follow-on biologic is to be used in patients 

capable of having an adverse immune response to it, it should not be sufficient to 

study the follow-on biologic only in an indication in which the patients are less capable or incapable of having an adverse immune response to it. 

In summary, extensive experience confirms that manufacturing differences such 

as those between the processes of an innovator and follow-on are likely to lead to 

differences in product safety or efficacy; not infrequently, these will be detected best 

or only in clinical testing. That is not to say that a full clinical testing program must 

be required for follow-on biologic products. On a product-by-product basis, and particularly where there exist good measures of desired effects (so called 

pharmacodynamic measures) and where a high degree of similarity is demonstrable, 

abbreviated clinical testing will sufficiently address key areas of uncertainty regarding safety and efficacy. But experience has made clear that clinical studies must be 

considered a necessary and mandatory part of properly evaluating any and all biologic products and must be a fundamental piece of any proposed regulatory pathway 

for the approval of follow-on biologics. 

21 

2. ANY PATHWAY FOR FOLLOW-ON BIOLOGICS MUST NOT ALLOW FOR DETERMINATIONS

OF ‘‘COMPARABILITY’’ FOR PRODUCTS SO DIFFERENT IN STRUCTURE THAT MAJOR SAFETY AND EFFICACY CONCERNS NECESSARILY ARISE

Since it is not possible to make two biologic products identical, follow-on biologics 

policy will, by definition, allow abbreviated applications for molecules that are highly similar to a reference, despite known or potential differences. However, one must 

draw a line as to how much of a difference should be allowed as there is no scientific 

basis for allowing abbreviated testing of a new biologic on the basis of it being only 

distantly related to an existing one. Some differences are so substantial that the biologics should be considered different products entirely. Some types of known differences are so substantial and so likely to result in clinically meaningful differences, there is no reason not to treat such different drugs as if they are different 

drugs. 

Differences in Amino Acid Sequence 

One such difference is ‘‘minor differences in amino acid sequence,’’ a difference 

that, according to S. 623, would still allow a molecule to be considered ‘‘to contain 

highly similar principal structural features.’’ The amino acid sequence defines a protein. Even a minor difference creates a different (mutant) protein, and a product 

containing such a mutant protein is a different product from the non-mutant form. 

Given the enormous potential for such a product to have different effects, any such 

product should be subject to all the standard safety and efficacy testing to which 

you would subject any innovator drug. 

Differences in even just one amino acid can have devastating effects on the function of a protein. Single amino acid mutations in a person can be lethal or result 

in serious diseases such as sickle cell anemia and cystic fibrosis. Single amino acid 

mutations in a virus can change it from benign to deadly or from treatable to resistant to treatment. And single amino acid changes in therapeutic biologics, sometimes 

made in an attempt to improve potency, durability, or other desirable traits, often 

have adverse effects on the molecule, with the potential to pose great danger to patients. 

The AspB10 insulin analogue is a prime example. This was a biological product 

that had only one amino acid difference from the insulin amino acid sequence. At 

the time it was being studied, it seemed reasonable to think that this insulin analogue would be safe. However, to the great surprise and concern of all involved, 

when AspB10 was given to laboratory rats, it triggered the development of breast 

cancers. 

In marketed protein products, FDA has never, to my knowledge, allowed a change 

in even a single amino acid. When a change in an amino acid has occurred during 

pre-market development, FDA has required extensive testing of the new molecule 

rather than assuming the properties of the former molecule were retained. To allow 

marketing of new mutant protein therapeutics with anything short of the testing 

required of any new protein therapeutic potentially exposes patients to very real 

risks. 

As noted above, the need to tolerate some differences in a follow-on biologic from 

its reference product arises from technical limitations on the inability to exclude, or 

in some cases to identify, some differences. But there is no technical limitation preventing a manufacturer of a follow-on biologic from producing one with an amino 

acid sequence identical to that of a reference. 

Differences in Post-Translational Events 

As a scientist, I also find it troubling that S. 623 would allow products with differences ‘‘due solely to post-translational events’’ to be considered ‘‘highly similar’’ 

and eligible for demonstration of comparability within the broad statutory definition 

set forward for abbreviated applications. 

‘‘Post-translational modification’’ refers to the important processes that occur after 

the backbone of a protein has been synthesized. It can result in major chemical 

modifications of the protein, such as attaching additional chemicals, modifying the 

chemical structure, cross-linking, and removing large parts of the protein. Posttranslational modifications can, and often do, have a major impact on the activity, 

half-life in circulation, and immunogenicity of a protein. Many types of posttranslational modifications leave no scientific basis for a determination of comparability and submission of abbreviated applications. 

Any difference in post-translational modification will require significant clinical 

testing to determine what difference it makes clinically. But many are so profound, 

they should simply be considered to make the biologic a different biologic, requiring 

a full application. 

22 

Complex Biological Products Including Live Viral Products 

Particularly concerning is the provision in S. 623 that ‘‘closely related, complex, 

partly definable biological products with similar therapeutic intent’’ (for example, 

two live viral products for the same indication) also be considered ‘‘highly similar.’’ 

This provision allows abbreviated applications for living cells and organisms and 

other biologic products far more complex and difficult to define than proteins. 

The legislation acknowledges that these biologic products are only partly definable 

and complex. Therefore, by definition, one cannot know just how different they are. 

If one cannot know how different the products are, and the possibility exists that 

they are vastly different, then there can be no scientifically valid basis for determination that they are comparable. The inability to define these highly complex 

products ought to exclude the possibility that an abbreviated application lacking full 

clinical testing would provide sufficient protection of safety or efficacy—yet this proposed legislation would allow for that possibility. 

Of note in this regard, the legislation cites as an example of closely related products ‘‘two live viral products for the same indication.’’ However, anyone familiar 

with recent concerns about potential differences in different preparations of smallpox vaccines, of influenza vaccines, and of live polio vaccines will surely appreciate 

that comparability determinations should not replace full clinical testing for such 

complex, partly definable products. 

No Limitations Placed 

Finally, I would draw your attention to the fact that after drawing extremely 

broad boundaries around what types of differences (and what types of products) 

would fall within the scope of comparability determinations and abbreviated applications, S. 623 undermines even those boundaries. It gives the Secretary leeway to 

determine any two biological products ‘‘to contain highly similar principal molecular 

structure’’ regardless of known or indeterminate differences. So in essence, S. 623 

places no limit on the types of physical and chemical differences that might be considered minor enough to permit a demonstration of comparability and an abbreviated application. 

Language From Orphan Biologics Regulations 

The language in S. 623 describing what differences still leave products ‘‘highly 

similar’’—and therefore eligible for demonstrations of comparability (or interchangeability) and for submission of an abbreviated application—appear identical to the 

language in the orphan drug regulations for biologics, regulations I helped write and 

implement. While, on the surface, that might appear to make the language a reasonable standard for follow-on biologics, in fact the objectives of the determinations 

of similarity in the Orphan Drug Act are very different from those for follow-on biologics. Whereas different but related products (for example, those with ‘‘minor amino 

acid differences’’) might have similar effects, in orphan regulations, we established 

a broad regulatory definition ensuring that orphan drug exclusivity would block the 

marketing of similar molecules even if there were full clinical studies supporting the 

safety and effectiveness of those molecules. But the fact that two related products 

with such differences may treat the same condition does not make them the same 

drug; nor does it provide any significant assurance of a similar safety and efficacy 

profile. So there is no basis for taking the definitions that FDA developed to preclude approval of products supported by complete data and using them to identify 

products that can be approved through an abbreviated application with partial data. 

3. NO FOLLOW-ON BIOLOGIC PRODUCT SHOULD BE CONSIDERED INTERCHANGEABLE

WITH ITS REFERENCE PRODUCT

Given the complexity of biologics, the high potential for process differences to result in product differences, the limited ability to detect differences between a followon and reference biologic, and the very real potential for these differences to be 

clinically meaningful, a determination even of comparability for a follow-on product 

is particularly challenging. The provisions in S. 623 calling for a determination of 

‘‘interchangeability’’—specifically, that the product ‘‘can be expected to produce the 

same clinical result as the reference product in any given patient’’—are very concerning from a scientific perspective. 

Ensuring comparability of a follow-on biologic to a reference biologic with an acceptable degree of assurance will be quite challenging, made much more so by the 

follow-on manufacturer’s limited access to information about, and lack of experience 

with, the innovator’s process as well as their lack of access to intermediate, in-process materials. Ensuring interchangeability is essentially impossible. 

No amount of non-clinical testing of a biologic product can ensure or predict it will 

have identical effects to another product. Although clinical testing can place limitaVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00026 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
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tions on the possible extent of differences, for most products, only extremely extensive comparison studies could rule out clinically significant differences. For example, 

if a reference biologic caused a serious or fatal effect in 1 patient in 1,000, and a 

new drug had twice the risk, it would take a study of about 50,000 patients to have 

a good chance of detecting this important difference. Thus, there is no realistic potential for a scientifically valid determination of interchangeability. 

With the risk of clinically important differences always at play, with the possibility that substituting products would increase the risk of clinically important antigenicity, and in the absence of scientific data to establish a follow-on and an innovator biologic product as identical, it would be dangerous to allow the follow-on biologic to be considered ‘‘interchangeable’’ with its reference product. 

The European Union rightly acknowledged in its own process of developing a 

pathway for follow-on biologics that follow-ons can be similar, but never identical 

to an innovator biologic. After very careful review of the data, the EU recognized 

the danger of applying ‘‘interchangeability’’ status to follow-ons, a misnomer that 

could lead physicians and patients to inappropriately assume sameness and substitute one for the other, with potentially serious adverse health consequences. Just 

2 weeks ago (Feb. 18), the French parliament, for example, adopted legislation to 

prevent follow-on biologics from being treated in the same way as traditional 

generics and banned the automatic substitution of one biologic medicine for another. 

A determination of interchangeability likely would encourage substitution of one 

product for another. The FDA itself expressed concerns about substitution of one 

biologic medicine for another in a statement last September: ‘‘Different large protein 

products, with similar molecular composition may behave differently in people and 

substitution of one for another may result in serious health outcomes, e.g., generation of a pathologic immune response’’ (http://www.fda.gov/cder/news/biosimilars 

.htm, September 2006). Even if products have a determination of comparability but 

not interchangeability, substitution could occur, potentially unbeknownst to the prescribing physician or patient and potentially with adverse health outcomes. Policy 

should attempt to limit that possibility as it addresses issues such as labeling and 

naming. 

Furthermore, if aspects of a follow-on biologics approach such as the designation 

of interchangeability led to substantial numbers of patients switching between 

therapies, it could severely impair the ability of pharmacovigilance systems to deal 

with emerging safety problems. When a new adverse event emerges or a known one 

increases in frequency, it may be impossible to attribute the adverse event to a specific product if patients experiencing the event have received multiple products. This 

is especially the case for some types of adverse events, such as those due to 

immunogenicity, that tend to arise in patients well after receiving the causative 

product. Should a particular follow-on biologic be associated with such a safety problem, the impact of being unable to determine which ‘‘interchangeable’’ biologic was 

responsible could be devastating. The ability to detect that a new follow-on biologic 

has a significantly higher risk would be highly impaired and the difference in risk 

could go unnoticed. When new risks are noticed, it could well be impossible to determine to which ‘‘interchangeable’’ biologic it was attributable, and appropriate use of 

the entire group of therapies might be severely impaired because of a safety problem 

with one. 

From the standpoints of science, clear communication, and public safety, interchangeability is not an appropriate designation for follow-on biologics. 

Unfortunately, not only is interchangeability for follow-on biologics included in 

S. 623, the statutory test for interchangeability is completely open-ended. As written, this statutory test could be used to determine that two drugs are interchangeable even if they do not contain the same active ingredient. This is entirely at odds 

with the concept of ‘‘therapeutic equivalence’’ that has been applied to small molecule drugs and which requires a finding of the same active ingredient, same dosage 

form and dose, and bioequivalence. If used as the basis for switching patients back 

and forth between biologics for chronic therapy, then this statutory test poses especially grave clinical implications as patients unwittingly switch between biologics 

whose safety and efficacy have not been shown to be the same. 

4. POST-MARKETING SAFETY SURVEILLANCE WILL ALWAYS BE REQUIRED, 

AND POST-MARKETING CLINICAL STUDIES MAY ALSO BE WARRANTED

All approved follow-on biologics will inevitably be associated with some risk that 

new safety problems will become apparent only in the post-marketing period because (1) not all differences between a follow-on and reference product will be detectable in pre-market testing, (2) one cannot predict with certainty which differences may have adverse impacts on safety and efficacy, and (3) some risks of any 

24 

pharmaceutical become apparent only after extensive use. To optimize patient safety 

and to control such risks, it is critically important that FDA not be limited in its 

ability to request post-marketing clinical studies when appropriate. Follow-on manufacturers should also be required to monitor a product for safety problems through 

a robust post-marketing safety surveillance program. 

Post-marketing clinical studies, post-marketing safety surveillance programs, and 

drug safety in general have been topics of major discussion on this committee and 

in these halls. Just last month, Chairman Kennedy and Ranking Member Enzi reintroduced legislation that has as core principles post-approval clinical trials ‘‘to assess signals of serious adverse events,’’ post-approval epidemiological studies to help 

‘‘screen for serious adverse events in expanded populations,’’ and post-marketing 

safety surveillance programs ‘‘to assess known serious risks and to identify unexpected serious risks.’’ Many of you have endorsed this safety bill and applauded 

these tenets of it. 

After all of the support and attention this committee has given to the issue of 

drug safety, it would be a major setback if this committee were to pass any legislation which does not put forth specific provisions enabling regulatory requirements 

for post-marketing safety surveillance programs and clinical studies of follow-on biologics, or if it limits the ability of expert reviewers to negotiate for post-marketing 

clinical studies that could protect public safety. 

For instance, S. 623 is silent on the matter of post-marketing safety surveillance, 

a tool essential to ensuring the safety of all biologics, including follow-on biologics 

or any pharmaceutical. This should concern all of us. Also disturbing are the specific 

limits the bill would place on the FDA’s ability to require post-market clinical studies from a follow-on manufacturer. Follow-on biologics will raise safety concerns— 

such as differences in immunogenicity profile or emergence of unexpected toxicities—that will require studies beyond the scope that pre-marketing studies can reasonably address. We should not prevent the FDA from requiring whatever studies 

are deemed necessary based on science. 

Restricting the FDA in its efforts to carry out its explicit mission of protecting the 

public health in the post-marketing period would be particularly difficult to explain 

to the American public given that such protections are already received by the European public. The EU recognized the importance of requiring appropriate safety 

measures as it developed guidelines for approval of follow-on biologic products. The 

EU further acknowledged in its guidelines the importance of post-marketing testing 

for the specific danger of immunogenicity. 

Any legislation that fails to articulate the need for post-marketing studies, and 

instead places limits on the FDA’s ability to seek post-marketing commitments, 

could lead conscientious regulators concerned about patient safety to require far 

more extensive pre-marketing testing, thereby significantly undermining the ability 

of a follow-on approval pathway to address access. Safety would nonetheless suffer 

anyway. Some safety concerns can be identified only after broad, large-scale or prolonged exposure such as can best be studied in the post-marketing period. 

5. THE FDA SHOULD NOT BE SUBJECT TO UNDUE CONSTRAINTS IN ITS ABILITY TO

ENSURE SAFETY AND EFFICACY OF FOLLOW-ON BIOLOGICS

Finally, legislation should not limit the FDA’s flexibility and discretion in making 

sound scientific judgments to ensure the safety and efficacy of follow-on biologics. 

I have several concerns about S. 623 in this regard. 

For instance, S. 623 provides that, when asked, the FDA should meet with followon sponsors to ‘‘reach agreement regarding the parameters of design and size of the 

studies’’ necessary for approval of the application. I applaud this provision but have 

pressing reservations regarding the binding nature of those agreements in the follow-on context. It is important that agreements not constrain FDA from requiring 

additional data beyond those pre-specified in advance of the application process. It 

is to be expected that it will be quite common for the FDA to identify needs for additional testing after initial advice is given for two reasons. First, there are many 

tests within the general categories of physical, chemical, biological, and clinical testing. To some extent, these tests need to be performed sequentially as the results 

of earlier tests often identify needs for further testing. The FDA cannot and should 

not be expected to identify all testing needs up front before early test results are 

available. 

Second, given the lack of FDA experience in reviewing follow-on biologics, reviewers would have no basis for anticipating new data needs that may arise. For these 

two reasons, it likely will be common that additional testing requirements, important to ensure comparability and thus safety and efficacy, will be identified after 

initial guidance. While the legislation provides a process whereby the FDA can reVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00028 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
25 

quest additional testing where a substantial scientific issue essential to approval 

has been identified and agreed to by the head of the reviewing division, the need 

to use such a process runs the significant risk of suppressing appropriate testing 

requests, thus diminishing assurance that the follow-on biologic is comparable. 

The provisions under discussion are similar to current provisions regarding binding agreements on clinical trials and on bioavailability and bioequivalence testing 

(also types of clinical testing) of drugs but differ in a very important respect given 

the context. Currently existing provisions apply only to clinical testing, and, when 

the FDA gives guidance on this testing, it already has before it both the results of 

chemical, physical, and biological testing and it has vast experience in determining 

appropriate clinical studies. In contrast, the proposed legislation here allows companies to seek binding guidance on all types of testing (e.g., all ‘‘studies of a biological 

product’’ under these provisions) before any testing results are available, and in an 

area in which there is no prior regulatory experience. 

The FDA should indeed provide industry with extensive guidance as to what testing will be expected in an application and consideration should be given to establishing a transparent process for this to occur. But as we enter this new field with 

new safety risks, the FDA should be unhampered in its ability to request and receive additional data from a manufacturer as the need becomes apparent. To do otherwise could jeopardize safety. 

Another worrisome constraint on the FDA comes in the mandate in S. 623 to the 

FDA to complete its final review and take final action on a follow-on biologic product 

application within just 8 months of the manufacturer’s submission of the application. This would be an unprecedented move that places inappropriately high priority 

on the review of follow-on biologics. Most new drugs and biologics are reviewed with 

a 10-month deadline to complete review, potentially much longer to reach final action. Even priority drugs and biologics have a 6-month review, and potentially take 

much longer to final action. The timeline of 8 months from submission to final action is a more accelerated timeline than that for most new drugs and biologics and, 

in some senses, more than for those given priority drugs. In other words, this legislation gives review of a follow-on biologic priority higher than that for most new 

drugs and comparable to that for a new and promising AIDS or cancer therapy. This 

kind of provision inappropriately limits FDA’s ability to allocate its severely limited 

resources to address the greatest public health priorities. It also runs the risk of 

giving FDA inadequate time to do its job. 

There are other aspects of this legislation with the potential to inhibit appropriate 

regulatory activity. For example, the proposed legislation specifies that studies to 

establish comparability should be designed ‘‘to avoid duplicative and unethical clinical testing.’’ The meaning of ‘‘duplicative’’ is unclear; but whereas replication of results is a basic scientific approach to ensure validity, admonition to avoid duplicative testing, depending on how the term is interpreted, could lead to inadequate 

testing. Regarding unethical testing, the language is unnecessary and could, depending on how it is interpreted, discourage appropriate testing requirements. 

THE EU APPROACH TO BIOSIMILARS

We are fortunate that the EU has already made substantial progress in developing and implementing a policy based in good science and public health and consistent with their unique regulatory and healthcare framework. We should be able 

to leverage that work to have a frank, transparent and scientific debate here in the 

United States, and thereby develop a model which will be compatible with our own 

regulatory and healthcare environment. 

The key features of the EU process stem from the recognition of the unique characteristics of biotechnology derived proteins. Several years ago, EU legislation clearly distinguished a ‘‘biosimilar’’ (the term they use for follow-on biologics) from a ‘‘generic’’ because of the manufacturing principles for biologics that are discussed 

above. The EU legislation did not attempt to define the scientific standards for approval of biosimilars. The EMEA, the science-based body responsible for approving 

the marketing of drugs in the EU, was trusted with that task. Furthermore, the EU 

legislation did not seek to constrain the ability of the EMEA to require data to ensure the safety and efficacy of biologics. The EU legislation clearly distinguished a 

‘‘biosimilar’’ from a ‘‘generic’’ due to the many scientific concerns discussed above; 

the EU also recognized the dangers of interchangeability. 

The EMEA provided a broad regulatory framework with guidances for approval 

of these products. They pursued a science-based, transparent and open process to 

establish concept papers and draft guidances, starting first with basic principles for 

all biosimilars. This was followed by more specific guidances with testing requirements for product classes. This transparent process included public scientific workVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00029 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
26 

shops in which all parties were invited to offer input. The EU testing requirements 

do allow for abbreviations in testing where science and safety permit. But clinical 

testing, immunogenicity testing, and post-marketing safety surveillance are critical 

parts of those requirements. In fact, those requirements were deemed essential to 

minimize the risk to patients. The EU pathway strives to achieve follow-on biologics 

that are truly highly similar to a reference product while acknowledging that important clinical differences may still exist upon market approval, making post-marketing clinical studies and safety surveillance important. 

CONCLUSION

In conclusion, I sincerely hope that the experiences and principles I have discussed have informed this debate. It is my hope that as you examine S. 623 and any 

other proposed legislative pathways for follow-on biologics, you will seek out and 

pursue scientifically driven public debate to ensure that public policy is well-founded 

in science and supports the development of follow-on biologics that are safe and effective. We must ensure that we pay the appropriate attention to the principles of 

patient safety that are being discussed in this country and in these halls right now. 

It is my hope and that of Johnson & Johnson that a scientifically based public 

process leveraging known scientific considerations will provide a framework and 

pathway for follow-on biologics in the United States—a pathway that has an overriding concern for patient safety and well-being. It is also critical that such a framework appropriately provide incentives for innovation so that the promise of new and 

innovative biologic therapies can continue to be realized for patients for generations 

to come. 

I thank you again for the opportunity to submit testimony for this hearing, and 

I look forward to answering any questions you may have. 

The CHAIRMAN. Thank you very much. We might call on Dr. 

Rossignol, if you’d be good enough. We appreciate very much your 

taking the time and working with us and this presentation. We 

look forward to hearing from you. 

STATEMENT OF NICOLAS ROSSIGNOL, ADMINISTRATOR, EUROPEAN COMMISSION PHARMACEUTICALS UNIT, BRUSSELS, 

BELGIUM 

Mr. ROSSIGNOL. Senator Kennedy, can you hear me now? 

The CHAIRMAN. Yes, I can. Yes. You’re on. 

Mr. ROSSIGNOL. Okay. Chairman Kennedy, Ranking Member 

Enzi and all of the members of the committee, thank you for giving 

me the opportunity to testify today. 

My name is Nicolas Rossignol and I am in charge within the European Commission of the implementation of the framework in Europe on follow-on biologics, which we call in Europe, biosimilars. 

If you allow me, Mr. Chairman and without playing with words, 

I will use the terms follow-on biologic and biosimilars as if they are 

interchangeable. 

It is indeed an honor to appear before you today to share the EU 

experience in an area which holds great hopes for patients but at 

the same time, raises new challenges. I will focus today on the key 

controversial questions around follow-on biologics, which the EU 

has faced already, which the United States is facing now, hence we 

are sharing knowledge we’ve gained that is most useful. 

I will not repeat my written testimony but solely focus on three 

key issues. First is patient safety or to put it bluntly, is it true that 

follow-on biologics are less safe? 

The second question is the question of sameness. Is it true that 

biologics are so complex that you in any way cannot make copies? 

And thirdly, interchangeability. Are biosimilars interchangeable? 

So let’s address first safety. The essential goal of our legislation 

is to safeguard public health, to ensure that all medicines, whatVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00030 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
27 

ever their legal status, meet the same EU high standards of quality, safety and efficacy. Our framework on biosimilars is no exception. Its primary objective is not to facilitate introduction of new 

products on the market. It is not to lower standards. The primary 

objective is to apply equal standards to ensure that biosimilars are 

equally safe and efficacious, as any other biologics. 

Indeed, it is the European Commission which approves all new 

biotech medicines and we do not approve biosimilars if they do not 

comply with our standards. Actually, one biosimilar application 

was already rejected because of non-compliance. 

But conversely, those follow-on biologics which do get an authorization, how by definition products for which European regulators 

are confident to say that they are as safe, as efficacious, as their 

counterparts. 

The second point is the sameness, i.e., can you make copies of 

biologics? If it’s clear that these biologics were no different from 

chemical drugs, then we would not be using a specific framework 

on biosimilars in the EU. The current scientific consensus in Europe is that biosimilars are not generics and not biogenetics and 

cannot be approved as generics. Because these products are complex, we need an abbreviated yet robust set of pre-clinical and clinical data to demonstrate that the biosimilar product is comparable 

to its reference. 

However, it is important, in my opinion, not to over-emphasize 

the molecular complexity of biosimilars. Yes, these are complex 

products. Yes, they are usually difficult to characterize but there 

is a range of complexity. We cannot treat them the same way we 

treat simple molecules like insulin, for example and far more complex biologics like vaccines. There is no one size fits all approach 

in this field. 

And also and this is the report of my team—molecular complexity is a scientific notion. It does not depend on the leader status of the product. In other words and that may be a myth—we 

have faith in the past in Europe, biosimilar products, the followon biologics are not new products in scientific terms. Biosimilar is 

just a new legal pathway to authorize their use. 

So in other words, biosimilars are just as complex in molecular 

terms, as their counterparts. They are just as difficult to fully characterize—not more, not less. 

The third and last point is interchangeability. Because 

biosimilars are not generics, medical practices which are standard 

for generics are not necessarily repeatable here. Like any other biology, biosimilars can carry safety risks which might not be fully 

detected at the approval stage. I have to say that the framework 

on biosimilars in Europe does not lead to a scientific conclusion on 

interchangeability. It doesn’t say if a biosimilar product is interchangeable or if it is not interchangeable. Simply because of the 

construction of the European Union, interchangeability is not a 

point that our unitization currently addresses. It is addressed to 

member state schools, not European communities. 

However, I want to stress that interchangeability may already 

occur today in Europe between a number of these products, one innovative product and another one, for example, pharmaceuticals 

that care professionals may, in some countries in Europe, subVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00031 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
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1Section 4, Part II, Annex I to Directive 2001/83/EC of the European Parliament and of the 

Council on the Community code relating to medicinal products for human use, as amended by 

Commission Directive 2003/63/EC of 25 June 2003, Official Journal of the European Union L 

159, 27/6/2003. P. 0046–0094. 

stitute one for another one, for example, because they have the 

same international long comparable name, like insulin again. 

Interchangeability is therefore a different notion from comparability that needs to be handled with great caution for all biologics. 

Mr. Chairman, I would like to conclude by summarizing what the 

EU experience tells us in this field. Our experience tells us that a 

framework on follow-on biologics is not only feasible but is also desirable, to make sure that products on the market are equally safe 

and efficacious. It also tells us that this framework should allow 

applications based on a reduced, abbreviated data package to be 

submitted. That for the very benefit of biosimilar manufacturers, 

the framework should also be sufficiently robust, science-based and 

stringent to avoid lowering standards of quality, safety and efficacy. 

Our experience tells us that what is at stake here, really, is in 

fact, the long-time trust and confidence of patients of care professionals in the regulatory system, in follow-on biologics in particular 

but more worldly by your technology. And we are, of course, prepared to collaborate further with the United States in this emerging, challenging but promising area. Thank you again for this opportunity to testify and I look forward to the questions. 

[The prepared statement of Mr. Rossignol follows:] 

PREPARED STATEMENT OF NICOLAS ROSSIGNOL

Mr. Chairman, honorable members of the HELP committee, thank you for giving 

me the opportunity to testify today. My name is Nicolas Rossignol. Since 2003 I 

have been working as an Administrator within the European Commission, in the 

division in charge of the European Community pharmaceutical legislation. The European Commission has three main roles in the area of pharmaceuticals: it proposes 

new legislation; it implements existing legislation; and it authorises and monitors 

the placing on the EU market of certain types of medicines, including all biotech 

products produced by recombinant DNA technology (e.g., insulin, growth hormones, 

etc.). The granting of this ‘‘marketing authorisation’’ is done on the basis of a scientific evaluation of the product, which is carried out by the European Medicines 

Agency (EMEA). 

Since 2003 I have been responsible within the European Commission for the implementation of the EU Pharmaceutical legislation in the specific field of ‘‘follow-on 

biologics,’’ which we call in Europe ‘‘similar biological medicinal products,’’ or 

‘‘biosimilars.’’ I have been involved in the legal, regulatory and scientific aspects of 

this topic. It is arguably one of the most complex issues that the European Community has faced in the area of pharmaceuticals in the last 5 years. 

My testimony today will focus on how the European Union reviews and approves 

‘‘follow-on biologics’’ or biosimilar products. I will address the following issues: 

• How and on which principles is the EU legal framework for biosimilars established? 

• What regulatory and scientific work has been achieved in the EU since the establishment of this framework? 

• What has been the EU practical experience so far with the regulatory environment on biosimilars, and what are the challenges? 

HOW AND ON WHICH PRINCIPLES IS THE EU LEGAL FRAMEWORK FOR BIOSIMILARS

ESTABLISHED?

The notion of ‘‘biosimilar product’’ or ‘‘biosimilarity’’ has been introduced in EU 

legislation in June 2003,1 and further elaborated with the adoption of the EU ‘‘PharVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00032 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
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2Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 

amending Directive 2001/83/EC on the Community code relating to medicinal products for 

human use, Official Journal of the European Union L 136, 30/4/2004. P. 0034–0057. 3 Recital (15) of Directive 2004/27/EC, see above. 

maceutical Review’’ in April 2004.2 This notion allows a manufacturer to submit an 

application and get an authorisation for a product claimed to be similar to another 

biological medicine—the ‘‘reference product.’’ The rationale for creating this new licensing route is that biologics similar to a reference product ‘‘do not usually meet 

all the conditions to be considered as a generic.’’ 3 Although the EU ‘‘generic’’ route 

remains legally open to biologics (the word ‘‘usually’’ implies that in some cases, generic provisions might be sufficient), this is more a theoretical possibility than a 

practical way forward given the current state of science. It is clear for EU regulators 

today that the complexity of biological molecules, the fact that they are produced 

in living organisms and their sensitivity to changes in the manufacturing process 

make it virtually impossible for applicants to produce an identical copy of a reference biological product. In other words, the licensing route for biosimilars is based 

on the principles that: 

• biologics are not chemical drugs; and 

• the generic approach is, in the quasi-totality of cases today, very unlikely to be 

applicable to biologics: biosimilars are not ‘‘biogenerics.’’ 

The regulatory framework for biosimilars is therefore the only one licensing route 

to be applied to biologics claimed to be similar to a reference product. Three main 

eligibility criteria can be spelled out: 

• First, the product must, obviously, be a biological medicine. In legal terms, this 

means that any type of biologic could be licensed as a biosimilar, including complex 

biologics such as blood-derived products, vaccines, gene/cell therapy products, etc. 

However, the approach is for scientific reasons more likely to be successful today 

for products which can be thoroughly characterised, such as proteins produced by 

recombinant DNA technology (e.g., insulin, growth hormones). Conversely, it is more 

difficult to apply to other types of biologics which by their nature are more complex 

(e.g., vaccines), or to those for which little regulatory experience has been gained 

so far (e.g., gene therapy). 

• Second, the reference product must have been authorised within the European 

Community. Importantly, it is not legally required that the reference product is still 

authorised at the time the biosimilar application is filed. 

• Third, the application has to be submitted after the expiry of data exclusivity. 

In the EU, innovative products benefit from a data exclusivity period, which currently varies from 6 to 10 years for old products, and which has been recently 

harmonised to the so-called ‘‘8+2+1’’ period. This means that an authorised product 

will get a data exclusivity period of 8 years, after, and only after which a company 

will be allowed to submit a biosimilar application. However, the actual placing on 

the market of the biosimilar will not be permitted until 10 years (i.e., 8+2) have 

elapsed from the initial authorisation of the reference product. In addition, the period will be extended to a maximum of 11 years (i.e., 8+2+1) if, during the first 8 

years of data exclusivity, the holder of the reference product obtains an 

authorisation for new therapeutic indication(s) which bring(s) significant clinical 

benefit in comparison with existing therapies. This balanced approach has been favoured in order to reward companies who develop innovative products, without impairing the development of the generics and biosimilar industry. 

As regards the kind of data required to file a biosimilar application, the EU legislation is based on the principle that a ‘‘one-size-fits-all’’ approach is unworkable in 

this area. The type and amount of pre-clinical and clinical data are not predefined 

in legislation but are determined on a case-by-case basis, on the basis of the relevant scientific guidelines. This approach reflects the wide spectrum of molecular 

complexity among the various products concerned, ranging from relatively simple 

molecules such as insulin to far more complex ones. Thus, the requirements to demonstrate safety and efficacy of a biosimilar are essentially product class-specific. In 

theory, a biosimilar application could therefore range from being almost ‘‘as 

abridged’’ as a generic application (with very limited non-clinical/clinical studies), to 

being nearly as complete as a full, stand-alone application. The task to determine 

this range as precisely as possible, concretely and on a scientific basis, i.e., by taking 

in consideration the characteristics of the concerned products, has been put in the 

hands of the European Medicines Agency (EMEA), to which the EU legislators have 

given a mandate to issue scientific guidance. 

30 

4http://www.emea.europa.eu; in addition, a guideline on pre-clinical and clinical issues related to a biological substance of extractive origin (Low Molecular Weight Heparins) is also in 

preparation. 5The register of medicinal products for human use authorised by the Commission is available 

at http://ec.europa.eu/enterprise/pharmaceuticals/register/alfregister.htm. 

6http://www.emea.europa.eu/pdfs/human/opinion/19089606en.pdf. 

WHAT REGULATORY AND SCIENTIFIC WORK HAS BEEN ACHIEVED IN THE EU SINCE THE

ESTABLISHMENT OF THIS FRAMEWORK?

The first EMEA guideline on biosimilars was released for consultation in November 2004. This was a general, ‘‘overarching’’ guideline designed to introduce the concept of biosimilarity in scientific terms. Since then, a number of guidelines have 

been issued,4 most notably on: 

• general quality aspects; • general pre-clinical and clinical aspects; • product-class-specific pre-clinical and clinical aspects on insulins, growth hormones, erythropoietins and granulocyte-colony stimulating factors; • immunogenicity of biotechnology-derived therapeutic proteins. 

All these guidelines relate to molecules which can be thoroughly characterised 

with state-of-the-art analytical methods and for which extensive regulatory experience is available. 

From a legal perspective, it is not necessary that EMEA issues guidance in one 

area to enable manufacturers to submit applications. Besides, EMEA guidelines are 

usually not legally binding—alternative approaches which depart from available 

guidelines, if properly justified by the manufacturer, may also be accepted. In the 

case of biosimilars, however, the legislation makes explicit reference to compliance 

with the detailed guidelines to be issued by the EMEA. 

Without going into the scientific details of these guidelines, one important underlying principle is worth being mentioned: to substantiate its claim of biosimilarity, 

a manufacturer must conduct a direct and extensive comparability exercise between 

its product and the reference product, in order to demonstrate that the two products 

have a similar profile in terms of quality, safety and efficacy. Only one reference 

product is allowed throughout this exercise. Approaches using indirect comparisons 

(i.e., through other products) are unlikely to be successful from a scientific viewpoint. 

The EMEA guidelines make it clear that it is not expected that the quality attributes (e.g., the molecular structure) in the biosimilar and the reference product 

should be identical. Actually, minor structural differences are reasonably expected 

given the very nature of biologics and the inherent variability in the way they are 

produced. However, those differences should in any event be justified on scientific 

grounds and would be considered on a case-by-case basis, in relation to their potential impact on safety and efficacy. The underlying scientific assumption is that differences between the biosimilar and the reference product are, a priori, regarded as 

having a potential impact on the safety/efficacy profile of the product. They will 

therefore influence the type and amount of data required by the regulators in order 

to make a satisfactory judgment of compliance with EU standards. For example, 

changes in glycosylation patterns are well known for having potential effects on the 

safety/efficacy profile of glycosylated proteins. 

In case the reference product has more than one therapeutic indication, the efficacy and safety of the medicinal product claimed to be similar has to be justified 

or, if necessary, demonstrated separately for each of the claimed indications. In certain cases it may be possible to extrapolate therapeutic similarity shown in one indication to other indications of the reference medicinal product, but this is not automatic (it may also be that the biosimilar applicant does not claim all the therapeutic 

indications of the reference product). Justification will depend on a number of factors, such as clinical experience, available literature data, etc. In essence, regulators’ 

judgment to approve therapeutic extrapolation is again product-specific. 

WHAT HAS BEEN THE EU PRACTICAL EXPERIENCE SO FAR WITH THE REGULATORY

ENVIRONMENT ON BIOSIMILARS, AND WHAT ARE THE CHALLENGES?

The EU framework on biosimilars is relatively new. Two products have been 

authorised so far under this framework5: the first is the growth hormone 

Omnitrope, which was authorised by the European Commission in April 2006. A 

second growth hormone, Valtropin, was also authorised in April 2006. One product 

(Alpheon, an interferon) was given a negative scientific opinion by the EMEA in 

June 2006.6 One of the main reasons for this is that the EMEA had major concerns 

regarding the comparability of Alpheon and its reference product (Roferon-A), beVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00034 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
31 

cause of differences identified between the two medicines, such as impurities. The 

EMEA was hence of the opinion that Alpheon could not be considered as a biosimilar. 

A number of additional applications are already in the pipeline at the EMEA. 

They mainly concern erythropoietins (EPOs), interferons, insulins and granulocytecolony stimulating factors (G-CSFs). An early dialogue between the manufacturers, 

the EMEA and the European Commission has proven critical to sort out the various 

regulatory and scientific issues that applicants may face. 

Open debate with all stakeholders has proven extremely useful to gather input, 

compare experience and build consensus, in particular when drafting guidance documents. As science evolves, our ability to better characterize biologics should increase, as well as our regulatory experience with these products. One can therefore 

expect, in the long term, that the ‘‘range of possibilities’’ (types of biologics for which 

the biosimilar approach is scientifically acceptable, amount of clinical data required 

to demonstrate biosimilarity, etc.) will become more and more precise. 

The ‘‘legal construction’’ of the European Community assigns certain competences 

to the European Commission, while some others are for the Member States. The 

issue of pricing and reimbursement, in particular, is basically of national competence in Europe. Therefore the EU harmonised regulatory framework on 

biosimilars does not address this issue. Given the limited number of products 

authorised so far and the fact that this framework is quite new, it is probably too 

premature to assess the actual impact of the introduction of biosimilar products on 

the price of biologics in Europe. However, this is a parameter the European Commission is likely to monitor with particular attention in the coming years. 

Some new issues have fueled the EU debate on biosimilars in the recent past. One 

of them relates to interchangeability between biosimilars and innovative products. 

It is important to bear in mind that the EU regulatory framework on biosimilars 

is designed to achieve one objective: to assess the quality, safety and efficacy of 

biosimilars so that these products comply with the same EU health standards as 

any other medicine. This framework, however, is not legally designed to evaluate 

whether a biosimilar is actually interchangeable in medical practice with the reference product, i.e., whether one product can be safely substituted for the other and 

have the same biologic response without triggering adverse reactions. Interchangeability is also beyond the scope of the existing EMEA guidelines on biosimilars. 

Finally, one last point in discussion today relates to the naming of biosimilars. 

Medicines usually have an International Non-proprietary Name (INN) (e.g., ‘‘insulin’’) which is defined by the World Health Organisation. Generics usually have the 

same INN as the reference product, and healthcare professionals often prescribe by 

INN. The biosimilar industry has been advocating that a biosimilar product, once 

proved biosimilar, should be entitled to have the same INN as its reference product. 

On the other hand, the innovative industry has claimed that a distinct INN should 

be assigned to biosimilars, in particular for the sake of traceability and 

pharmacovigilance. Our understanding within the European Commission and 

EMEA is that the rules of the INN naming system should remain international, 

science-based rules. The same scientific rules should apply to all products, be they 

innovative products or biosimilars. The INN nomenclature should not be used as a 

way to distinguish between biosimilars and other types of products. 

CONCLUSION

Overall, I believe it is fair to say that the flexibility of the EU regulatory framework on biosimilars has been positively welcomed by both sides of the pharmaceutical industry. The fact that the legal basis is relatively concise and focuses on 

the key legislative elements of this framework, while technical aspects are addressed through guidelines, has enabled us to undertake a cautious and balanced, 

‘‘not too stringent, not too loose’’ approach to allow biosimilar manufacturers to get 

streamlined access to market, without compromising public health. The defining 

principles which have guided us so far in regulating biosimilars will remain crucial 

to address the challenges still ahead of us. Our primary objective should remain to 

protect public health: biosimilars should meet the same standards of quality, safety 

and efficacy as any other biological product in the EU. Our regulatory framework 

should remain based on science: it should fully take account of the fact that biologics 

are, in the vast majority of cases, not simple molecules. And finally, our experience 

over the past few years demonstrates, I believe, that transparent and open dialogue 

with all sides of the industry is key to put in place a robust and adapted regulatory 

framework in this emerging field. 

Thank you. 

32 

The CHAIRMAN. Good. Thank you very much, Doctor. We appreciate your staying with us here for the question period. Thank you. 

Dr. Hussain, we thank you very much for your presence and look 

forward to hearing from you. 

STATEMENT OF AJAZ S. HUSSAIN, PH.D., VICE PRESIDENT AND 

GLOBAL HEAD OF BIOPHARMACEUTICAL DEVELOPMENT, 

NOVARTIS, PRINCETON, NEW JERSEY 

Mr. HUSSAIN. Good morning. I am Dr. Ajaz Hussain, Vice President and Global Head for Biopharmaceutical Development at 

Sandoz. I want to thank Chairman Kennedy, Senator Enzi and 

other distinguished members of the Senate HELP Committee for 

giving me this opportunity to represent Novartis Group of Companies. 

As a former research scientist, as a regulator at FDA, which 

dealt with interchangeability in these issues on a daily basis for 

about 10 years and as an American, who has at various points in 

my life also been a patient, I believe in the Gold Standards of the 

FDA approval process and want to see only safe and effective medicines made available to patients. I believe this is achievable for follow-on biologics as it is for all the drugs and biologics. 

Novartis supports—strongly supports a balanced position which 

advocates that the same standards of high quality and science be 

applied to all medicines and that there be respectful, legitimate intellectual property. We recognize a role that generic drugs play 

today and follow-on biologics will play tomorrow in our healthcare 

system. 

We believe the following are critical in any follow-on biologics regime. One, follow-on products can be made or designed to be used 

interchangeably with the original product. That’s what is meant by 

interchangeability. Science shows that the same product can be 

made in different ways. That is what we mean when we say a 

product is not the process and this is what we mean by comparable 

products. 

Three, every clinical step necessary to bring in new biologic market is not needed to show that a follow-on is as safe and as effective. 

Four, here is the good news, Senators. You don’t need to choose 

what specific steps are required. FDA already has the expertise to 

do this as shown by their approval of innovative products. What 

you need to do is to empower them to act and that was one of the 

frustrations I had with the policy development team, is to get stuck 

with not being empowered to do this. 

In the debate so far, you have been hearing essentially two opposite ends of the spectrum on the issue of follow-on biologics. Some 

say follow-on biologics are impossible and inherently dangerous 

and you can see the shift in bad direction already occurring but 

that position has moved to yes, it’s possible now. 

Others have argued that you should simply apply the generic 

drugs model. Novartis believes that there is a viable and responsible solution compatible with the current state of science, a middle 

ground. We believe it is time for an explicit regulatory pathway. 

The science is here and has been for at least a decade. With all due 

respect to my colleagues who don’t share this perspective, the eviVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00036 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
33 

dence that the science is here is the existence of the reference products themselves. Clearly, these products can and are being made 

and indeed, we have marketable versions of many biologics already 

on the market, independently developed, independently approved 

but also successfully in use for the same indications. 

Comparability is not a new concept, especially for the biopharmaceutical industry. Our ability to make and characterize biosimilar 

products and other complex biologics has progressed rapidly in the 

last few decades. Comparability itself is not new. It has enabled 

manufacturing changes without complete clinical trials for over a 

decade. It is a signs-based regulatory success story. It also proves 

that product is not the process. 

Some suggest that products have to be the same. However, batch 

to batch variation is inevitable for all biologics and as long as manufacturers ensure that subsequent batches stay within the same 

goal post of acceptable variation when the product is made available to patients. 

Comparability principles can likewise be enforced on follow-on 

biologics and unintended consequence of protectionism disguised as 

sameness is that it raises the hurdles for innovators and makes 

products for unmet medical needs increasingly unavailable to patients. 

Interchangeability is an important public health goal and a natural next step. All that is needed is a small step, a natural progression. Using public prior knowledge, a follow-on sponsor submits 

data comparing their candidate to an approved product. FDA already uses comparability data for manufacturing changes and 

there, interchangeability is presumed. 

The small step is allowing it for follow-on products by a different 

sponsor. Everything else follows. No access to innovative data is required. 

In conclusion, Novartis applauds the leadership of the Senators 

of this committee on this issue. We support a thoughtful, balanced 

approach based on established signs of comparability that makes 

safe and effective follow-on biologics available. Ultimately what 

matters is a safe and successful outcome for the patient. Thank 

you. 

[The prepared statement of Mr. Hussain follows:] 

PREPARED STATEMENT OF AJAZ S. HUSSAIN, PH.D. 

Good morning, I am Dr. Ajaz S. Hussain, Vice President & Global Head of Biopharmaceutical Development at Sandoz. I want to thank Chairman Kennedy, Senator Enzi and the other distinguished members of the Senate HELP Committee for 

giving me the opportunity to represent the Novartis Group of companies (‘‘Novartis’’) 

at this hearing. As a former research scientist, as a regulator with 10 years of experience at the FDA—where I was Deputy Director of the Office of Pharmaceutical 

Sciences until October 2005—and as an American who has at various points in my 

life also been a patient, I believe in the ‘‘Gold Standard’’ of the FDA approval process and want to see only safe and effective medicines made available to patients. 

I believe that this is as achievable for follow-on biologics as it is for all other drugs, 

generic and innovator, including biologics. 

Novartis is a world leader in the research and development of products to protect 

and improve health and well-being both by developing innovator drugs and biologics, and also by making generics available once patents have expired. Novartis 

is unique among pharmaceutical companies because it has made large investments 

in both branded and generic drugs. Given this, our position on follow-on biologics 

is not based on the commercial interests of one particular product. Instead, Novartis 

strongly supports a balanced position, which advocates that the same standard of 

34 

1 Note that the Novartis Corporate Headquarters are in New York, and Novartis has facilities 

in Arkansas, California, Colorado, Georgia, Massachusetts, Michigan, Nebraska, New Jersey, 

New York, North Carolina, and Wisconsin with total U.S. employees numbering 29,000. 

high quality and science be applied to all medicines, and that there be respect for 

legitimate intellectual property, while recognizing the role that both generic drugs 

and follow-on biologics can play in the health care system. Novartis’ success as a 

global leader of the innovator biopharmaceutical industry is demonstrated by the 

approval and launch of 15 new molecular entities in the United States since 2000— 

more than any other company. Novartis’ global research base, the Novartis Institutes for Biomedical Research, is located in Boston, Massachusetts where 1,300 researchers work towards developing the next generation of therapies. We also are relocating our Novartis Vaccines and Diagnostics Division Global Leadership to Commonwealth of Massachusetts in the third quarter of this year, and will be bringing 

together hundreds of additional researchers to develop the next generation of vaccines.1 We are committed to a future of innovation and new medicines, but we also 

believe in free markets and competition, and we are not afraid of them. 

In the debate so far, you have been hearing essentially two opposite ends of the 

spectrum on the issue of follow-on biologics. At one end of the spectrum, some have 

argued that follow-on biologics are impossible and inherently dangerous, while others suggest that this is just a re-run of the 1984 debate when generic drugs were 

said to be impossible too and that everything we need to develop such products can 

already be done today. And the former, those adverse to follow-on biologics, do not 

accept that interchangeable products can ever be produced by other than the original manufacturer. In such a polarized context, Novartis appreciates this opportunity 

to share an alternative perspective; one that we believe encompasses a viable and 

responsible solution compatible with the current state of the science. 

In considering this public health issue, we start from the premise that follow-on 

biologics are essential to the future economics of health care both in order to stimulate innovation, and, as important, to ensure that patients have access to the medicines they need at affordable prices. That a fair solution can enable both the innovator industry and the generic industry to prosper such that patients can benefit 

across the board, is a concept too often lost in this debate as both extremes try to 

pursue their respective ‘‘wish lists.’’ For its part, Novartis believes that a balanced 

solution is possible, one that will provide greater access to safe and effective medicines through the availability of competitively-priced biologics when patents expire. 

Toward this end, Novartis believes it is time for an explicit regulatory pathway that 

encourages the development and approval of follow-on biologics, including interchangeable products. 

We define follow-on biologics broadly to include comparable versions of alreadyapproved biologics and also improved versions of current therapies that depend on 

the same mechanism of action are used in the same indications as the originator 

product, and are developed based upon an extensive and sound set of data generated 

by the subsequent sponsor, which includes stand-alone product and process development and the demonstration of comparability with the reference product on all relevant levels, that is, chemical, pre-clinical, and clinical (including immunological) 

and appropriately qualifying differences. 

THE SUCCESS OF THE BIOPHARMACEUTICAL INDUSTRY DESERVES COMPARABLE

REGULATORY PROGRESS

The biopharmaceutical industry has made phenomenal progress since the first 

biotechnology-based medicine was licensed in the United States in 1982. Technologies to make and characterize protein products and other complex biologics have 

progressed rapidly in the last two decades, and the use of comparability to facilitate 

manufacturing changes has become established by innovator companies and regulators around the world since FDA led and then first formalized the concept in the 

United States in 1996 with the Comparability Guidance. Comparability allows for 

flexibility in the development of products that is essential to their optimal manufacture and iterative improvement. It is a science-based regulatory success story, with 

very few exceptions. 

Significant and continual advancements in scientific disciplines such as analytical 

characterization, product and process design, process control, and clinical assessment based on underlying mechanisms of action provide a sound scientific basis to 

utilize the fundamental principles and procedures of comparability evaluation for 

follow-on biologics. We are confident that this science-based approach will enable 

the industry to progress to the greater availability of affordable biologics to which 

we all aspire. 

35 

In supporting a new regulatory pathway based on comparability such as that described in the ‘‘Access to Life-Saving Medicines Act,’’ Novartis is merely recognizing 

the next logical step in the evolution of the biopharmaceutical industry. The biotech 

industry is a success story with multiple blockbuster products and well-capitalized 

companies, as well as those small and emerging companies that hopefully will contribute to its future. Its very success, creativity, and growth, since insulin was approved as the first biotechnology product back in 1982, is what makes this next step 

possible. With key patents expired and expiring, the time is appropriate to enable 

greater access to these medicines. 

In proposing that the development and approval of follow-on biologics be enabled, 

Novartis is drawing on its own decades of experience as well as its current capabilities and portfolio across the full breadth of the biotechnology and pharmaceutical 

industry. While care must be taken and standards maintained, the dramatic 

progress in biotechnology has already enabled development of the first follow-on biologic products. Indeed, some would say the entire industry is already a follow-on industry because most of the first-generation biotechnology products themselves were 

follow-ons to their naturally-sourced counterparts. We believe that this great success 

achieved by the biopharmaceutical industry working with the FDA regulatory experts should be the bridge to an even greater future. We envision the advancement 

of public health through the increased therapeutic options that become available 

and are accessible when follow-on biologics are approved through the appropriate 

application of the new regulatory pathway. Just as we trust the FDA to judge the 

appropriateness of comparability for innovators, so we can trust them to apply the 

same principles carefully and responsibly to all other sponsors. 

INTERCHANGEABILITY IS AN IMPORTANT PUBLIC HEALTH NEED

A regulatory pathway that encourages the integration of appropriate public prior 

knowledge, as well as one that enables a subsequent sponsor to submit data comparing their candidate to a previously approved product, are natural progressions 

in enabling the safest and most effective products to be made available to patients. 

Moreover, just as comparability for innovators’ products pre- and post- any manufacturing change has presumed interchangeability to their final product, so the potential for interchangeability of a product from a subsequent sponsor, who has demonstrated comparability to an existing product, must be a legitimate consideration 

if not a foregone conclusion. 

The industry and FDA accept that batch-to-batch variation is inevitable for biologics, and, as long as manufacturers ensure that subsequent batches stay within 

the same ‘‘goal posts’’ of that accepted variation, then the product is made available 

to patients. Comparability principles ensure that, for biologics, the same rules apply 

for after-approval manufacturing changes, and they can likewise be imposed on follow-on biologics. In none of these cases is ‘‘sameness’’ a useful or scientifically-valid 

concept, any more than it has been at any time for any biologic. To argue otherwise 

(for example insisting on ‘‘sameness’’ requirements that are not the current regulatory standard) creates hurdles to follow-on biologics that are greater than those 

required for innovator products and counter-intuitive. Similarly, an unintended consequence of such protectionism disguised as ‘‘sameness’’ raises the hurdles for innovator products, and makes products for unmet medical needs increasingly unavailable to patients. What we need are consistent and appropriate regulatory standards 

applied to all biologics independent of their sponsor. 

In addition, a regulatory pathway that allows any sponsor to further innovate and 

develop a new second-generation product that is expressly different from but related 

to the first-generation product, and that represents an improvement in the medical 

options for patients, can be enabled by a pathway based on principles of comparability. This element encourages second-generation biologics but is precluded in 

the European approach and yet may represent significant opportunities in the ‘‘Access to Life-Saving Medicines Act.’’ 

BIOTECHNOLOGY MEDICINES HAVE THE CONFIDENCE OF THE PUBLIC

It is essential that the high standards for safety and efficacy that patients expect 

and that the biopharmaceutical industry has provided in collaboration with FDA are 

maintained through appropriate and consistent regulatory requirements for all biologics. These standards have been achieved through the application of rigorous, 

science-based regulatory requirements by experts for over a century under the PHS 

Act. The current statute reinforces the requirements for safety, purity and potency. 

However, just as we trust the FDA to assess the unknown (new) biologic about 

which we necessarily have the least experience, (namely the innovator products), 

using these criteria, so too we can entrust the Agency to evaluate follow-on biologics 

36 

which refer to products for which we now have decades of experience. We believe 

Congress should confer on FDA the flexibility to accommodate progress in science, 

and help enable the regulatory requirements to evolve appropriately as well. As 

such, FDA can, through public notice-and-comment rulemaking, and guidance as appropriate, implement a comparability-based pathway for follow-on biologics without 

requiring arbitrary, unnecessary or unethical duplication of pre-approval studies or 

clinical trials, and by allowing appropriate extrapolation between indications based 

on mechanism of action. We can also allow FDA to use their experience with comparability to evaluate a follow-on biologic sponsor’s data, and judge the appropriateness of the products being designated as interchangeable—all while recognizing that 

FDA does not regulate the practice of medicine. The EU may have chosen to defer 

to member States on interchangeability (the EMEA has not rejected interchangeability for biosimilars as some have misrepresented), but the history of generic 

drugs in the United States makes it much more fitting that FDA recommend the 

designation—they have the skill and the public health responsibility that make this 

appropriate. It should also be noted that, throughout this process, no access to the 

innovator’s data is required—the approval of the follow-on biologic can rest solely 

and surely on the shoulders of the subsequent sponsor’s comparative data which it 

obtains by running side-by-studies of the innovator reference product and its own 

follow-on biologic. 

PROTECTION OF INTELLECTUAL PROPERTY IS THE LIFEBLOOD OF INNOVATION

Strong intellectual property protection, including patents, trade secrets, and confidential information, is essential to promoting innovation that results in new therapies to meet patient needs. However, Novartis believes that, by having a regulatory 

pathway that allows more rapid and efficient realization of this innovation through 

greater use of comparability and prior knowledge for second-generation products as 

well, these IP rights are enhanced not undermined by a follow-on biologics pathway. 

Moreover, with each follow-on sponsor developing its own independent data package, and not relying on the innovator’s data, we believe these property rights are 

respected even for those products on which the patents have expired and competition appears imminent. Historically, the biotech industry has established robust patent estates. However, when these patents expire (including patents claiming those 

PHS Act products for which up to 5 years of patent-term restoration already has 

been granted under existing Hatch-Waxman), increased competition and access to 

safe and effective medicines should proceed in the free market. Litigation over patents will still occur, but those litigation proceedings should, and in fact do not need 

to be coupled to the regulatory approval process. Nonetheless, Novartis is prepared 

to work with the committee and its staff to develop appropriate legislative provisions that would apply at the conclusion of the FDA approval process. Such a process for follow-on biologics could include a 45-day notification of an issued approval, 

during which time the innovator would be alerted to an approval referencing its 

product, and the innovator could institute litigation if it believed that its patent or 

other intellectual property rights have been violated. 

Novartis believes that, if follow-on biologics are to become available to patients 

in a timely manner, it is essential to ‘‘decouple’’ patent litigation from the approval 

of new products using a comparability-based regulatory pathway. The complexity of 

biotechnology product patent estates is such that we do not believe waiting for resolution of biotech patent litigation in the Courts will be other than a barrier to the 

timely availability of follow-on biologics. Consequently, we believe companies should 

be able to decide how best to approach the market if they believe there are not outstanding patents, or that any patents still in force are invalid or not infringed just 

as they can for any PHS Act biologic today. 

In legislating this ‘‘decoupling,’’ it may be appropriate for Congress to consider 

other mechanisms by which to make the exclusive marketing window more predictable for innovators. Novartis supports a non-patent research incentive such as may 

be achieved through modeling on EU data exclusivity provisions, more appropriately 

called market-exclusivity provisions, for innovator biologics approved after enactment of any new legislation, as a way to enhance regulatory certainty for all sponsors (which would be independent of the patent estates). Such an approach would 

prevent diversion of excess resources being used by either innovators or the sponsors of follow-on biologics on slow and expensive patent litigation, and enable those 

resources to be dedicated to the development and new and more efficient manufacturing of biologics. However, beyond harmonizing this one discrete component of the 

EU system, in general, the EU approaches on follow-on biologics per se, their socalled ‘‘biosimilars,’’ suit an EU environment of 27 distinct countries with different 

legislative and regulatory histories as well as very different health care and reimVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00040 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
37 

bursement systems. The United States needs a solution that suits U.S. needs and 

statutory environment as it has been evolving here for over 200 years following 

adoption of the U.S. Constitution. 

THE DEVELOPMENT OF NEW REGULATORY REQUIREMENTS MUST BE TRANSPARENT

AND THE RULES FAIR

For any new regulatory pathway, the FDA will need to go through a process of 

developing regulations. While promulgation of regulations need not be blocking applications in the meantime, their development can be expected to facilitate the 

choices for those sponsors and patients who can afford to wait a little longer. The 

FDA has a mission to enhance the public health, and follow-on biologics will be part 

of that as a result of enhanced patient access and competition. Novartis supports 

such an open process, while ’not accepting that it should ever serve to block followon biologics while the regulatory implementation process proceeds. Unlike the EU, 

the United States has a long established and very accessible public participatory 

process, in which submissions to dockets are available to the public. It will be 

through this notice-and-comment rulemaking, as well as the development of guidance, to which the experienced innovator industry and others will be able to contribute and ensure that only safe and effective follow-on biologics are approved. 

CONCLUSION

Novartis envisions a win:win public health and public policy solution whereby a 

follow-on biologics industry is enabled, patients get greater access to high-quality 

and improved biotechnology products at competitive prices, and that provides 

innovators relief from outdated requirements and a less burdensome pathway to improve existing products. As recognized by the FDA leadership, it is not appropriate 

to use outdated regulatory requirements just because those parameters were considered historically useful. In this and other important regards, the opportunities to 

innovators through the creation of a new regulatory pathway based on comparability such as, for example, in the ‘‘Access to Life-Saving Medicines Act,’’ should 

be at least as great as any available to generics, especially with respect to secondgeneration products. We do not believe that this is a zero-sum game. PHRMA’s own 

numbers say 418 biotechnology medicines are in development, and yet, only 4 recombinant PHS Act applications were approved in 2006. It is time for all of us to 

work with FDA to improve the review for all biologics such that every patient can 

get access to safe and effective medicines that will compete in the market place and 

be more affordable, while also encouraging the development of the new therapies 

which are so desperately needed. 

The CHAIRMAN. Thank you, thank you very much. We try to do 

5-minute rounds, if you would, please. 

Let me ask the whole panel a question to get your reaction. Recently, I had the good opportunity to meet with a number of the 

major biotech industries in my own State and I was interested in 

the coming together after a good deal of debate and discussion, 

around the idea that there was a pathway to move on this, as long 

as it was basically driven by the science, protect safety and also 

promoted the innovation and that it was feasible. Let me ask each 

of you, what are the specific recommendations that you’d have for 

us to achieve that pathway? If you’d be good enough. 

Mr. BANWART. Chairman Kennedy, from our point of view, we reiterated the five principles in my testimony and we think it is important that the FDA be authorized to use their innovation and 

their scientific knowledge to pursue the pathway to follow-ons. So 

we think the most important aspect there is the enabling legislation that would allow the FDA to do this job and in addition, to 

provide them the resources to do the job. So it’s—in our view, it’s 

a matter of the what and the enabling legislation to create the 

what. 

The CHAIRMAN. Dr. Siegel. 

Dr. SIEGEL. Well, I’d say that the considerations are—the most 

important considerations are largely those I mentioned in my adVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00041 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
38 

dress. I think we really do need to have good public debate to bring 

the science out. I think this hearing is a terrific step in that direction. I commend the European model and approach in that regard. 

I think it is important that we not go beyond the science. You can’t 

just take a molecule that has never been in people and that you 

can’t be sure what it is and all of a sudden, market it to thousands 

of people. It’s too risky. You need to identify what the risks are, 

you need to do the appropriate clinical trials. You need to ensure 

that the FDA is fully empowered to ask for the data and the types 

of studies it needs. You can build a policy based on high degrees 

of similarity but you should not apply that policy to products that 

are not highly similar, to products that are so complex that you 

couldn’t determine if they are highly similar and you should not 

say that similar things tell you that they are the same. It’s an important difference and it’s an important difference in how we practice medicine. Legislation and policies should take that into account. 

The CHAIRMAN. You believe that FDA has the knowledge and the 

know-how and the ability to do that, at the present time? 

Dr. SIEGEL. I think the FDA does. I think it will be a learning 

process. I think there are certain—in the legislation before this 

committee at the present time, there are certain constraints on the 

FDA’s ability to ask for studies that it needs, both post-marketing 

and pre-marketing. There are timelines for the FDA to reach complete decisions whereas typically in legislation, there are timelines 

for FDA to have complete reviews and if more data is needed, to 

ask for it. In this legislation, it constrains the ability to ask for 

data. There are certain types of studies that can’t be asked for. So 

I think the FDA has developed to the type of expertise. I think it 

will learn as it goes. I think it needs to be given the opportunity 

to set appropriate standards and to do this the right way. 

The CHAIRMAN. Good. Dr. Rossignol, Senator Schumer indicated 

earlier in his presentation, there are different marketing techniques obviously in Europe and exclusivity is 11 years. They have 

effectively about half the profit in terms of innovation that American companies have. Would you comment on whether you think we 

should look at 5 years, if they have 11 years? Is there a relationship there? If you would make just an additional comment on that. 

And then I’ll ask Dr. Hussain to make a final comment and my 

time will be up. 

Mr. ROSSIGNOL. Thank you, Mr. Chairman. In response to the 

first question, I would simply name three criteria. First I think, 

from our experience in the Union, I would have to say is a short 

experience. I mean, the framework on biosimilars or follow-on biologics was created really in 2003 so its only 4 years but I would 

say first that we had to be cautious and not to create something 

that would be too flexible or not stringent enough and that could 

then spread suspicion on the actual safety and efficacy standards 

of all biotech products. First start cautious, I think is one key 

point. The second key point is that the framework should be flexible and adapted to the type of products. When you talk about pilots, this is a big world and you have to separate and distinguish 

between those biological products that can today characterize relatively well, like small proteins, like insulin, growth hormones and 

39 

you have to distinguish these from more complex products. In Europe today, take vaccines for example, we don’t believe scientifically 

that a biosimilar approach would be appropriate for these products, 

simply because its very difficult to characterize them. 

The third point is really more a point of procedure and constant 

dialogue with all the stakeholders. I think this has been instrumental and key now in our context, in the European context to discuss both sides of industry and to actually gather expertise which 

primarily lies in the companies today because this is a relatively 

new field. 

Regarding the exclusivity provisions, i.e., your second question, 

Mr. Chairman, I think I will respond in a general way. We do have 

specific provisions for data exclusivity in Europe to protect innovation, to reward innovation and I have put some information together in my written testimony and I will be more than happy to 

provide further information on this. But I have to say that this is 

one context, which is the European context, which is very specific, 

especially in terms of pricing and reimbursement. So as a general 

comment, I would say that this context has to be taken into account when reflecting on applying our framework somewhere else 

in the world. 

I think that you have to distinguish between the science and rewarding innovation, idea rights, et cetera. The science is presenting 

everywhere and there is no reason why, in principle, scientific requirements should be different on one side of the Atlantic than on 

the other. And in this respect, on science, we already have ongoing 

collaboration with the FDA. We believe they have the appropriate 

expertise to assess these types of products and we are absolutely 

prepared to continue collaboration and to extend our collaboration 

in this respect. But this is all science and science should be the 

same everywhere. 

But protection of innovation, rewarding innovation and the balance between innovation and access to affordable medicines is 

something, in our opinion, that has to be seen in the context, in a 

specific national context, which is different in Europe than in the 

United States. 

The CHAIRMAN. Thank you. Very helpful response. My time is up 

but I want to ask Dr. Hussain, if you’d maybe just respond to the 

first issue. 

Mr. HUSSAIN. Mr. Chairman, I’ll be brief. I just want to make 

two points before I sort of give you the answer. One is, I think as 

a quote/unquote General Company Sandoz is a new era company 

also at the same time. We want to bring innovative solutions to 

making interchangeable biosimilar products, follow-on biologics. In 

that regard, we have invested, as an example, in MIT technology 

to really seek and discover hybrids—that’s just one piece of the 

puzzle. The reason I say that is, the solution to this challenge is, 

you have to empower FDA because FDA has to judge the science 

on which our applications will be based on. This is proprietary 

science and technology and you can hear my perspective and my 

colleague’s perspective but the solution will be with FDA. So FDA 

has to judge the science. FDA has to ensure the safety and FDA 

has to recognize innovation because we bring innovative science 

and technology to be interchangeable. And I think the only solution 

40 

is to empower FDA. So from that perspective, I think, as one of the 

frustrations I had—I led the policy development for 3 years on follow-ons myself and the frustration was lack of involvement. 

The CHAIRMAN. Thank you very much. 

Senator Enzi. 

Senator ENZI. Thank you, Mr. Chairman and I’ve really learned 

a lot today and I have a lot of questions as a result of probably misunderstandings and I will submit many of those in writing and I 

hope that you will respond to them as promptly as possible. Is Mr. 

Rossignol still with us? 

The CHAIRMAN. Yes, I hope he is still on. We have to thank our 

technicians here. This is a wonderful opportunity to hear from—it 

was a wonderful opportunity. 

[Laughter.] 

The CHAIRMAN. It is and we thank you. 

Dr. ROSSIGNOL. I can still hear you. 

Senator ENZI. I thank you for rejoining us. I do like the term, 

biosimilars and I notice that it is not bio-sames. I understand that 

vaccines and plasma proteins are excluded from the biosimilar law 

in Europe. Could you discuss why it was decided that they should 

be excluded from the European Commission law? 

Mr. ROSSIGNOL. Thank you, Senator Enzi. Well, actually they are 

not excluded. I think that there is a difference in Europe between 

the actual legal framework and the current scientific consensus 

and I want to stress three words—current scientific consensus. If 

you talk only about the legal system, actually our legal system first 

does not preclude the theoretical legal possibility that the biologic—any biologic—could be authorized as a generic. So that legal 

possibility is foreseen in EU education. However, when biological 

product does not meet the conditions of the generic, then you have 

the biosimilar framework. So that’s the legal construction. 

If you talk about science now and the current scientific consensus 

in Europe—the current scientific consensus is that realistically, 

this framework on biosimilars can only be applied to products 

which can be thoroughly characterized and I should also add for 

products for which we have already in-depth regulatory and clinical 

experience. So to give you some concrete examples, the small proteins I named already—insulin, growth hormones, interferon, to a 

certain extent, alpha proteins—these types of products which are 

relatively simple molecules can be already today relatively solely 

characterized, and are considered in Europe, as being eligible scientifically to the biosimilars. For the others, although legally they 

are eligible scientifically, the consensus is that they are basically 

so complex that it’s not apporpriate today, given the current state 

of science, to approve them under this legal pathway. Is that clear? 

Senator ENZI. Very helpful, thank you. Dr. Siegel, I appreciate 

your testimony. I did note that you do not support the ClintonSchumer bill as it would put unsafe products on the market. I 

think I got that right. Others have indicated that no clinical trials 

are required when innovative manufacturers initiate a new manufacturing process. And therefore, there should be no clinical trials 

for follow-on biologics. Can you explain the differences between 

changes in the manufacturing process for an innovator and the creVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00044 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
41 

ation of a manufacturing process required for a generic to create 

follow-on biologics? 

Dr. SIEGEL. Yes. First let me say the premise of that question 

really—others have said that but it’s based on a misunderstanding. 

When innovators make manufacturing changes that come anywhere close to the types of the changes that would be implicit in 

having a new manufacturer, they are required to do clinical trials. 

They often, in fact, avoid making such changes. I can speak now 

from the innovator side of the equation as well as from the regulator side of the question because they recognize that those major 

changes in how a product is made do potentially change the product and it means that they will need to do studies and there will 

be a significant likelihood that those studies will show that the 

product isn’t the same. So that’s driven by the science. The types 

of changes you see, for example, an innovator—you’ll see with the 

follow-on biologic is the use of a different master cell line, a master 

cell bank and cell line and that is something an innovator would 

almost never do and regulators would only permit, with substantial 

testing and often discouraged, changing the manufacturing facility, 

changing the process. These are major changes. 

There are also important differences between how an innovator 

changes their process because there can be important changes in 

a final product that can’t be detected in the final product. If you 

have a new contaminant or a new variant of a product, you may 

see it in large amounts in what is initially made by the cells, even 

less so once that’s been purified and even less so once that’s been 

formulated because formulation can interfere with certain testing. 

But the purification process can bring contaminants and variance 

down to levels that are below detectability but are still important. 

So an innovator will look at every stage of process for what’s 

changed or different, understands the process, knows what’s important in the process, knows what needs to be controlled, what variations in a protein are critical and what are not. So there is a tremendous knowledge base. There is access to materials. There is understanding the testing but there is also just an extent of changes 

that will go on with the follow-on that are large and that, in fact, 

do require innovators to do clinical testing as well. 

Senator ENZI. Thank you. This is extremely complex and my 

time has expired. I do have several questions for each of you and 

I will submit those. Thank you, Mr. Chairman. 

The CHAIRMAN. Senator Clinton. 

Senator CLINTON. Thank you very much and I want to thank all 

of the witnesses, those who are present here and Dr. Rossignol, 

thank you for being with us by long distance. This has been very 

impressive and important testimony. 

I think we all agree that safety is paramount. That is the bottom 

line and what the testimony today highlights is the need for greater FDA post-market authority across the board. The WaxmanSchumer-Clinton legislation was written to reflect the current reality with regard to post-market studies on the brand side. There 

are no post-market studies because the FDA does not have the authority. So if the reality does not provide great enough safety assurances, then we should raise the standard across the board and 

provide FDA with an enforceable authority to require post-market 

42 

studies on both brands and follow-on biologics. Clearly, when 

changes are made in the existing manufacturing process or facility, 

as Dr. Siegel said, that raises questions, which is one of the reasons why the innovators don’t do it. Well, that seems to me to be 

somewhat backwards because if there are needs to make such 

changes, the FDA should be empowered to act in a more expeditious manner in order to facilitate such changes. 

So in effect, we have tied the hands of the FDA, both with what 

could very well be legitimate changes in the innovators processes 

and facilities or cell banks or lines or whatever else has to be 

changed in the opinion of the innovator to bring a safe and efficacious product to market and we don’t have the authority for the follow-on biologics. 

So I think, Mr. Chairman, as we look at this, I would go back 

to Mr. Banwart’s very strong emphasis on let’s empower the FDA 

to do what we want the FDA to do. I think there has been significant concern by this committee and the Congress over the last several years about some of the problems at the FDA, some of the inadequate authority that the FDA has, some of the morale problems 

as well. So to me, this goes to a central issue here as to how we 

empower the FDA to do the job we expect it to do in order to remain the Gold Standard globally, when it comes to drug and biologic approvals and marketing. 

I also would like to say that our piece of legislation is intended 

to catalyze this conversation. What we are interested in is moving 

in a thorough and very careful way but expeditiously because the 

amount of money that is being spent is just extraordinary and I appreciate Mr. Banwart coming forward because with biologic products alone, costs, as I understand it, have increased 45 percent in 

3 years. We all know we’ve got to do a lot to get costs under control 

in our healthcare system. This is an area that—if we don’t address 

everything else we want to do in healthcare—will not be sufficient 

because we will not be able to keep up. 

So I very much appreciate the thoughtful testimony today, Mr. 

Chairman and look forward to working with our colleagues on both 

sides of the isle and frankly, with the industry—both the innovator 

industry, the brand name industry as well as the generics and the 

biotech industry because what we’re trying to do is in the best interests of safety, science, patient health and the cost of healthcare. 

I think that is the bottom line for all of us. So I appreciate it. We’ll 

have some follow-up written questions because of the complexity of 

some of these concerns. But thank you again for testifying and 

thank our witness from the EU because it’s wonderful to have cooperative, friendly relations with our neighbors across the Atlantic. 

So, thank you, Mr. Chairman. 

The CHAIRMAN. Thank you. 

Senator Hatch. 

Senator HATCH. Well, thank you, Mr. Chairman. I want to thank 

each of you for being here. Mr. Rossignol, for you to take this time 

from Europe. It means a lot to us. 

In all honesty, let me just start with you, Mr. Banwart. I understand how important it is to have low-cost healthcare for employees 

and to try and keep the costs within reason and of course, that’s 

43 

what Hatch-Waxman was really designed to do in a lot of ways, 

plus a lot of other things that we designed in that particular bill. 

While I admire Congressman Henry Waxman and Senator Clinton’s work on this bill, I can’t support it because I don’t think it 

does provide the safety that we should have. Frankly, the safety 

provisions that we wrote into the original Hatch-Waxman bill back 

in 1984, indicated that we were deeply concerned about patient 

safety. I’m not convinced that if a follow-on biologic is approved the 

way that Congressman Waxman’s bill dictates, patient safety, it 

seems to me, would be a problem because the legislation does not 

require any clinical trials on these products as they move through 

the pipeline. Now I would be interested, first in your thoughts, Mr. 

Banwart and then yours, Dr. Siegel and then yours, Dr. Hussain, 

on that particular issue. And if you could be short—I’ve got a number of other questions I really feel I have to get to. 

Mr. BANWART. Thank you, Senator Hatch. Obviously safety is our 

number one concern as well and whatever process, whatever enabling legislation this committee would bring forward, we would assume that it would put safety at the top of the list. 

Senator HATCH. This particular bill does not, in my opinion. It’s 

innovative and very thoughtful and I think it’s a good start. But 

you would agree that we should have clinical trials? 

Mr. BANWART. We need to make sure that we empower the FDA 

to do the job safely. 

Senator HATCH. Now, Dr. Siegel, I would appreciate your opinion 

in particular. I understand you have some ideas on how we might 

be able to reach biosimilar approaches. 

Dr. SIEGEL. Well, in the interest of not taking up too much time 

because these are complicated questions, I’ll be glad to answer in 

more detail and I’ve addressed some of these—— 

Senator HATCH. If you would, I would appreciate you getting 

with us and letting us know. 

Dr. SIEGEL. I would simply say there are a lot of critical issues. 

The pharmacokinetics, whether a drug gives rise to an immune response, which most biologics do. 

Senator HATCH. But you would agree clinical trials are improving? 

Dr. SIEGEL. Absolutely. Both before and after approval, absolutely essential. It will depend on the nature of the product, how 

much and the nature of the disease and other factors but absolutely critical. 

Senator HATCH. Well, thank you. Dr. Hussain? 

Mr. HUSSAIN. Senator, I think we have the first approval from 

Europe as well as from the United States on this and I think clinical trials are part of the compatibility exercise and I think are 

often necessary. I don’t see the interpretation of the proposed bill 

as not requiring clinical trials. So I don’t envision that this will 

proceed without clinical trials. But I do want to sort of share with 

you a perspective that there are different aspects and different 

study designs that allow you to bring a rationale and a very designed approach to what clinical trials would be needed. So these 

are not exactly the same clinical trials you would have for the unknown original trial. 

44 

Senator HATCH. Mr. Rossignol—is it Dr. Rossignol or Mr. 

Rossignol? 

Mr. ROSSIGNOL. Mr. Rossignol. 

Senator HATCH. Okay. Now as I understand it, your basic provisions took effect in 2003 on biosimilars and that includes 10 to 11 

years of protection against follow-on products. There is a combination of primary and secondary legislation and you use a guidance 

system to be able to make sure that these products are safe and 

efficacious, to use your terms and ours as well. As I understand it, 

the guidance will be issued through open public procedures with 

participation by expert committees, national authority, scientific 

community and industry approaches as well, which I find to be 

very, very interesting. I don’t know quite how you put it together. 

I’d like you to write to us and let us know how you accomplish that 

goal. With product specific requirements established, pre-clinical 

and clinical testing required for all products, how—I hope I’m summarizing it well enough and special attention to immunogenicity 

and post-marketing testing and surveillance. Is that fair? Is that 

a fair description so far? And then I want to ask you these questions. I want to ask you some questions on that. If this is fair, tell 

me if it isn’t, tell me as well. But could you please explain how substitution for medicinal products work in France. Are other EU 

countries following similar practices? And why isn’t substitution 

appropriate for biosimilar medicines? If you could answer those 

four questions, that would be helpful. 

Mr. ROSSIGNOL. First I have a concern that your description of 

the EU system is indeed the correct one. I would simply add in relation also to the comment made by Senator Clinton, that in Europe we have the legal basis for post-authorization safety studies 

and actually the Vice President of the Commission announced last 

week that this will be strengthened further in Europe to make sure 

that all products are safe and even post-authorization, post-marketing. 

It is true that in Europe we have a system based on watching 

legislation which is relatively concise and flexible and supplemented, if you like, by guidance. I believe it is quite helpful to have 

this system in place. Why? Simply because this is an emerging field 

with respect to those products you’re talking about and therefore 

it is very difficult to have one—monolithic if you like—system to 

address all these types of problems. 

We do require clinical trials, pre-approval. We do require a comparable exercise, which is not restricted to clinical studies. It actually spans across the quality aspects, the pre-clinical aspects and 

the clinical aspects. So the comparability package is actually quite 

an extensive one. 

I have to say also that in response to your last question on substitution, to be very concise. As I said in my statement, substitution or interchangeability is not assessed value in this station, so 

it is really a member state practice in Europe and it differs from 

one country to the other. So it’s very difficult to give you an answer 

here. But I want to stress that today, we have examples of substitution, i.e., practice pharmacies for one product instead of the 

other, which are two products which are actually another two products. So in other words, what I’m trying to say is that the substiVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00048 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
45 

tution problem—interchangeability problem is maybe specifically 

applying—policy, when it is actually not specific to biosimilars. The 

problem already occurs today with other products at least in Europe, in certain countries where pharmacies are actually instructed, in some countries to substitute and to use, for example, 

the internationally known proprietary name. You find out that the 

majority of—and change one product with another without necessarily having the scientific background behind it. So we need to 

bear in mind that this issue of substitution is a key issue in the 

field of biotech products in general. 

Senator HATCH. I want to thank you, Mr. Rossignol. Mr. Chairman, I think one of the big issues where we really could use help 

and I understand that you two doctors can help us with this—is 

just how we can really provide an element of protection here and 

without making the process so stringent that we can never get any 

products approved. We really need some help up here because we 

all know that it’s almost impossible to have biologic implications— 

these are large molecule individual therapy-type situations. But 

that’s where the future is, and we want to be helpful and have a 

similar drug price competition patent term restoration, which is the 

real name of Hatch-Waxman, approach towards these problems. 

And we could really use some extra help and from scientists all 

over the country. We would appreciate hearing from you on the 

best way of doing this and providing the most efficacious and safe 

way of doing it as well. 

Thank you, Mr. Chairman for giving me that extra time. 

Mr. HUSSAIN. Mr. Chairman, if I could just—sorry. You want to 

go first? 

Mr. BANWART. Go ahead. 

Mr. HUSSAIN. Mr. Chairman and Senator, this has been a significant talk process. Personally—I’ll speak on my personal scientific 

aspect in this instance. I was personally not very comfortable with 

the generic substitution type of approach for follow-on proteins and 

the word follow-on was deliberately chosen to sort of illustrate 

some of the challenges here. But at the same time, I think in practice, you can achieve interchangeability through a science-based assessment in either one step or in a two-step processes that could 

be labeled as indications that this product has shown to be substituted—interchangeable to this and that is the reason I use the 

word interchangeable to distinguish from substitution. So label indication could be a mechanism to really—that is based on hard scientific data and even switching clinical studies that you might 

want to provide. If there is a risk-based approach that says the 

immunogenicity aspect of this is so critical, then there might be a 

two-step process that you might not get an interchangeability status unless you have additional post-marketing data that you collect 

because you really cannot do a clinical study. So that is a way forward here, in sort of my opinion and I think both my former FDA 

colleagues have been thinking about that for a long time. 

Dr. SIEGEL. On the question of substitution, I think the only scientifically valid way forward is through some combination of naming, labeling and education to ensure that inadvertent substitution 

doesn’t occur, to ensure that people realize that these products are 

not identical or the same. One cannot know that they are the same. 

46 

To look at say, a major safety risk that could be due to a trace contaminant—it would take tens of thousands of people studied to tell 

if that risk went from 1 to 2 percent, a doubling of the risk. If you 

look at immunogenicity concerns, which are big concerns, many of 

these products have immunogenicity in 5 or 10 percent of the patients. You could do a study of 500 to 1,000 patients and still not 

know if immunogenicity had doubled with the new product and exposing a patient alternatively, to one or both, could be exposing 

them to double the risk or could create immunogenicity risks that 

neither one alone exposure would bring around. So I think the 

science is a long way from addressing substitution but if your question is more broadly about a path forward to have abbreviated applications with abbreviated testing, I firmly do believe that with 

products that are sufficiently close in terms of their chemical, physical characteristics, that with appropriate testing, including clinical 

testing, that there can be a science-driven and product specific abbreviated testing approach to an abbreviated application. 

Senator HATCH. Mr. Chairman, my time is up but on this particular point, could I have a follow-up question—since he’s really 

gone into some immunogenicity problem. And I think it is really 

important. I appreciate your remarks about the problem of 

immunogenicity or the ability of most or all biologic products to 

stimulate an immune system response in the body but is it not 

true, just for our benefit here, since we’re not scientists—we’re just 

trying to do the best we can with your help—is it not true that an 

immune system response could occur immediately or it might not 

occur until years after patients start using a follow-on biologic. Is 

that true? 

Dr. SIEGEL. Typically, immune responses will occur some weeks 

or months after somebody is first exposed to a new protein. 

Senator HATCH. It can occur years later, too. 

Dr. SIEGEL. Yes, it can, especially if there is a change in the 

product that they are exposed to. 

Senator HATCH. Well then, don’t you think that FDA should be 

given the authority to track some of these patients? Or at least 

have companies track patients in these clinical trials and allow the 

FDA to determine which follow-on biologics should be tracked in 

the future? 

Dr. SIEGEL. I think that’s essential. I think we’re already seeing 

in some parts of the world where adverse events occur and you cannot determine which product the patient took and it’s difficult or 

impossible to know whether those events, immunogenicity or otherwise, which products are attributable to. You can lose the value of 

a whole class of products if you can’t tell which of its members are 

potentially problematic. 

Senator HATCH. Well, this has been very helpful to us here 

today, the three of you have been very helpful and I have a number 

of other questions I’ll submit in writing. Mr. Chairman, I apologize 

for taking a little longer than I should have. 

Mr. HUSSAIN. Mr. Chairman, if I could just give my aspect, if I 

may. Immunogenicity is not just a protein issue. It also happens 

with small molecules and I think we really need a rational sciencebased discussion on this and I think the best place to do that is 

at FDA. 

47 

Senator CLINTON. Mr. Chairman, if I could just have a point of 

clarification? I appreciate greatly the line of questioning that Senator Hatch puts forth and I don’t think there is anybody in the 

Congress who has more expertise on this. Our legislation provides 

the FDA with the authority to require clinical testing. That is in 

our legislation. So that some of the issues that we were talking 

about were based on the assertion that we did not do so and in 

fact, our legislation does give the FDA the authority and what we 

are trying to do is enhance the FDA’s authority to deal with this 

whole range of issues. There is a differentiation between the postmarketing and the pre-approval and with respect to post-marketing, I agree completely with what Senator Hatch said. We 

should have follow-on testing by the companies and I think that 

should apply to both brand name and generics, both with drugs 

and with biologics because I think we’re in a world now that is very 

different, even from the days of Hatch-Waxman, to try to figure out 

how we best can understand the complexity, the drug and biologic 

interactions, the immunoeffects. So I just wanted to clarify that our 

legislation does provide that authority to the FDA. 

Senator HATCH. Well, if I could just clarify—it’s not clear but I’m 

sure that’s what you intend. What we need to do is keep working 

to get the very best legislation we possibly can. I’m sure under the 

leadership of the Chairman, we’ll be able to do that. 

Senator CLINTON. Yes. Well, we would love to have another 

Hatch-Waxman or Waxman-Hatch, whichever you prefer. 

Senator HATCH. I want Clinton in there, too. 

[Laughter.] 

Senator HATCH. I want our Chairman and Vice Chairman in as 

well. 

The CHAIRMAN. We have, if Senator Reed would permit, Senator 

Coburn told me that he has to go to an important Intelligence 

briefing in just a few minutes. So if I could recognize Senator 

Coburn. 

Senator COBURN. You know, one of the things I think—just to 

kind of summarize, my reading of the testimonies. We’re dealing 

with a completely different set of compounds than the FDA has 

ever dealt with before. And when you say biologic, you can talk 

about a very small protein. You can talk about a complex protein 

that has carbohydrates associated with it or you can talk about 

very giant chemical molecules. What I hear being discussed in both 

my readings and from talking to people, is I think the approach of 

this—and we don’t know where we’re going on this yet—is we’re 

trying to write a law or to devise regulations based on where we 

don’t want to go. I would suggest to the members of this committee 

is that what we ought to do is try to devise a stepped process based 

on what the FDA is going to learn and what we’re going to learn 

in science. I’m not going to get into the battles of follow-on testing 

and clinical trials and everything else. I think a lot of that has to 

do with IP protection, investments in this, and appropriate competition. 

But the question I have is when we don’t know answers to questions, the one thing we want to make sure we do with our legislation is to make sure we don’t impede an opportunity for greater development and faster responses to new products coming to the marVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00051 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
48 

ket. We don’t want to totally impede somebody’s investment effort 

and IP and then take it away—so there has to be some protection 

for that. But at the same time, we ought to create a system where 

some of the intellectual property isn’t taking advantage of the 

American people to the extent it is. 

I think with the Clinton-Schumer bill, we ought to design provisional changes, step-by-step changes that allow the FDA to look at 

this and categorize this. We’re not going to need the same law for 

all biologics. I think we need a different law for different groups 

of biologics, and I don’t think we can know right now what that is. 

I’d love to have each of your comments on that. I think you’re kind 

of seeing that’s where the EU is going as well. Any comments on 

that? 

Dr. SIEGEL. First let me say, I would agree entirely that there 

are things we can do with small molecules, for example, in terms 

of understanding the differences and making those differences so 

small that we can infer certain things about one based on its similarity to another that you can’t do, for example, with live viruses. 

Biologics law, however, is pretty flexible in terms of allowing one 

to determine safety, purity and potency as appropriate for the situation. So I wouldn’t say necessarily we need new law for viruses. 

For example, each year there is a different strain of influenza. 

Each year, there is a new influenza vaccine for that. They are appropriately tested but it would be inconceivable to do large-scale efficacy tests each year against that strain because you wouldn’t 

have the data in time. So I’m simply saying—— 

Senator COBURN. My point is this—you can have very large proteins that could come through a very simple manufacturing process, in the future, which we don’t have today, that could be very 

pure, very low in immunogenicity and we’re going to apply a law 

now that we don’t have for that and we’re going to have to come 

back and change it and maybe in a very short period of time. So 

my point is, we don’t know what we’re going to need. So anything 

we do in this area ought to have tremendous flexibility to build in 

what the science is going to show us in the future and I will bet 

you right now, I’m right. You will have complex molecules that you 

will produce very simply and with very low immunogenicity in the 

future and where a lot of these questions as far as interchangeability won’t even apply. And yet we’re making all our decisions 

today on the basis of what we know today, not what we think may 

come about in the future. So that was my point. 

Dr. SIEGEL. Well let me just then say, I certainly agree that we 

should be careful to leave scientific discretion to the agency because each product is different because the science changes. But to 

Senator Clinton’s point, I do want to say that yes, there is not any 

question that this bill authorizes the agency to require testing but 

I would note, for example, that in the approval of new drugs and 

biologics, the bill doesn’t simply authorize the agency to approve 

clinical testing. It states there needs to be adequate and well controlled tests. It sets the floor—that floor is dictated by science and 

the presence in legislation of that floor gives guidance to industry, 

which is useful, gives guidance to the agency, which is useful, gives 

guidance to court systems, which is useful. There is a scientific 

basis for a floor here. That’s the point I’m making. 

49 

Senator COBURN. Thank you, Mr. Chairman. 

Mr. HUSSAIN. Senator, I think you raise an important point and 

I think legislation should really look forward and be set in a way 

that allows innovation and then new technology, science to really 

move quickly. But I think that the question I’m struggling with, 

the thing of this discussion is, I think we are specifically focused 

on follow-on. So these are products based on science and technology 

that are here now. So I think there is an aspect of the follow-on 

part for that and there is an aspect of getting more and more innovative medicines together. So I think there are aspects built into 

the proposed legislation which actually goes in that direction, like 

the second generation products, which European biosimilars regulations do not address. I think that’s an important point and I really applaud that sort of thinking, to promote science and innovation 

with industry. 

Senator COBURN. Thank you. Thank you, Senator Reed. 

The CHAIRMAN. Senator Reed. 

Senator REED. Well, thanks very much Mr. Chairman and gentlemen, thank you for your testimony today. I’m just wondering 

and I’d like to ask all the panelists, how do drugs and biologics 

compare in terms of intellectual property protection? Do these differences have any significance as we consider creating a pathway 

to approval of follow-on biologics? That’s a topic I don’t think has 

been addressed. 

Mr. BANWART. Thank you, Senator. Representing Caterpillar, we 

certainly appreciate protection of intellectual property and we respect and honor patents of others and we expect others to respect 

and honor our patents. So intellectual property protection is important but we believe that after an appropriate period, that the marketplace should be subject to competition and that’s been well proven in other fields and while there are technical differences, we believe that a positive spirit and approach here could result in a 

workable solution as well. 

Senator REED. Okay. 

Dr. Siegel. 

Dr. SIEGEL. I would encourage you to and would welcome having 

others with greater expertise in my company speak to this issue 

but I would note that there are important differences—small molecules, since they are easier to define exactly what they are and 

how patents protect that. Large molecules, because they are enormous by comparison, often thousands of fold and because patents 

are increasingly more limited in what they cover, it’s relatively 

easy to engineer around those patents through minor changes to 

different parts of the product that can break that sort of IP protection and that really does need to be taken into account in any legislation. 

Senator REED. Thank you. 

Mr. HUSSAIN. Senator, I’ll just share with you, I think, that in 

the Novartis Corporation position on this, I think strong intellectual property protection, including patents, trade secrets and confidential information is essential to promoting innovation that results in new therapies to treat patients. With respect to each follow-on response, developing their own independent data packages 

50 

and not relying on innovator’s data, we believe this protection can 

be respected while also allowing the new product to proceed. 

Senator REED. Thank you. Director Rossignol, do you have a 

comment? 

Mr. ROSSIGNOL. Well, as I said, I think the EU experience is 

going to be very interesting from a scientific point of view and we 

actually already discussed that international level with WHO and 

our experience in science, i.e., a set of data basically, that we require to approve these products and that, I think, can be easily 

shared and discussed. When it comes to the protection of product 

rights regarding innovation, et cetera, I think at least from my personal perspective, it needs to be a bit careful in extrapolating the 

EU model because the EU model is—without offending anybody in 

Europe, is quite complex and it is not, let’s say, fully optimized 

across all member states in Europe and therefore, yes, we have a 

harmonized system now for data to pursue the same things. We 

don’t have what seems to be in the draft bill on market exclusivity 

for follow-on biologics that would be interchangeable. We don’t 

have that market exclusivity and Europe is restricted to—but in 

general, I would simply say that our system is very specific to 

yours when it comes to rewarding innovation and striking the right 

balance between rewarding innovation and smoothening the access 

to a further dimension. 

Senator REED. Well, thank you very much. I guess my conclusion 

from hearing the responses and maybe I want to test this again is 

that there are significant differences, at least, to suggest that we 

have to look carefully at not adopting the same regime for intellectual property protections that we have for drugs or for—is that a 

fair summary of the—— 

Dr. SIEGEL. I believe so, yes. 

Mr. HUSSAIN. I think so, yes. 

Senator REED. Thanks very much. Again, this is a field that I’m 

a novice at, I’ll confess. But I might not be alone. Does such a thing 

as a generic vaccine presently exist and would a generic vaccine be 

possible if a pathway to approve follow-on biologics were to be created and what might be some of the safety implications of generic 

vaccines? 

Mr. BANWART. I’ll defer to my colleagues. 

Senator REED. Thank you. 

Dr. Siegel. 

Dr. SIEGEL. Well, vaccines are regulated under the Public Health 

Service Act where there are no provisions for generics at the 

present time. But vaccines—you know, if biologics are a skyscraper 

to the starter house that small molecules are, then vaccines are 

megalopolises full of skyscrapers and stadiums and all sorts of 

other enormous buildings. I think recent history has shown us that 

for a lot of vaccines—you know, small pox vaccine, influenza vaccine that two vaccines that are the same virus can have very different effects and that’s something that needs to be paid really 

close attention to. 

Senator REED. Doctor. 

Mr. HUSSAIN. I think I’ll just reflect back on the FDA knowledge 

and since I think FDA has done a tremendous job in approving vaccines and actually using brand knowledge to define what the apVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00054 Fmt 6633 Sfmt 6601 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
51 

propriate pathway should be for vaccines. I think there are wonderful examples in the history on that. 

Senator REED. Thank you very much. I note that—— 

Senator CLINTON. Senator Allard is here. 

Senator REED [continuing]. Is here and Senator Kennedy is not 

so I think, Senator Allard, you should probably ask some questions. 

Senator ALLARD. Thank you. I’m trying to get so I understand 

what follow-on biologics are. It seems to me that if you have a vaccine, for example or if you have a medication that has a source, different sources, I think sometimes the source and how that is collected and everything is as important as what the chemical makeup is. We have some products, I think that are extracted for animals. I think a pituitary extract, comes from animals and it seems 

to me that—I don’t know how on follow-on biologics—if you’re dealing with a pituitary extract—I mean, how can you assure safety? 

I think a source and how it’s handled from that very source is as 

important as anything on that extract. I wondered if you could 

comment on that. 

Mr. HUSSAIN. Well, I think from two perspectives. One, I think— 

just reflecting back on the name follow-on protein products at FDA 

was—this was being discussed and they were very specific that this 

should be the common protein product and not address and get into 

that aspect of that. 

Senator ALLARD. Okay. 

Mr. HUSSAIN. So that—— 

Senator ALLARD. So you’re excluding those kind of products? 

Mr. HUSSAIN. No, I’m just sort of sharing with you the concern 

that you raise with respect to source material. It is important but 

at the same time, I think there are technologies and there are approaches to address those challenges and I think we actually have 

a wonderful example of that currently under review with the technology, the collaboration, the momentum on—so I think yes, there 

are aspects to that but I think there are ways to address that approach, too. 

Senator ALLARD. Well, you know, on vaccines for example, I 

know a lot of technology is changing on vaccines. You’ve got to kill 

virus. You might have a lot of protein in it, hormone or whatever 

and then you’ve got a modified live virus and then you have these 

other modifications where you take just the immunogenic aspect of 

the bacteria or the virus, which is a purer form with less reaction. 

And how do you treat those with a follow—in terms of—what’s a 

follow-on biologic for something like that? How do you define that? 

Dr. SIEGEL. First, let me second that for many biologics, especially those that are not made by DMA technology but even those, 

the source is critically important as is the process because of the 

limitations of testing. All of those things need to be controlled. But 

what is critical is probably for the purposes we’re discussing here 

is less whether it is used as a vaccine than—although that can be 

factor in terms—it certainly is a factor in terms of what testing is 

needed, but the nature of the product itself. So as you referred to, 

there are some component vaccines that are just a highly purified 

protein made by recombinant and DNA technology whose characterization is of the same order as some of the protein products that 

we’re talking about that are therapeutics. Many vaccines, however, 

52 

are far more complex, are live organisms, killed organisms, whatever, where the issues of determined comparability would be far 

less readily addressable. Even in the simpler vaccines though, they 

present the same issues as therapeutics do, of possible differences 

and of course, often in the setting of being given to thousands or 

millions of healthy children. So that—how the product is used is 

also going to influence what the appropriate testing is. 

Mr. HUSSAIN. I agree with that. 

Senator ALLARD. Pardon? You agree with that, okay. Well I just 

think that this is—it is a complex issue. I think what—not having 

some biological training, I think it’s hard for people to understand. 

I’ve had some biological training and this is kind of a new concept, 

follow-on biologics, so I’m trying to understand it myself on how 

you’re going to apply it with the testing that we currently require 

and the safety required for consumption. Those of you that are 

here, do you think that’s a possible regulatory regime that we can 

implement? 

Mr. HUSSAIN. What I would suggest is, I think, as there is possibly an example, I think the legislation could sort of recognize that 

this could be possible. It may not be possible fully at this time but 

I think this is what I think the European system has explicitly not 

excluded that and at the same time, I think with that level of complexity, getting into cells and getting into viruses and getting into 

those, may change over time. 

Senator ALLARD. Yes? 

Dr. SIEGEL. Is your question specifically about viruses, vaccines? 

Or is it sort of general? 

Senator ALLARD. Well, I mean, we’ve got a generic term—followon biologics. 

Dr. SIEGEL. Right. 

Senator ALLARD. And I think it kind of makes our discussion 

kind of complicated because there is a lot of things that follow in 

under that and I’m trying to figure out how you—— 

Dr. SIEGEL. I think and Johnson & Johnson thinks that we can 

move forward in a careful way with those products that we can 

characterize the best and understand the best and with appropriate 

testing, that there is a path forward, that there are some classes 

of products, there are some uses of products—whatever, that will 

present substantially more challenges, some of which with science 

does not yet allow a path for new approaches to regulation. 

Senator ALLARD. Dr. Rossignol, did you want to comment on that 

question? 

Mr. ROSSIGNOL. Yes, thank you. Just again to share the EU experience in this field, I think it was mentioned by Dr. Hussain that 

indeed, legally we do not exclude the possibility today to have follow-on biologics or biosimilars approved, even if they would be vaccines or even more complex products. So that’s not really excluded 

but I have to say that today, we are realistically on scientific 

grounds, the approach is really applicable to products which can be 

fully characterized and also products which have a good track 

record of—and clinical expertise and clinical experience. And if you 

talk about generic vaccines, specifically, we don’t have that in the 

pipeline and the current consensus is really that we would not see 

that unless under very exceptional circumstances, we would not see 

53 

these types of products as being approved as biosimilars in Europe. 

Actually, the products we have in the pipeline are relatively simple 

biologics which are still far—let’s say relatively more complex than 

chemicals but you’re talking here about insulin growth hormones— 

maybe globally the way heparin is but not really products like vaccines or more complex products. 

Senator ALLARD. So we’re talking—the follow-on biologics would 

be things—be hormones of various types, basically, is that what 

we’re looking at? 

Mr. ROSSIGNOL. No, not specifically. I have to stress, no product 

in theory is excluded. I’m just trying to describe the scientific consensus today and really, the scientific consensus today is that you 

can have an abbreviated data package only if you are able to fully 

characterize your product to the best extent you have, even the current analytical terms you have. And that is, for the moment at 

least, applicable only to those products which are relatively simply 

in molecular terms. 

Senator ALLARD. My problem is that this is such a broad term. 

And how do we narrow it down to what we’re talking about? 

Dr. SIEGEL. I think you’re on the right track. It’s not just hormones but the products that Mr. Rossignol are speaking of, for example, have molecular weights of 15, 20,000 typically. A typical aspirin might be—I think it’s under 200. A typical small molecule 

may be in a few hundred. Some biological proteins are well over 

100,000. Antibodies typically are 150,000 or more and then you get 

into genes and cells and viruses that raise other orders of complexity. So what he is saying and what I’m saying as well is that 

there are areas where there is a lot more scientific basis for characterizing the product and for using similarity as part of a regulatory 

paradigm. 

Senator ALLARD. Yes. I mean, like our human growth hormone 

is, I think, traditionally at least in this country, is produced with 

cell culture. Am I right? I think it is cell culture. I visited an operation in Argentina. They’ve got cows, cattle that they have genetically modified to produce human growth hormone in the milk and 

they are extracting it out of the milk. And so I guess the source 

of that, in my mind, creates potential problems and that’s one of 

the points that I wanted to make. I think the source can be a real 

concern, even though you’re dealing with the same chemical. 

Dr. SIEGEL. Absolutely. 

Mr. HUSSAIN. May I? 

Senator ALLARD. Yes. 

Mr. HUSSAIN. I think really the source is as critical and I think 

it does have to be addressed and it creates challenges to be addressed in different ways. But I think if you could consider from 

the progressive signs and technology, not only from the range of 

the source material, the characterization, the analytics, the manufacturing process but also consider the progress we are making in 

the science of understanding the biochemical—as well as understanding the mechanism for actions. It opens up a whole host of opportunities to design your clinical trials in different ways. FDA has 

a wonderful initiative called the Critical Path Initiative where they 

are looking at biomarkers and so forth. So if one looks at all the 

opportunities that are out there, you may have challenges in terms 

54 

of characterization but you have opportunities for better ways of 

defining safety and efficacy and so forth. So I think—I really believe you have an opportunity to really share this legislation that 

is open to the opportunities that we can bring to our patients. 

Senator ALLARD. Thank you. 

Senator CLINTON. Well, thank you very much and one thing I’m 

taking away from the hearing this morning is that there seems to 

be agreement that we can and should approach a pathway for follow-on biologics being very conscious of all of the difficulties that 

such a pathway presents. 

I know that in some of the back and forth with Senator Hatch, 

we were talking about some of the markers on that pathway and 

we’re speaking about the pre-approval clinical testing and I think 

Dr. Siegel said that he didn’t think the legislation we’ve introduced 

has adequate safeguards for the pre-clinical approval testing. Is 

that a fair characterization of what you said, Dr. Siegel? 

Dr. SIEGEL. I think one could better protect patients with legislation that made clear the need for clinical testing. 

Senator CLINTON. So that’s really—we agree that we have to 

have clinical testing and we obviously are looking for a way to 

make that part of the pathway. But I wanted to ask Dr. Hussain, 

who didn’t have a chance to respond to Senator Hatch on this, how 

do you assess scientifically the provisions in the legislation with respect to potential safety issues and the clinical testing approval 

process? 

Mr. HUSSAIN. Senator, I think from my perspective, aspects of 

comparability with the science-based includes aspects of clinical 

trials and so forth. So those are inherent in the proposed legislation. So that was my interpretation of that reading. Clearly I think 

there is possibly a need for a bit of a clarification because Dr. 

Siegel comes from CBER and I come from CDER and his office got 

moved into my office so that’s how we have interacted. I think from 

the CDER perspective, a far more kinetic study, a pharmacokinetic 

study, a pharmacodynamic study is not called a clinical study 

whereas I think it is called a clinical study. So I think there are 

different types of clinical studies and different aspects of clinical 

testing so I think clearly what we’re seeing is clinical assessment. 

There is the pharmacokinetic assessment or a pharmacodynamic 

assessment or a comparative clinical trial. I think which clinical 

trial is appropriate really depends on how well you have characterized the product and then determine what clinical trials uncertainty should be managed and what commitment would be necessary. So the best situation for that is FDA has the ability and 

for example, each applicant will provide the data that justifies 

what clinical pathway should be taken. So I think that flexibility 

needs to be there and I think nobody has said that there is no clinical trial. I think everybody is doing clinical trials. 

Dr. SIEGEL. I would add, though—I don’t think there is confusion 

around that term. Pharmacokinetic and pharmacodynamic testing—pharmacokinetic testing, at least, is going to be critical but I 

think not sufficient. One needs to look at immunogenicity, one 

needs to have some safety experience, one needs—and this will be 

most possible where there are good pharmacodynamic measures so 

55 

you can be sure that you have the same effects of the same drugs 

at the same dose, which is true for some biologics but not for all. 

Senator CLINTON. Well, I want to thank again all of our witnesses. The record will remain open for 10 days. A number of our 

members who wanted to get here could not make it. I want to 

thank Director Rossignol for being with us today. You’ve been extremely helpful in explaining the European Union approach and I 

also appreciate the way you characterized the legal authority 

versus the scientific consensus because I think that is something 

important to keep in mind, that we need to give the FDA authority 

and we need to empower them with adequate resources to begin to 

design this pathway and obviously, not everything is going to be 

ready or should go down together. We’re going to have be more discriminating but we should leave that to the scientists and to the 

structure that we try to establish. 

So again, I want to thank all the witnesses and we look forward 

to a very useful collaboration as we try to deal with some of these 

difficult issues confronting us. Thank you very much. The hearing 

is adjourned. 

[Additional material follows.] 

56 

1 CBO, ‘‘How Increased Competition from Generic Drugs Has Affected Prices and Returns in 

the Pharmaceutical Industry,’’ July 1998. 2 Emily Cox, Andy Behm, and Doug Mager, ‘‘2005 Generic Drug Usage Report,’’ Express 

Scripts, June 2006. Available online at http://www.express-scripts.com/ourcompany/news/ 

outcomesresearch/onlinepublications/study/genericDrugUsageReport2005.pdf. 3Statistics from the Generic Pharmaceutical Association (Available online at: http:// 

www.gphaonline.org/Content/NavigationMenu/AboutGenerics/Statistics/default.htm). 4Fortune 500 2006, ‘‘Most Profitable Industries: Return on Revenue,’’ April 17, 2006. 

5 Biotech Drugs Come of Age; Policymakers Take Note, Health Affairs, Sept./Oct. 2006 (report- ing that in 2005 revenues for biological drugs totaled $50.7 billion, an increase of 15.8 percent 

over 2004). 6 National Association of Realtors data, available at http://www.realtor.orq/research/ 

index.html (reporting the existing home median price was $210,000 in January 2007). 7 College Board, Trends in College Pricing 2006, available at http://www.collegeboard.com/ 

proddownloads/press/cost06/trendscollegepricing06.pdf (reporting that average total tuition 

and fees at a 4-year private college or university for the 2006–2007 academic year was $22,218). 

ADDITIONAL MATERIAL 

PREPARED STATEMENT OF AARP 

AARP appreciates the opportunity to present its views on the issue of follow-on 

biologics. AARP has endorsed the Access to Life-Saving Medicine Act (S. 623) because we believe this legislation will create a much needed pathway for the approval 

of safe, comparable, and interchangeable versions of biologics. We call on Congress 

to pass the legislation this year. 

The Drug Price Competition and Patent Restoration Act of 1984 (commonly 

known as Hatch-Waxman) provided for the approval of generic versions of brand 

name prescription drugs. As a result, today, generic prescription drugs save consumers and health care payers billions of dollars each year.1 Further, research has 

shown that billions more could be saved annually if the use of existing generics were 

optimized.2 Popularity of these lower cost alternatives continue to rise, to the point 

where approximately 56 percent of all prescriptions filled in the United States, more 

than one billion prescriptions every year, are lower cost generic prescription drugs.3

At the time Hatch-Waxman was enacted some critics claimed that the legislation 

would harm research and development of new prescription drugs and consumers 

would suffer because companies would no longer invest resources to find new cures. 

History has shown these critics wrong. The pharmaceutical industry hasn’t suffered—it is now the fifth most profitable industry in the country.4

Hatch-Waxman created an abbreviated pathway for the approval of generic drug 

applications and consumer and health care payors benefited. Now Congress has the 

opportunity to pass the Access to Life-Saving Medicines Act, which gives the Food 

and Drug Administration (FDA) the authority to approve generic versions of biologics. Once this legislation has been enacted, consumers and health care payers can 

begin to see savings on these life-saving medications. 

THE COST OF BIOLOGICS HURT CONSUMERS AND HEALTH CARE PAYORS

Biologics are used every day to treat diseases and conditions such as cancer, multiple sclerosis, anemia, and rheumatoid arthritis. These treatment therapies are, in 

many cases, truly cutting edge technology. Use of biologic drugs is increasing every 

year.5 Research and development into this vital field is growing—there are currently 

hundreds of applications in the pipeline. For example, for someone with rheumatoid 

arthritis it can make the difference between having the ability to walk and having 

to live with debilitating constant pain. 

While biologics hold great promise for treating some of the most serious diseases, 

these treatment regimens can be very expensive. Some treatments can cost tens of 

thousands of dollars per month or hundreds of thousands of dollars per year. For 

example, Epogen, a drug used to treat anemia, can cost as much as $10,000 per 

year. Cerezyne, used to treat Gaucher disease, can cost as much as $200,000 per 

year—which is almost as much as the average price of a home in January 2007.6

Similarly, a person diagnosed with colon cancer may have to use Avastin, which can 

cost $100,000 per year, which is more than the average cost of a 4-year college education.7

Some individuals are fortunate enough to have insurance and the means to be 

able to afford these medications. However many are not so lucky. For example, a 

few of the choices for an individual managing rheumatoid arthritis are biologics 

such as Embrel, Remicade, and Humira. These drugs are among the top 20 largest 

sales in the biologics industry. For an individual with no access to prescription drug 

57 

8Sales figures obtained from Lamerie Business Intelligence. 

9 Elise Wang, et al., A Global ‘‘Generic Biologics’’ Guidebook, Citigroup, Nov. 6, 2006, pg. 30. 10David J. Gross, Leigh Gross Purvis, and Stephen W. Schondelmeyer, Trends in Manufacturer Prices of Brand Name Prescription Drugs Used by Older Americans, 2006 Year-End Update, AARP Public Policy Institute Data Digest #DD154 (Washington, DC: AARP), March 2007 

(finding that on average, pharmaceutical manufacturer prices for the 193 brand name drugs 

most widely used by older Americans rose at nearly twice the rate of general inflation in 2006). 11PCMA, Potential Savings That Might Be Realized by the Medicare Program from the Enactment of Legislation such as the Access to Life-Savinq Medicines Act (H.R. 6257/S. 4016) That 

Establishes a New cBLA Pathway for Follow-on Biologics, available at http://www.theright 

prescription.org/learn/rx-resources.html, page 7. 12 In 1999 the global pharmaceutical market was approximately $331 billion, of which biologics represented less than 3 percent. In 2005, total pharmaceutical sales were roughly $602 

billion, of which biologics represented 7.6 percent. Id. at 4. 

coverage, they could choose between Embrel at $1,384.42 per month, Remicade at 

$598.97 per use, and Humira at $2,831.76 per month.8

The astronomical cost of these drugs not only impact consumers, but also health 

care payers, such as employers, private health care plans, and public programs such 

as Medicare and Medicaid. Indeed, spending on biologic drugs continues to outpace 

even that of traditional brand name prescription drugs,9 whose cost increases—at 

twice the level of inflation—are also too high.10 For instance, according to a recent 

study commissioned by the Pharmaceutical Care Management Association (PCMA), 

approximately 30 percent of Medicare’s Part B prescription drug spending is for only 

five biologic drugs.11 Sales for existing biologics continue to rise.12 One way to control these costs is to provide a pathway for the approval of generic versions of these 

products. 

LEGISLATION ENSURES SAFETY AND ACCESS

When brand name prescription drugs go off patent, a generic manufacturer can 

begin marketing its lower cost alternative after being approved by the FDA. However, no such pathway currently exists for biologics. Once these drugs go off patent, 

the manufacturers continue to reap the rewards of their patent long after its expiration and consumers continue to pay high prices. 

Although biologics are more complex than prescription drugs, this complexity is 

not a valid reason for preventing the development of generic versions. Technology 

has progressed to the point where biologics are better understood and characterized. 

As a result, it is now possible to create generic versions of these treatment therapies. 

The Access to Life-Saving Medicines Act grants FDA the authority to create a 

pathway for the generic approval of biologics. The legislation does not mandate that 

the FDA approve a certain number of applications—only that FDA provide for the 

pathway of approval. And the legislation leaves the scientific determinations up to 

those who are best equipped to address them. 

As the science advances, we can continue to expect prescription drugs to become 

an increasingly important component of health care, and for biologic drugs to become a larger component of drug spending. It is critical not only for individuals, but 

for all health payers—including Federal and State governments, employers and insurers—that we begin to take steps to lower the cost of these drugs. Use of generic 

alternatives is an important element towards the goal of holding down health care 

spending over time. Creating an FDA pathway to generic alternatives for biologics 

has become a necessary part of the equation as well. 

CONCLUSION

The Access to Life-Saving Medicines Act provides FDA the authority to produce 

a safe, comparable or interchangeable version of a biologic. The Hatch-Waxman Act 

created a similar pathway for prescription drugs. Twenty-three years later, the time 

has come for generic approval of biologics. Our members, and all Americans, need 

Congress to enact this bi-partisan legislation this year. We are pleased to see this 

committee and Members from both Houses of Congress and both sides of the aisle 

moving forward on this issue. 

PREPARED STATEMENT OF THE COALITION OF STATE RHEUMATOLOGY ORGANIZATIONS

BIOLOGIC AGENT GENERICS (‘‘BIO-SIMILARS’’)

The Coalition of State Rheumatology Organizations is a national organization 

composed of 26 State and regional professional rheumatology societies formed in 

order to advocate for excellence in rheumatologic care and to ensure access to the 

58 

highest quality care for patients with rheumatologic and musculoskeletal disease. 

Rheumatologists are entrusted with the safe care of patients with rheumatoid arthritis and other autoimmune diseases that require the careful choice of safe and 

effective medications. 

Rheumatologists are keenly aware of the dramatic long-term, life changing clinical 

improvements that biological agents have on some of the most crippling and disabling conditions that affect Americans. These biologic response modifying agents 

are available for the treatment of rheumatoid arthritis and other autoimmune diseases and have a significant impact on improving our patients’ quality of life, preventing disability, decreasing morbidity and lowering mortality. 

We are writing regarding H.R. 1038/S. 623 known as the Access to Life-Savings 

Medicine Act introduced by Senator Schumer, Senator Clinton, Congressman Waxman and others. This act attempts to establish a process by which the FDA will 

allow approval of lower cost copies (‘‘follow-ons’’) of biological treatments in the 

United States. We are particularly concerned with language in this legislation that 

would allow ‘‘. . . data demonstrating that the biologic product is COMPARABLE 

to the reference product’’ and allows ‘‘. . . data demonstrating that the biologic 

product and reference product contain SIMILAR principal molecular structural features notwithstanding MINOR DIFFERENCES in heterogeneity profile, impurities 

or degradation patterns.’’ We are concerned that this language does not recognize 

the unique complexities and difficulties inherent in the production of these biological 

medicines and the potential immunologic consequences of untested biologic agents 

that are not entirely similar. 

These powerful agents have significant effects on the body’s homeostatic immune 

function and can themselves be antigenic (can cause an immune response unique 

to the specific and unique structure). The immune response may vary with only 

minor differences between two very similar molecules. Even minor differences can 

cause a dramatic change in a molecules’ secondary and tertiary structure resulting 

in a protein with vastly different immune mediated reactions. Each patient’s response is unique and immune system dependent. These facts need to be considered 

in the approval process for generic biologic agents that are composed of complex proteins. There may be differences in effectiveness and a differential propensity to adverse reactions with even the subtlest alterations in primary, secondary or tertiary 

molecular structure. Adverse effects can include immunologic reactions to the medication, as well as potential long-term effects on the patient’s ability to fight infection 

and ability to maintain malignancy surveillance. 

The biologic protein molecules are produced by very complex manufacturing processes involving genetic engineering and living cell cultures that are currently required to meet precise and fastidious quality standards. Because of their protein nature, these agents are immunogenic requiring purity and consistency without a 

great degree of heterogeneity. Rheumatologists are just as familiar with the use of 

generic medications as other medical specialists. Generic medications are produced 

by organic chemistry processes and are currently required to comply with FDA reviewed efficacy and safety standards before marketing. The complexity of biologic 

medications and their effects demands that these standards are ever more important to maintain. 

We recognize that follow-on biologic products are a natural evolution of biotechnology and we welcome the introduction of these medications. However, we 

must insist that safety standards of these drugs be even more rigorous than those 

for standard oral small molecule medications. There must be a scientifically based 

and logical application of an open and rational review process in order to assure the 

safety of our patients while generating the greatest possible benefit. 

Unfortunately, the proposed legislation short-circuits the rational scientific process already in place and creates major concerns regarding safety and potential for 

immunogenic reactions as well as decreased efficacy. Abrogating the normal regulatory process that functions as a protective patient barrier will put all patients at 

risk of decreased efficacy, decreased quality and decreased safety. 

The development and use of biological response modifiers in the rheumatologic 

therapeutics is relatively young. Significant unknowns and issues remain in using 

agents affecting the immune system. The current legislation could have unintended 

consequences with resultant increased patient risk. A process for evaluation of follow-on biologics should not deem minor the significant potential clinical problems 

related to increased heterogeneity, impurities, degradation patterns, amino acid sequences and immunogenicity related to secondary and tertiary molecular structure 

in the realm of ‘‘comparable biologics.’’ These agents must be subject to careful scrutiny and scientific investigation before approval. A responsible regulatory process 

needs to examine all of the structural and functional features of the protein product 

with particular emphasis on differences relative to those currently manufactured 

59 

and currently approved. Product safety must be comprehensively examined before 

exposing patients to these very powerful immunologic agents. 

Several examples of problems currently exist that illustrate potential problems. 

Products have been withdrawn from the market due to subtle differences in protein 

structure such as L-tryptophan, thrombopoetin and colony stimulating factors. Pure 

red blood cell aplasia has been linked to an erythropoietin ‘‘biosimilar’’ medication 

after it was introduced in over 90 countries. One case occurred in every 5,000 patients exposed and required a great deal of investigation before the cause was ultimately defined. In rheumatology, we have seen a variety of patient adverse reactions to the three different TNF alpha blockers currently available. There can also 

be significant differences in individual clinical responsiveness to one anti TNF agent 

as opposed to another. 

Sponsors of the current legislation point to the European Union as having established a regulatory pathway for the approval of follow-on biologics. However, the 

regulations instituted by the European Medicines Evaluation Agency (EMEA) are 

proceeding with a clear, proper and cautious regard for patient safety and we applaud this approach. 

We welcome the introduction of a responsible regulatory process for the development of safe follow-on biologics. We support their development, as it will improve 

the access to care for more patients with most serious rheumatic diseases. However, 

this pathway must assure the safety and efficacy of these agents before their widespread or even limited use. We would be more than happy to work with you or participate in the development of a logical, open and rational process. 

INTERAMERICAN COLLEGE OF PHYSICIANS & SURGEONS, 

WASHINGTON, DC. 20006, 

February 20, 2007. 

DEAR CONGRESSMAN: The Interamerican College of Physicians and Surgeons was 

founded in 1979 to promote cooperation among U.S. Hispanic physicians and to advance their professional and educational needs. The ICPS reaches a vast majority 

of the Hispanic medical community in the United States and Puerto Rico—over 

39,000 physicians—and a growing number of health professionals in Mexico, the 

Caribbean, Central and South American and Spain. The ICPS is the largest association of Hispanic physicians in the Nation. 

The ICPS has serious concerns about the Waxman/Clinton ‘‘Access to Life-Savings 

Medicines Act’’ introduced on February 14, 2007. As physicians, we rely on the FDA 

gold standard to ensure the safety of the treatments we prescribe for out patients. 

This legislation ties FDA’s hands in being able to provide physicians and patients 

with assurance that ‘‘follow-on’’ biologic medicines have been tested in order for us 

to know the safety profile of these treatments. All patients are not the same, and 

minority populations do not always respond to treatments in the same manner as 

other patients. Without mandatory testing, we, as physicians would be putting our 

patients at risk. In this environment of heightened discussion of drug safety, this 

legislation is, in our estimation, all risk and no benefit. 

We would welcome the opportunity to further discuss our concerns and work toward legislation which accomplishes safety and savings for all patients. 

Thank you. 

Sincerely, 

RENE F. RODRIGUEZ, 

President. 

THE AMYOTROPHIC LATERAL SCLEROSIS ASSOCIATION, 

WASHINGTON, DC. 20004, 

February 23, 2007. 

Hon. HENRY WAXMAN, 

U.S. House of Representatives, 

Washington, DC. 20515. 

DEAR CHAIRMAN WAXMAN: The ALS Association appreciates your efforts to reduce 

the cost of biologics and to increase access to these potentially life-saving treatments. As you may know, biologics show great promise in the treatment of ALS, 

or Lou Gehrig’s disease, and we strongly believe that patients must have timely access to treatment options that can save lives and improve quality of life. However, 

we are concerned about the potential impact of the ‘‘Access to Life-Saving Medicine 

Act.’’ While we are in the process of evaluating the full implications of the legislaVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00063 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
60 

tion for people with ALS, we are strongly opposed to any effort that attempts to attach the legislation to the reauthorization of the Prescription Drug User Fee Act 

(PDUFA). 

The ALS Association is the only national voluntary health organization dedicated 

solely to finding a treatment and cure for amyotrophic lateral sclerosis (ALS). More 

commonly known as Lou Gehrig’s disease, ALS is a progressive neurodegenerative 

disease that erodes a person’s ability to control muscle movement. As the disease 

advances, people lose the ability to walk, move their arms, talk and even breathe, 

yet their minds remain sharp; aware of the limitations ALS has imposed on their 

lives, but powerless to do anything about it. They become trapped inside a body they 

no longer can control. 

There is no cure for ALS. In fact, it is fatal within an average of 2 to 5 years 

from the time of diagnosis. Moreover, there currently is only one drug available to 

treat the disease. Unfortunately, that drug, Rilutek, originally approved by the FDA 

in 1995 has shown only limited effects, prolonging life in some patients by just a 

few months. 

The hopes of people with ALS—those living today and those yet to be diagnosed— 

are that medical science will develop and make available new treatments for the 

disease; treatments that will improve and save their lives. Advances in biotechnology and the development of biologics present the ALS community with new 

opportunities to bring treatments from the lab to the bedside. While reducing the 

cost of biologics and other drugs is an important goal, policymakers must be mindful 

of potential unintended consequences. As we continue our evaluation of the Access 

to Life-Saving Medicine Act, we will share with you our views on the legislation. 

In the meantime, we urge you and your colleagues not to include the legislation as 

part of the reauthorization of PDUFA. 

It is absolutely critical that Congress act promptly to reauthorize PDUFA and 

provide the FDA with the resources it needs to facilitate the development and availability of treatments for diseases like ALS. We fear that attempts to add issues such 

as the Access to Life-Saving Medicine Act will only delay PDUFA reauthorization 

to the detriment of patients. 

The ALS Association appreciates your attention to our concerns and for your previous strong support of our cause and your constituents living with ALS. We look 

forward to working with you and your staff on these and other issues as the 110th 

Congress moves forward. 

Sincerely, 

STEVE GIBSON, 

Vice President, 

Government Relations and Public Affairs. 

SOCIETY FOR WOMEN’S HEALTH RESEARCH, 

March 2, 2007. 

Hon. HENRY WAXMAN, 

House of Representatives, 

Washington, DC. 20515. 

DEAR MR. WAXMAN: On behalf of the Society for Women’s Health Research, we 

are writing to you to express our thoughts and concerns regarding your recently introduced legislation H.R. 1038, ‘‘Access to Life-Saving Medicine Act.’’ While we commend the legislation’s intentions to increase access to and reduce biological medicine 

costs through encouraged development of ‘‘follow-on’’ biological drugs (also known as 

biotech drugs or biopharmaceuticals), we are concerned about patient safety and feel 

it is important that such products meet appropriate ‘‘equivalency’’ standards. Since 

biological products are considered unique and any slight difference from the original 

product could have significant consequences for different populations, the Society believes that additional clinical testing should be required where appropriate. 

The Society for Women’s Health Research is the Nation’s only non-profit organization whose mission is to improve the health of all women through research, education and advocacy. Founded in 1990, the Society brought to national attention the 

need for the appropriate inclusion of women in major medical research studies and 

the need for more information about conditions affecting women disproportionately, 

predominately, or differently than men. 

The Society has long advocated for increased funding for research on women’s 

health and encourages the study of sex differences that may affect the prevention, 

diagnosis and treatment of disease. Differences between the sexes exist, and whether a person is male or female matters in the prevalence and severity of a broad 

61 

range of diseases, disorders, and conditions. It matters at every stage of life—from 

the very beginning to the very end. It matters at every level—from the single cell 

to the entire body. 

Science has shown us that even small differences can have enormous impacts on 

different populations, such as women and minorities. Such differences will exist in 

biologic products and therefore, follow-on biologics. It is imperative that these differences be studied and known through clinical testing as it is the only means to 

assure the safety profile of each product. 

The Society recommends greater discussion of these issues as well as consideration and open discussion on what determinations the Europeans made in establishing their requirements for follow-on biologics. Only through an open forum with 

the input from scientists, physicians and those of us who represent the concerns of 

patients can we appropriately address this important issue. 

Sincerely, 

PHYLLIS GREENBERGER, 

President. 

MARTHA NOLAN, 

Vice President of Public Policy. 

BIOTECHNOLOGY INDUSTRY ORGANIZATION (BIO), 

WASHINGTON, DC., 

March 8, 2007. 

Hon. EDWARD M. KENNEDY, 

Chairman, 

Committee on Health, Education, Labor, and Pensions, 

U.S. Senate, 

Washington, DC. 20510. 

Hon. MICHAEL B. ENZI, 

Ranking Member, 

Committee on Health, Education, Labor, and Pensions, 

U.S. Senate, 

Washington, DC. 20510. 

DEAR CHAIRMAN KENNEDY AND RANKING MEMBER ENZI: The Biotechnology Industry Organization requests the submission of this letter to the record of your March 

8, 2007 hearing, to highlight our concerns about pending legislation to establish a 

mechanism for FDA approval of so-called ‘‘comparable’’ biological products. In particular, we urge that the committee not rush to complete action on legislation in this 

area to meet a compressed deadline that does not allow Senators to give this important and complex topic the deliberative consideration it deserves. 

The members of the Biotechnology Industry Organization work on the forefront 

of medical advancement, developing innovative biological products that have revolutionized the treatment of diseases, including cancer, heart disease, infections, arthritis, and multiple sclerosis. In order to ensure a future of continued innovation by 

the biotechnology industry, it is essential that your discussions on developing an approval process for follow-on biological products be driven by responsible science, 

with a focus on protecting patient safety and preserving incentives to innovate. 

BIO agrees with and supports the written testimony provided by Dr. Jay Siegel, 

Group President of Research and Development for Biotechnology, Immunology, and 

Oncology for Johnson & Johnson—a member company of BIO. The safety issues 

alone raised by this testimony argue for careful, deliberate consideration of any follow-on biologics pathway by the Congress. 

In addition to ensuring patient safety, any follow-on biologics pathway created by 

the Congress must preserve incentives for research and innovation by ensuring protections for intellectual property and providing data exclusivity for innovative therapies and cures. 

Unfortunately, the Access to Life-Saving Medicines Act (S. 623), which proposes 

to create such a pathway, is deeply flawed in all three respects. As Dr. Siegel’s testimony powerfully explains, this bill would jeopardize patient safety in numerous 

ways. 

Further, contrary to its title, the bill would eviscerate incentives to develop lifesaving new medicines through its one-sided alteration of long-standing patent law 

in ways that favor follow-on biologics manufacturers, who would be able to restrict 

and infringe the intellectual property rights of various parties including innovative 

biotechnology companies. S. 623 also should be opposed for its lack of data excluVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00065 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
62 

sivity for innovative biologics. Data exclusivity provisions have served as an incentive for innovation under Hatch-Waxman and are part of the European system for 

regulating ‘‘biosimilars’’ (i.e., follow-on biologics). The legislation contains no prohibition on the FDA approving a follow-on product relying on innovator data immediately following approval of the reference product. Devaluing property rights and 

the absence of data exclusivity disincentivizes the necessary investment for a strong, 

vibrant pioneer biologic industry, upon which any follow-on market wholly depends. 

In addition, we urge Congress to consider action relating to establishing a statutory pathway for approving follow-on biologics independent of the reauthorization of 

the Prescription Drug User Fee Act (PDUFA). Before a framework for follow-on biologics can be established, Congress must carefully consider and resolve complex scientific, legal, and economic issues. Meanwhile, it is important that Congress complete the PDUFA reauthorization in a timely manner and as a top priority. Although PDUFA formally expires on September 30, 2007, reauthorization needs to 

occur earlier this year to avoid potential delays in review of innovative new medicines. Attaching follow-on biologics legislation to PDUFA would potentially jeopardize reauthorization of the user fee program to the detriment of patients waiting 

for new therapies, FDA’s internal scientific capabilities, and biomedical innovation. 

BIO represents more than 1,100 biotechnology companies, academic institutions, 

State biotechnology centers and related organizations across the United States and 

31 other nations. On behalf of our members, we appreciate your consideration of our 

views and look forward to a continuing dialogue on this important topic. 

Sincerely, 

JAMES C. GREENWOOD, 

President and CEO. 

RESPONSE TO QUESTIONS OF SENATORS KENNEDY, ENZI, BINGAMAN, AND BURR

BY JAY P. SIEGEL, M.D. 

QUESTIONS OF SENATOR KENNEDY

Question 1. Dr. Siegel, do you think it is possible for a manufacturer to present 

a data package that would justify FDA saying a follow-on product is interchangeable? 

Answer 1. Given the limits of technology, it is not possible for a manufacturer to 

present a data package capable of scientifically justifying any claim or determination of a follow-on product to be interchangeable with its reference product. Laboratory testing has the potential, in some cases, to demonstrate a high degree of similarity. Such a demonstration could, in some cases, allow a determination of the safety and efficacy of a follow-on biologic based on a more limited clinical data set than 

would be required of an entirely novel molecule. I believe, however, there is no technically or practically feasible data package that could support a claim of interchangeability while ensuring patient safety. 

Follow-on biologics are, by definition, different products, and the potential for 

clinically important differences from the reference product exist. As I testified, it 

would take testing in several thousands of patients to ensure that the serious adverse events rate had not doubled from 1 percent to 2 percent. Testing simply cannot establish that clinical effects will be identical; inadvertent switching of a patient 

doing well on one medication to a different, though similar medication will run the 

risk of an adverse change with regard to clinical response. 

Even if the testing profiles of two products appeared essentially identical, inadvertent substitution pursuant to a designation of interchangeability could subject 

patients to additional risks. For example, if the risk of immunogenicity for patients 

exposed to a reference product is 5 percent, and for patients exposed to a 

follow-on biologic is also 5 percent, given the various factors that can lead to 

immunogenicity, the risk of immunogenicity in patients switched between the products could well be 10 percent, even if the two drugs were established to have equal 

efficacy profiles. 

A designation of interchangeability for products with potential differences, and 

the resultant switching of patients, could significantly impair the ability of 

pharmacovigilance (i.e., drug safety and surveillance) systems to limit the risks associated with emerging safety problems. If an adverse event occurred, it could be 

difficult or impossible to determine which ‘‘interchangeable’’ product was responsible. This could both delay detection of a new problem and impair ability to correctly identify the source of the problem. 

As with any other biologic with activities similar to those of another product, e.g., 

the various interferons alfa, antibodies to tumor necrosis factor, and erythropoietins, 

63 

follow-on biologics that have been found to be safe and effective should be administered only with the full knowledge and consent of the patient and the treating physician regarding which product is being given. Follow-on biologics policy should both 

limit the possibility of substitution without a physician’s knowledge and support 

good pharmacovigilance through labeling and naming. 

Question 2. Dr. Siegel, doesn’t the FDA already make a finding of interchangeability every time it approves a manufacturing change? For instance, if a manufacturer were to change a cell line the FDA does not require that the manufacturer 

change the label or inform consumers that such a change has taken place. 

Answer 2. Manufacturing changes for an existing product do not pose the same 

risks I discussed above with regard to interchangeability for follow-on biologics. 

There are two reasons this is the case: 

• First, in the case of manufacturing changes, the risk of being unable to track 

which product is accountable for an adverse event and the risk of patients being exposed to additional dangers by being switched between two products are both minimized because there is a limited period in which the pre- and post-change product 

co-exist on the market. Indeed, in my experience, when there is a change that raises 

concerns about a possible change in profile, FDA will ask that the period of overlap 

in the market be minimized. In contrast, follow-on biologics would often co-exist in 

the market with the reference product and possibly other follow-ons for extended periods. 

• Second, the extent of changes, and therefore the risks of undetectable but meaningful differences, with a follow-on biologic are quite high compared with those typical of a biologic undergoing a manufacturing change. The manufacture of a followon biologic will typically entail simultaneous, substantial changes to many key aspects of manufacturing—including changes in cell line, many aspects of the manufacturing process, and facility. While these changes are unavoidable for follow-on 

manufacturers, manufacturers of an approved product, understanding the risks of 

comparability determinations, are extremely cautious about attempting any of these 

changes and would be extremely ill-advised to propose multiple simultaneous 

changes this radical. 

The risk of clinical differences inherent in such extensive changes is further substantially increased in the case of follow-on biologics since the follow-on manufacturer, unlike the innovator, has limited or no access to intermediaries and to the 

extensive knowledge of the product and its manufacturing process that make it possible for innovator companies to assess and avoid the risk of clinically important 

changes to their products. 

Let me explain this point further: When a manufacturer of a biologic that has already been marketed and/or extensively studied, makes substantial changes in its 

manufacturing process, that manufacturer is able to compare not only final product 

but also various components and intermediates that are produced during various 

stages of both the new and old manufacturing process. For example, depending on 

the changes made, comparisons might be made of the unpurified biologic (made by 

the old and new processes), and/or of purified product prior to formulation. This 

testing is very important because it may detect the presence of new variants or contaminants that, after purification and/or formulation, may be reduced or masked 

such that they are still present but undetectable in final product. 

Manufacturers of follow-on biologics will not have any of the components and intermediate materials for testing and will have access only to the final, marketed reference product. 

Additionally, optimal comparisons of ‘‘before change’’ and ‘‘after change’’ materials 

require an understanding of which parameters are key to ensuring the safety and 

efficacy of the molecule and what the best approaches to assessing them are. This 

understanding comes from years of working with the reference product and is not 

available to manufacturers of follow-on biologics. Further, when differences are detected, the key question becomes whether the difference is clinically important. 

While manufacturers of innovative products have extensive experience that sometimes helps address this question, the manufacturer of a newly developed follow-on 

biologic will have limited experience with the molecule. 

Because the manufacture of a follow-on product will necessarily entail drastic 

changes to the process absent in-process materials, comparative testing capabilities 

and knowledge, it is inapposite to attempt to equate FDA standards for changes to 

the manufacture of an innovator product—as stringent as those standards are—with 

what can or should be the standards for follow-on biologics. 

64 

QUESTIONS OF SENATOR ENZI

Question 1. The Intellectual Property provisions in the Clinton-Schumer bill have 

been described as unbalanced by some. Do you think this is a fair criticism? If this 

law was in place, how would it change your investments that you make in research 

and development? 

Answer 1. As I stated in my testimony, it is critical that any pathway for followon biologics provide appropriate incentives for innovation so that the promise of new 

and innovative biologic therapies can continue to be realized for patients for generations to come. 

In my current position as Group President of Research & Development for Biotechnology, Immunology and Oncology for the Johnson & Johnson Family of Companies, I experience first hand the issues presented by the enormous effort and investment it takes to bring a new biological entity to the market through the regulatory 

approval process. Only a small portion of potential drug candidates reach human 

trial phase and only a small portion of those drugs actually reach the market. And 

it has been demonstrated that well over $1 billion in research and development is 

spent for each new drug brought to market (Source: Tufts Center for the Study of 

Drug Development Impact Report, Vol. 8, No. 6 November/December 2006). 

Thus, the high cost of drug development and the uncertainty associated with the 

outcome of pre-clinical and clinical trials necessary for marketing approval makes 

investment in this area an extremely costly and risky business. While we are committed and dedicated to developing new therapies to address unmet medical needs, 

this risky and costly drug development can occur only when there is both a sound 

scientific case and a sound business case to support the programs. 

In the face of this, S. 623 would provide a pathway for the abbreviated approval 

of follow-on biologics that relies heavily on the investment made by the innovator 

company, with no provisions to ensure that the innovator of a biological product will 

be able to recoup the enormous investment made before facing competition from follow-on manufacturers. Unlike the 1984 Hatch-Waxman Act, which sought to balance the goal of facilitating the rapid introduction of lower-cost generic drugs with 

the goal of promoting innovation in the pharmaceutical industry, S. 623 includes little or nothing to promote innovation in the industry. 

It may be asserted that no such provisions protecting innovation are necessary because the innovator can rely on its patents to protect the product from competition 

for a sufficient period of time to recoup the investment and promote innovation. 

However, as we have seen from the patent litigation that has ensued as a result 

of the 1984 Hatch-Waxman Act, patents alone are an imperfect and highly uncertain system upon which to rely for market exclusivity for pharmaceuticals. 

The ability to rely on patents for protection of innovation will be even more limited for biologics. The patent system governing the acquisition and enforceability of 

biological patents is generally moving towards the issuance of patents with increasingly narrow claims. Additionally, many biologics are imperfectly protected only by 

process patents that may be ‘‘designed-around’’ by an alteration of the process that 

avoids infringement. But proposed follow-on biologics legislation, including S. 623, 

will allow for approval of follow-on biologics that are ‘‘similar’’ but not ‘‘identical’’ 

to the innovator product. Particularly with the broad range of differences allowed 

under the definitions of ‘‘highly similar’’ in S. 623 (e.g., even allowing the follow-on 

biologic to have a different amino acid sequence of the product), there will be ample 

opportunities for follow-on biologics to ‘‘design-around’’ the typical patents protecting 

a biologic. 

Thus, under a statutory scheme such as that outlined in S. 623, a follow-on 

version could be similar enough to an innovator product for the purposes of regulatory approval, but different enough to avoid patent infringement. The combined 

effect of these forces could reduce effective market protection for innovator products 

that, in turn, could stifle the environment for investment in the development of new 

biologic medicines. There is no doubt that this would impact development decisions. 

While I do not claim to be an expert in pharmaceutical intellectual property litigation, experts in Johnson & Johnson inform me that S. 623 contains a number of provisions which would actually weaken the ability of innovators to enforce what patents they are able to obtain. For instance, the bill would restrict the innovator’s 

ability to bring a patent infringement suit against an infringer unless they identify 

all of their patents in a timely manner, and then the suit may be brought only in 

the judicial district in which the infringer consents, thus depriving the innovator the 

ability to bring suit in the judicial forum of its choosing. Further, unlike the 1984 

Hatch-Waxman Act, there is no stay of the regulatory approval of the follow-on biologic when a patent infringement suit is filed. Finally, if certain conditions are not 

met by the innovator, in some cases the innovator may only recover a ‘‘reasonable 

65 

royalty’’ in a patent infringement action, a provision which amounts to a compulsory 

license for the follow-on biologic; in other cases, the innovator is prevented from 

bringing an infringement suit at all. 

We would be pleased to offer input as you consider the important question of incentives for innovation as you examine legislative approaches to follow-on biologics. 

Question 2. Johnson & Johnson operates in Europe. Are you satisfied with the 

process that the Europeans have created to license follow-on products? 

Answer 2. We are fortunate that the EU has already made substantial progress 

in developing and implementing a policy based on science and public health. While 

the United States should have a policy that is designed for our own regulatory, 

legal, and healthcare environment, there are many aspects of the EU process and 

policy that are admirable. 

EU legislation clearly distinguished a ‘‘biosimilar’’ (the term they use for a followon biologic) from a ‘‘generic,’’ acknowledging the differences between products containing small synthetic molecules and those based on biotechnology-derived proteins 

produced by living cells. The quote below from the EMEA guideline on biosimilar 

products (CHMP/437/04) provides a good summary of the philosophy underlying the 

EMEA’s position on biosimilars (follow-on biologics). 

‘‘It should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there 

may be subtle differences between similar biological medicinal products from 

different manufacturers or compared with reference products, which may not be 

fully apparent until greater experience in their use has been established. Therefore, in order to support pharmacovigilance monitoring, the specific medicinal 

product given to the patient should be clearly identified.’’ 

The EU legislation did not attempt to define the scientific standards for approval 

of biosimilars; it entrusted that task to the EMEA, the science-based body responsible for approving the marketing of drugs in the EU. The EMEA pursued a sciencebased, transparent and open process in which all parties were invited to offer input 

to establish concept papers and draft guidances, starting with basic principles for 

all biosimilars. This was followed by more specific guidances with testing requirements by product groups. The EU requirements allow for abbreviations in testing 

where science and safety permit, but clinical testing, immunogenicity testing, and 

post-marketing safety surveillance are recognized as important to minimize the risk 

to patients and are critical parts of the EU approach. 

The European Union rightly acknowledged in its own process of developing a 

pathway for follow-on biologics that follow-ons can be similar, but never identical 

to an innovator biologic. 

Specific legislation with regard to interchangeability has been left to Member 

States and several weeks ago (Feb. 18), the French parliament adopted legislation 

to prevent follow-on biologics from being treated in the same way as traditional 

generics and banned the automatic substitution of one biologic medicine for another. 

Johnson & Johnson is pleased with, and participated in, the open and transparent 

process used in Europe to determine the testing standards for follow-on biologics 

that are truly highly similar to a reference product. We should be able to leverage 

that work to have a frank, transparent and scientific debate here in the United 

States, and thereby develop a model that will be compatible with our own regulatory 

and healthcare environment. 

Question 3. If there is general agreement that an abbreviated pathway for biologics is appropriate, why shouldn’t we just modify the Clinton-Schumer bill to address the identified concerns instead of creating new legislation? 

Answer 3. Johnson & Johnson fully supports efforts to identify a pathway for follow-on biologics. As I indicated in my testimony at the Senate HELP hearing on 

March 8, this pathway should be science-based, with paramount attention to patient 

safety and well-being. To that end, there are a number of principles critical to address in any abbreviated system for follow-on products. Four of these principles are: 

(1) There will always be a need for appropriate pre-marketing testing in humans 

to ensure that a follow-on biologic is safe and effective; (2) A follow-on product 

should be highly similar to its reference product and as similar as is achievable— 

there need not and should not be allowance for determinations of ‘‘comparability’’ 

for products that are unnecessarily different or so different in structure that they 

should be considered different products entirely; (3) A follow-on product should not 

be considered interchangeable with its reference product; (4) FDA must be fully empowered to require effective post-marketing safety surveillance, to seek commitments for post-marketing clinical studies, and to request data and studies in support of sound scientific decisions without constraints. 

66 

In addition to reflecting an overriding concern for patient safety and well-being, 

any legislation for follow-on biologics should ensure a science-based, open and transparent process allowing broad-based expert input into the establishment of testing 

standards. Importantly, it should also provide incentives for innovation so the promise of new and innovative biologic therapies can continue to be realized for patients. 

The principles enumerated above, the need for incentives for innovation, and the 

establishment of an open and transparent process for the creation of testing standards should be critical elements of the foundation and starting place for any proposed legislation for follow-on biologic products. S. 623 is not based on these principles, provides no incentives for innovation, and does not encourage or even suggest 

an open process. Therefore, S. 623 should not be used as a starting place for followon biologic legislation. 

QUESTIONS OF SENATOR BINGAMAN

Question 1. To address the issues around substitution of one biologic for another, 

how would you recommend that data be obtained in the post-market period to assure safety of both the innovator compound and the follow-on (or biosimilar)? Please 

discuss pros and cons of each potential stakeholder contributing to the data gathering process: manufacturer, third party payer, prescribing health professional, patient, regulatory agency. 

Answer 1. Because a follow-on biologic cannot be established to be identical to the 

reference innovator product, interchangeability should not be permitted. This has 

been recognized in the European Union. Unless there are clinically important reasons for making a deliberate choice to substitute one biologic for another, substitution as we generally understand it should be avoided. 

Appropriate pharmacovigilance (post-marketing safety surveillance) requires that 

the causative product for an adverse event be identifiable to the greatest extent possible. To achieve this end, patients and prescribing health professionals should be 

aware of precisely which biologic the patient is taking. Switching between therapies 

should be carried out only when there are clinically important reasons and with full 

knowledge of the patient and physician. Follow-on biologic policy should optimize 

the ability to identify the product actually received through approaches such as 

naming, labeling, and physician and patient education. 

As part of reviewing the application for a follow-on biologic, just as for any other 

biologic, FDA should determine what studies should be performed in the post-marketing period to address outstanding questions. This determination will depend on 

the information provided about the molecule and its clinical effects in the application, upon knowledge about other molecules in the class, and upon a determination 

of what information should be required pre-marketing. 

It is important to recognize that the prohibition in S. 623 against FDA requesting 

any post-marketing studies of the follow-on biologic other than those requested of 

the innovator is scientifically problematic. Data in the follow-on application (e.g., 

presence of a trace contaminant, weak signals of a possible toxicity based on lab 

findings, suboptimal clinical data addressing a safety concern) may point toward the 

importance of specific post-marketing studies for the follow-on product. Knowledge 

emerging since the approval of the innovator may raise key questions already addressed by years of experience with the innovator that need to be addressed for the 

follow-on biologic. 

To ensure good pharmacovigilance for any biologic, patients should be encouraged 

to report possible adverse events to their healthcare provider and physicians should 

be encouraged to report appropriately to the FDA and manufacturer. In addition, 

all manufacturers should be required to have in place systems for the ongoing collection and evaluation of post-marketing data as a method for detecting risks across 

the product lifecycle. The specific range of programs for the collection of post-marketing data can range from prospective trials, epidemiologic studies, registries, or 

simply post-marketing surveillance. 

Question 2. Can you propose a possible mechanism for communicating to stakeholders (above) during the process of post-market surveillance? Would different information go to different stakeholders at different times, or would all the information be equally accessible to all stakeholders? 

Answer 2. Health care professionals and others who become aware of possible new 

safety concerns should report new safety information to the FDA and drug sponsors/ 

manufacturers in a timely manner. In most cases, post-marketing safety information will not result in the need to urgently communicate new safety information, 

and in these cases, periodic reporting of specific data from surveillance programs 

and appropriate studies should occur in a timely fashion at a frequency agreed between the manufacturer and FDA prior to approval. This ‘‘raw’’ data should be subVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00070 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
67 

ject to expert evaluation before further dissemination. Dissemination of such raw 

data to recipients not equipped to evaluate its significance and place it in context 

could inadvertently cause unwarranted concern or result in inappropriate cessation 

of life-saving or enhancing therapy. 

After evaluation, new information that adds significantly to understanding the expected effects of a drug should be further distributed to all stakeholders, including 

patients. However, it is critical that information to patients be balanced and delivered in the context of the needs of and alternatives for the individual patient. This 

is typically best done by the informed health care professional. 

QUESTIONS OF SENATOR BURR

Question 1. Do you support the Clinton-Schumer bill in its entirety? 

Answer 1. As I indicated in my testimony at the Senate HELP hearing on March 

8, Johnson & Johnson does not support S. 623—not in its entirety and not as a 

starting place for follow-on biologics legislation. Any legislation for follow-on biologics should be based on well-grounded science, with paramount attention to patient safety and well-being. In addition to an overriding concern for patient safety, 

any legislation for follow-on biologics should provide incentives for innovation so 

that the promise of new and innovative biologic therapies can continue to be realized for patients for generations to come, and should encourage an open and transparent process to establish testing standards that ensure the safety and effectiveness for this new category of products. Unfortunately, S. 623 does not reflect these 

principles. 

What follows is a brief outline of areas I consider most problematic: 

• S. 623 fails to provide important clarity pertaining to a requirement for 

pre-marketing clinical data to ensure that a follow-on biologic is safe and 

effective. 

• Extensive experience confirms that manufacturing differences such as those 

between the manufacturing processes for a reference innovator product and 

those for a follow-on biologic are likely to lead to differences in product safety 

or efficacy. Not infrequently, these will be detected best or only in clinical 

testing. 

• As a rule, and as experience has made clear, clinical studies must be considered a necessary and mandatory part of properly evaluating any and all biologic products and should be a fundamental piece of any proposed regulatory 

pathway for the approval of follow-on biologics. 

• FDA requires that innovators conduct clinical testing after major manufacturing changes before marketing product made by the new process. American 

consumers have been protected from major clinical risks to date as a result 

and will continue to be so protected only if follow-on biologics are required 

to undergo appropriate clinical testing. 

• S. 623 allows for determinations of ‘‘comparability’’ for products that 

are so different in structure that they should be considered different products entirely. 

• There is no scientific basis for allowing abbreviated testing of a new biologic 

on the basis of it being only distantly related to an existing one. Some differences are so substantial that the biologics should be considered different 

products entirely. 

• S. 623 allows a molecule to be considered ‘‘to contain highly similar principal 

structural features’’ even if it contains ‘‘minor differences in amino acid sequence’’ or differences ‘‘due solely to post-translational modifications.’’ Differences in even just one amino acid and many types of differences due to 

post-translational modifications can have devastating effects on the function 

of a protein. Such differences scientifically define the product as a different 

product and provide no scientific basis for abbreviating the data requirements 

to demonstrate safety and efficacy. 

• Due to the inability to make an identical biologic, follow-on policy will necessarily go beyond generics policy in allowing abbreviated testing for products 

whose active ingredients are highly similar (as opposed to equivalent as with 

generics). S. 623 unnecessarily goes much further allowing abbreviated applications for products that are intentionally and/or avoidably different from a 

reference. There is no need justifying the risks incumbent in such a policy. 

• S. 623 would also allow ‘‘closely related, complex, partly definable biological 

products with similar therapeutic intent’’ (for example, two live viral products 

for the same indication) to be considered ‘‘highly similar.’’ This provision inapVerDate Aug 31 2005 11:52 Sep 17, 2008 Jkt 000000 PO 00000 Frm 00071 Fmt 6633 Sfmt 6621 S:\DOCS\34053.TXT SLABOR1 PsN: DENISE
68 

propriately allows abbreviated applications for living cells and organisms and 

other biologic products far more complex and difficult to define than proteins. 

• Even after drawing extremely broad boundaries around what types of differences (and what types of products) would fall within the scope of comparability determinations and abbreviated applications, S. 623 undermines 

even those boundaries. It gives the Secretary leeway to determine any two biological products ‘‘to contain highly similar principal molecular structure’’ regardless of known or indeterminate differences. So in essence, S. 623 places 

no limit on the types of physical and chemical differences that might be considered minor enough to permit a demonstration of comparability and an abbreviated application. 

• Allowing products with avoidable structural differences from a reference to be 

deemed comparable is not only unnecessary (as the differences are avoidable), 

and risky (the presence of such differences leaves little or no basis for abbreviated testing), it also discourages innovation by allowing follow-ons to design 

around patents and undermine the incentives for innovation. 

• S. 623 allows a follow-on product to receive a determination of interchangeability with its reference product, a scientifically unsound proposition that presents serious challenges to pharmacovigilance systems and 

patient safety. 

• From the standpoints of science, clear communication, and public safety, 

interchangeability is not an appropriate designation for follow-on biologics. 

• Unfortunately, not only is interchangeability for follow-on biologics included 

in S. 623, the statutory test for interchangeability is completely open-ended. 

As written, this statutory test could be used to determine that two drugs are 

interchangeable even if they do not contain the same active ingredient. This 

is entirely at odds with the concept of ‘‘therapeutic equivalence’’ that has been 

applied to small molecule drugs and which requires a finding of the same active ingredient, same dosage form and dose, and bioequivalence. 

• If the designation of interchangeability leads to substantial numbers of patients switching between therapies, it could severely impair the ability of 

pharmacovigilance systems to deal with emerging safety problems. When a 

new adverse event emerges or a known one increases in frequency, it may be 

impossible to attribute the adverse event to a specific product if patients experiencing the event have received multiple products. This is especially the 

case for some types of adverse events, such as those due to immunogenicity, 

that tend to arise in patients well after receiving the causative product. 

• S. 623 places limitations on FDA’s ability to require post-marketing 

studies that might be critical to ensuring safety, and is silent on post-marketing surveillance. 

• Follow-on biologics will raise safety concerns—such as differences in 

immunogenicity profile or emergence of unexpected toxicities—that will require studies beyond the scope that pre-marketing studies can reasonably address. 

• S. 623 places specific limits on the FDA’s ability to request commitments for 

post-market clinical studies from a follow-on manufacturer. It specifically 

would not allow FDA to request studies specifically targeted to address residual concerns raised by the limited testing done by the follow-on biologic application. 

• In addition, S. 623 is silent on the matter of post-marketing safety surveillance, a tool essential to ensuring the safety of all biologics, including followon biologics or any pharmaceutical. 

• S. 623 subjects the FDA to undue constraints in its ability to ensure 

safety and efficacy of follow-on biologics. 

• As we enter this new field with new safety risks, the FDA should be unhampered in its ability to request and receive additional data from a manufacturer as the need becomes apparent. To do otherwise could jeopardize patient 

safety. 

• The bill provides that, when asked, the FDA should meet with follow-on sponsors to ‘‘reach agreement regarding the parameters of design and size of the 

studies’’ necessary for approval of the application. The binding nature of these 

agreements presents a troubling departure from requirements pertaining to 

new drugs and traditional generic drugs: Whereas binding agreements in 

those contexts are limited to pivotal studies (i.e., clinical trials and bioavailability and bioequivalence studies) and made after review of extensive 

preliminary data, here, the binding agreements are not so limited and could 

69 

be requested prior to generation of any data. The FDA cannot and should not 

be expected to identify all testing needs up front before early test results are 

available. Also, existing provisions apply to determinations FDA has made 

many times over many years (i.e., drug, biologic and generic approvals), so 

FDA has a vast experiential basis for determining what tests are required. 

By contrast, FDA has never made a comparability determination for a followon biologic such as proposed in S. 623. It is therefore unreasonable to require 

the FDA to anticipate all testing needs in advance and potentially dangerous 

to limit FDA ability to request additional data. 

• Another worrisome constraint on the FDA comes in S. 623’s mandate to the 

FDA to complete its final review and take final action on a follow-on biologic 

product application within just 8 months of the manufacturer’s submission of 

the application. This would be an unprecedented move that places inappropriately high priority on the review of follow-on biologics: Most new drugs and 

biologics are reviewed with a 10-month deadline to complete review, potentially much longer to reach final action. Even priority drugs and biologics 

have a 6-month review, and potentially take much longer to final action. Also, 

timelines for new drugs and biologics address the time for a complete review 

of an application. After complete review, FDA may request any data not 

found in the application. In contrast to the approach for innovator products, 

S. 623 sets an aggressive timeline not for a complete review, but for a final 

action. At the end of the 10-months review period, the FDA is not allowed 

to request additional important data; it must make a final decision. Given 

complexities of a comparability determination and the potential associated 

risk, legislation should promote, not limit, requests for important data. 

• S. 623 also specifies that studies to establish comparability should be designed 

‘‘to avoid duplicative and unethical clinical testing.’’ The meaning of ‘‘duplicative’’ is unclear; but whereas replication of results is a basic scientific approach to ensure validity, admonition to avoid duplicative testing, depending 

on how the term is interpreted, could lead to inadequate testing. Regarding 

unethical testing, the language is unnecessary and could, depending on how 

it is interpreted, discourage appropriate testing requirements. 

• S. 623 provides no data exclusivity provision for innovators and thus 

does not provide adequate incentive for exclusivity. 

• S. 623 does not ensure an open and transparent process for setting scientific standards. 

Question 2. I am sorry to see that we do not have a witness testifying on the impact of the Clinton-Schumer bill on the financial viability of innovator biotech companies. If we did have such a witness, I think the witness would say that venture 

capital for biotech companies would dry up because this bill guts any drive for 

biotech companies to innovate. Why should a biotech company go through huge clinical trials, manufacturing challenges, studies, etc. to get a biologic approved when 

the day after approval a follow-on biologic company can send them a letter asking 

for a list of every single patent that is a part of making that biologic. And after providing that list, the innovator can only sit back and wait for the follow-on biologic 

company to submit an application at the FDA saying that their product is comparable to the innovator’s product—not the same—but comparable. This bill has no 

data exclusivity for the innovator. There is no patent protection for the innovator. 

And there is no marketing exclusivity for the innovator. Why should venture capital 

firms invest in biotech companies if the companies have no guarantee of recouping 

their research investment? Dr. Segal, I would appreciate your comments on this concern. 

Answer 2. The majority of biotechnology companies are small, privately held companies with no product revenue stream. Relatively few are currently profitable. 

These small companies have been the source of many innovative ideas and products. 

Raising sufficient venture capital is both a necessity and a great challenge for many 

of these small, innovative biotech companies. 

A bill like S. 623 that provides no marketing exclusivity for the innovator and contains provisions that weaken patent protections could very well have the effect of 

driving away venture capital money upon which the small start-up companies in the 

industry depend. Of course, this would decrease the amount of research and development being done by the industry on innovative biotech therapies. 

70 

1The register of medicinal products for human use authorised by the European Commission 

is available at http://ec.europa.eu/enterprise/pharmaceuticals/register/alfregister.htm. 

RESPONSE TO QUESTIONS OF SENATORS KENNEDY, ENZI, BINGAMAN, AND BURR

BY NICOLAS ROSSIGNOL

QUESTIONS OF SENATOR KENNEDY

Question 1. Are EU requirements for clinical testing of follow-ons specified in statute or in regulation and guidance? 

Answer 1. The EU legislation on ‘‘biosimilar’’ products (the EU equivalent of follow-on biologics) lays down that the type and amount of data (i.e. toxicological and 

other non-clinical and appropriate clinical data) shall be determined on a case-bycase basis in accordance with relevant scientific guidelines. Requirements for clinical testing are specified in guidelines established by the European Medicines Agency (EMEA) (www.emea.europa.eu). 

Question 2. Could you explain the function of product class guidelines in the European Union? 

Answer 2. There are currently four ‘‘biosimilar’’ product-class guidelines in the 

EU, which address product-class-specific pre-clinical and clinical aspects on insulins, 

growth hormones, erythropoietins and granulocyte-colony stimulating factors. In addition, one on low-molecular weight heparins is also in preparation. 

The purpose of EU product-class guidelines is to outline the general non-clinical 

and clinical requirements. The guidelines present the current view of the EMEA on 

how comparability of two products (biosimilar and reference) of the relevant class 

should be demonstrated. 

The non-clinical section of the product-class guidelines addresses the pharmacotoxicological assessment. The clinical section addresses the requirements for pharmacokinetic, pharmacodynamic, efficacy and safety studies as well as the risk management plan. Criteria for extrapolation of clinical data to other indications approved for the reference medicinal product are also discussed. 

The guidelines are by definition rather general, since no two cases are likely to 

be the same and the biosimilarity is assessed essentially on a case-by-case basis (see 

response to Question 1). 

Question 3. Is an applicant able to submit an application for approval of a biosimilar for a reference product for which a product class guideline has not yet been 

issued? 

Answer 3. Yes. The type and amount of pre-clinical and clinical data required will 

be determined on a case-by-case basis. 

Question 4. Isn’t it the case that applications for biosimilar products in Europe 

have been filed before the development and issuance of product class guidelines for 

those products? 

Answer 4. Two products have been authorised so far under the EU framework on 

biosimilars1: The first is the growth hormone Omnitrope (somatropin), whose application was received by the EMEA on July 1, 2004 and which was authorised by the 

European Commission in April 2006. The second is the growth hormone Valtropin 

(somatropin), whose application was received by the EMEA on June 3, 2004 and 

which was also authorised in April 2006. 

These two applications have indeed been filed before the product-class guideline 

on non-clinical and clinical issues for biosimilar products containing somatropin was 

developed (work on this guideline started in the beginning of 2005). 

Question 5. Is an applicant able to consult with the EMEA if a product class 

guideline has not been issued or if the applicant has an approach that differs from 

that in the guideline? 

Answer 5. Yes, the applicant can indeed contact the EMEA to discuss these matters. 

Question 6. Isn’t it the case that an applicant may deviate from a guideline so 

long as the applicant justifies the deviation? 

Answer 6. In general, EU guidelines are not legally-binding, so an applicant may 

deviate from a guideline as long as he justifies the deviation. In the specific case 

of biosimilars, nevertheless, the EU legislation lays down that the type and quantity 

of supplementary data to be provided must comply with the related detailed guidelines. In other words, if the guideline is very prescriptive on one particular requirement, the applicant must comply with this requirement. However, existing EU 

71 

guidelines on biosimilars are usually general in nature and do not lay down highly 

prescriptive requirements, but rather recommendations (‘‘the applicant should 

. . .’’). 

QUESTIONS OF SENATOR ENZI

Question 1. Thank you for your testimony and joining us today. As you know we 

are considering adopting similar legislation. As you have already implemented it, 

how long would you imagine it would take the FDA to implement similar legislation? 

Answer 1. It is extremely difficult to predict how long it would take the FDA to 

implement similar legislation. This depends on a number of factors such as the type 

of products included within the scope of the regulation, the involvement of stakeholders, etc. I can only say that the scientific work necessary to put in place the 

current EU regulatory framework on biosimilars took the European Medicines Agency and the European Commission about 2–3 years. 

Question 2. You mention in your testimony that the EMEA has rejected one application. Understanding that some of the information is confidential; could you describe why that was rejected? 

Answer 2. One biosimilar application (Alpheon, an interferon) was indeed reviewed and given a negative scientific opinion by the EMEA in June 2006. One of 

the main reasons for this is that the EMEA had major concerns regarding the comparability of Alpheon and its reference product (Roferon-A), because of differences 

identified between the two medicines, such as impurities. The EMEA was hence of 

the opinion that Alpheon could not be considered as a biosimilar. The EMEA also 

had concerns that there was not enough data on the stability of the active substance 

and of the medicine that was going to be marketed. Also, the process used for making the finished medicine had not been adequately validated. 

More scientific information on the evaluation of Alpheon is available on the 

EMEA website: http://www.emea.europa.eu/pdfs/human/opinion/19089606 en.pdf. 

Question 3. You indicated that your process of developing your law was an open 

process that included active participation of industry. Could you describe the benefit 

you saw in involving industry from the earliest point of developing the European 

legislation? Could you suggest any way to insure that legitimate scientific issues are 

considered but dilatory tactics do not derail the process? 

Answer 3. Involving the industry, but also other interested parties such patients 

associations or healthcare professionals, enabled us to gather as much expertise in 

the field as possible (which, depending on the type of product concerned, may be 

limited). This allowed regulators and scientific experts at the EMEA/European Commission to confront their vision with the practical experience of manufacturers, doctors, etc. It also helped us to better understand which therapeutic areas and product 

classes are likely to emerge first in the field of biosimilars (e.g., insulins, growth 

hormones . . .). 

Last but not least, involving both sides of the industry enabled a constructive exchange of contradictory views and facilitated the development of a balanced, unbiased regulatory framework. Transparent involvement of both the generics/biosimilar 

and the innovative industry, together with strong assurance of the independency of 

the scientific experts involved in the establishment and implementation of the regulatory framework, are in my opinion key factors to ensure that legitimate scientific 

issues are considered but dilatory tactics do not derail the process. 

QUESTIONS OF SENATOR BINGAMAN

Question 1. To address the issues around substitution of one biologic for another, 

how would you recommend that data be obtained in the post market period to assure safety of both the innovator compound and the follow-on (or biosimilar)? Please 

discuss pros and cons of each potential stakeholder contributing to the data gathering process: manufacturer, third party payer, prescribing health professional, patient, regulatory agency. 

Answer 1. Within the European Community, all products (innovative or biosimilar) made of recombinant DNA molecules—i.e., the vast majority of follow-on 

biologics today—are scientifically evaluated by the European Medicines Agency 

(EMEA) and authorized by the European Commission. The EMEA acts in close cooperation with the national authorities of the EU Member States and receives all 

relevant post-marketing information, e.g., suspected adverse reactions. The scientific 

analysis of the received information can affect the status of the product and lead 

to an amendment, suspension or revocation of the marketing authorization. It is 

72 

2http://ec.europa.eu/enterprise/pharmaceuticals/index.html. 

therefore a fully centralized system where the European regulatory Agency has a 

prominent role. 

The holder of the marketing authorisation is legally responsible to ensure that all 

relevant post-marketing information is brought to the attention of the Agency. Patients are also encouraged to communicate any adverse reaction to health-care professionals. However, as the EU system for pharmacovigilance is currently under revision,2 it is difficult to provide further details at this stage. 

In my opinion, the issue of substitution is not specific to follow-on biologics, but 

is rather an issue for all biologics. It is expected that the likelihood of substitution, 

in practice, will be higher for biosimilars, but substitution can also happen (as it 

does currently in the EU) between innovative products. One key aspect to be considered when addressing post-marketing monitoring is traceability, which can easily be 

lost if suitable products’ naming and prescription systems are not in place. In this 

regard, the data gathering process at the stage of the patient/health professional 

prescribing the product is particularly crucial to ensure not only that information 

is indeed gathered, but also that this information is accurate, usable and can be 

transformed into scientific knowledge on the concerned product. 

Question 2. Can you propose a possible mechanism for communicating to stakeholders (above) during the process of post-market surveillance? Would different information go to different stakeholders at different times, or would all the information be equally accessible to all stakeholders? 

Answer 2. The EU system is based on two levels: the first level concerns regulatory agencies, the second level affects the general public and healthcare professionals. 

At the first level, it is essential that information is shared as fast as possible, with 

all regulatory agencies concerned. The European Medicines Agency acts as a focal 

point that gathers all post-market information and ensures information sharing and 

networking between Member States regulatory authorities. 

At the second level, the information is usually released by the EMEA in a public 

manner, so it is equally accessible to all stakeholders. Typically, this second step 

is triggered only once the first level of information sharing between regulatory authorities has been completed and a way forward has been agreed. Information publicly released should be understandable for the whole public. In certain cases, it 

makes sense that two separate sets of information are released: one for specialists 

(healthcare professionals, prescribers), and one for the general public. 

QUESTIONS OF SENATOR BURR

Question 1. Do you support the Clinton-Schumer bill in its entirety? 

Answer 1. I am afraid that I am not in a position to answer this question. I can 

only underline the EU experience, which in my opinion demonstrates that the development of a regulatory framework and adapted scientific criteria to approve biosimilar products that are safe, of good quality and efficacious, is something feasible. 

As mentioned in my testimony, there is no reason in principle why the science 

should be different on the other side of the Atlantic. 

Question 2. I am sorry to see that we do not have a witness testifying on the impact of the Clinton-Schumer bill on the financial viability of innovator biotech companies. If we did have such a witness, I think the witness would say that venture 

capital for biotech companies would dry up because this bill guts any drive for 

biotech companies to innovate. Why should a biotech company go through huge clinical trials, manufacturing challenges, studies, etc. to get a biologic approved when 

the day after approval a follow-on biologic company can send them a letter asking 

for a list of every single patent that is a part of making that biologic. And after providing that list, the innovator can only sit back and wait for the follow-on biologic 

company to submit an application at the FDA saying that their product is comparable to the innovator’s product—not the same—but comparable. This bill has no 

data exclusivity for the innovator. There is no patent protection for the innovator. 

And there is no marketing exclusivity for the innovator. Why should venture capital 

firms invest in biotech companies if the companies have no guarantee of recouping 

their research investment? Mr. Rossignol, I would appreciate your comments on this 

concern. Answer 2. The EU experience suggests that a regulatory framework that strikes 

the right balance between rewarding innovation, on the one hand, and allowing generic/biosimilar competition, on the other hand, is feasible and can effectively support the development of the biotechnology industry. It is also likely that the entry 

73 

of biosimilar products on the market will further stimulate innovators to develop 

new products or new versions of existing products. 

The EU regulatory framework on biosimilars does not contain specific market exclusivity, data exclusivity or patent protection provisions for the innovator. Rather, 

it relies on existing, general provisions which apply in principle to all pharmaceuticals. I am not aware of any EU evidence demonstrating that the EU framework 

on biosimilars has deterred venture capital investment in the biotech sector. 

It should also be stressed that one of the key goals—if not the most important— 

of any framework on biosimilars of follow-on biologics should be to protect patients’ 

safety. In this regard, the EU innovative industry in Europe was rather supportive 

of putting in place a suitable framework on biosimilars, precisely to avoid double 

standards and make sure that biosimilars do not put patients’ safety at risk. 

RESPONSE TO QUESTIONS OF SENATORS KENNEDY, ENZI, AND BURR

BY AJAZ S. HUSSAIN, PH.D. 

QUESTIONS OF SENATOR KENNEDY

Question 1. Dr. Hussain, do you think it is possible for a manufacturer to present 

a data package that would justify FDA saying a follow-on product is interchangeable? 

Answer 1. A complete data package on a follow-on product that demonstrates comparability at every level—structural, functional and clinical—with an innovator 

product, should be considered suitable for such a designation by the FDA. Such 

judgments are made every day by the Agency, when the sponsors of innovator products provide data to substantiate that their products are the ‘‘same’’ pre- and postmanufacturing changes, and the same regulatory standard can be applied by the 

Agency to follow-on products. In such instances with innovator products an achievement of comparability pre-supposes interchangeability. While in some cases the 

FDA will require analytical, preclinical and clinical date, this may not always be 

the case (especially as science and technology continue to improve), but in all instances it is a data-driven process in which the Agency already has extensive experience. Such comparability assessments have been used very successfully, with very 

few incidences of failure resulting in any loss of safety of efficacy in products reaching patients, and they have been critical to upgrading manufacturing capabilities for 

many existing biologics (both those regulated as drugs under FD&CA and those regulated as biologics under PHSA). 

Question 2. Dr. Hussain, doesn’t the FDA already make a finding of interchangeability every time it approves a manufacturing change? For instance, if a manufacturer were to change a cell line the FDA does not require that the manufacturer 

change the label or inform consumers that such a change has taken place. 

Answer 2. If an innovator product uses a comparability protocol to make a manufacturing change, and the FDA is satisfied with the data provided on the pre-change 

and post-change material then the product is presumed interchangeable and there 

is no change in the label. The only indication that the batches are different will be 

the lot number so the material is fully traceable, but it will be invisible to the patient that any manufacturing change has occurred. And indeed, once comparability 

has been demonstrated, the patient can have confidence that the product will provide them with the same clinical outcome—that is the whole point of comparability 

and why it has been so successful for the manufacturers and the regulators for well 

over 10 years. 

Question 3. Dr. Hussain, looking at the EU guidelines on different biosimilar 

products, we see that what the EU expects varies by product. For example, for insulin, the EU suggests only pharmacokinetic and pharmacodynamic studies to show 

efficacy. For growth hormone, the EU expects an adequately powered comparative 

effectiveness trial. Doesn’t this variation show that, when we legislate, we need to 

give FDA the flexibility and discretion to ask for what it needs, and not write unnecessary requirements into law? 

Answer 3. Just as FDA evaluates and approves innovator products, it is entirely 

appropriate that FDA be given the flexibility to require the data that they as experts believe to be necessary to fulfill the statutory criteria of safety and efficacy 

(for FD&C Act approved products) or safety, purity and potency (for PHS Act licensed products). The complexity of the products will determine the extent of the 

data required of a subsequent sponsor to establish comparability, and the European 

guidelines reflect this. However, we do not need to wait for FDA to promulgate guidances, albeit they may choose to over time, as there is enough publicly available information with those biologics on which the patents are expiring for subsequent 

74 

sponsors to be able to propose follow-on candidates. It will be up to those sponsors 

to work with the Agency to assure them that their products are comparable. And 

indeed, as Mr. Rossignol, from the EU testified during the hearing, the science is 

global and so what has been learnt and discussed in Europe on the science, can also 

be employed here. Giving FDA the flexibility to adjust their requirements as the 

science evolves, but to leave the burden with the sponsors to assure that their products meet the appropriate regulatory criteria is entirely appropriate for follow-on 

biologics, just as it is for innovator biologics. 

Question 4. Dr. Hussain, we all understand the importance of protecting innovation. Do you believe that allowing follow-on biologics is consistent with promoting 

innovation? Can allowing follow-on competition actually stimulate innovation in biologics? 

Answer 4. I believe that there is nothing like competition to stimulate innovation, 

and nothing like perpetual monopolies to stultify it. Just as the Hatch-Waxman 

Drug Price Competition and Patent Term Restoration Act of 1984 led to an era of 

high productivity for both generic and innovator pharmaceutical companies, so I believe that the new regulatory pathway such as contained in S. 623 will stimulate innovation in both sectors too, not least because in addition to the competitive comparable/interchangeable pathways it explicitly contains a second generation pathway for innovators to facilitate their improvements to their own and each others already-licensed biologic products. A pathway based on established regulatory principals but that encourages the use of prior scientific knowledge by all sponsors is 

an ideal way to reduce inappropriate regulatory requirements and to stimulate innovation to the ultimate benefit of patients as well as the industries that serve them. 

QUESTIONS OF SENATOR ENZI

Question 1. Thank you for your testimony. You note that you support the ClintonSchumer bill as it will provide follow-on biologics to the market quickly. Would you 

support changes in the legislation that would address some of the concerns that you 

have heard today as long as they do not significantly delay competition in the pharmaceutical marketplace? 

Answer 1. As long as the regulatory standards proposed in the legislation apply 

consistent and appropriately high regulatory standards to all biologics I would anticipate being supportive. However, I think the pathway proposed in the ClintonSchumer bill is sufficiently specific to be reassuring to all sponsors that the FDA 

can apply its established regulatory experience, but flexible enough in its burden of 

proof remaining with the sponsor such that they are able to be creative and achieve 

the regulatory requirements with any data that they believe suitable—this basic 

conceptual approach will be hard to improve. Indeed it is the basis of the current 

PHS Act under which most biologics are currently licensed by the FDA, which has 

also proven remarkably accommodating to the massive progress in the technology. 

Clearly, in addition to the pathway, it will always be important to respect legitimate intellectual property, but Novartis believes that patent issues can best be handled by the Courts, as is the case today for innovator PHS Act biologics, and should 

not be made a responsibility of the FDA who are neither qualified nor resourced to 

handle them. Thus, these patent issues should be ‘‘decoupled’’ from the pathway. 

Novartis would support some form of exclusivity for the sponsor of innovator products approved in the future, and used as the reference product for a follow-on biologic, whereby they would not face market competition for a set period postapproval. This could recognize the market uncertainties for these products, and as 

in the original Hatch-Waxman statute, enable the development of products with limited or no patent protection. Such an exclusivity would encourage the further creation of innovator products. However, data exclusivity is not a term we have used 

in our testimony because the follow-on product will not have access to, nor need, 

any of the data provided by the innovator to the FDA as part of their original approval. 

What I would find questionable would be continued general debate that simply 

delays the recognition, which I am not sure anyone disputes, that ultimately the decision of the FDA must be on the individual application submitted to the Agency, 

and that this application by the follow-on sponsor will be confidential, just as that 

of an innovator sponsor. All that is needed is for FDA to have the requisite authority and the discretion to use it as warranted by the individual submissions they receive, irrespective of whether the sponsor is a traditional innovator company, generic company or some other equally competent sponsor. The quality of the application is what matters, and its evaluation by the FDA, not the general business model 

of the sponsor. 

75 

Question 2. Would you support other legislation that would bring follow-on biologics to the market quickly? 

Answer 2. As long as the regulatory standards proposed in the legislation apply 

consistent and appropriately high regulatory standards to all biologics, and as long 

as intellectual property is appropriately respected, I would anticipate being supportive of a new pathway that enabled the FDA to approve interchangeable followon biologics. The timing, however, will be determined by when the sponsors of follow-on products submit their applications and the outcome of the subsequent review 

by the FDA. That is what will govern how quickly these products can be made available after FDA has been granted the necessary authority to review them. 

Question 3. Novartis as a corporation operates in the European Union. You suggest that the data exclusivity of the European law should be inserted into the U.S. 

version of follow-on legislation. Could you discuss why you think expanded data exclusivity is preferable to patent extensions that are present in the Hatch-Waxman 

law? 

Answer 3. The European Union has certain useful parallels in their Biosimilars 

Pathway (which was enacted into legislation in 2003), and through which Novartis 

obtained the first European approval of a biosimilars—Omnitrope, a recombinant 

Human Growth Hormone in April 2006. While, the market conditions in Europe are 

very different to those of the United States, and probably, as Mr. Rossignol indicated, have less relevance to the United States, than the pathway provisions, 

Novartis is a strong advocate for the protection of legitimate intellectual property 

worldwide. Part of intellectual property is patent protection, and part of this are the 

various forms of exclusivity, such as the European so called 8+2+1, whereby the regulatory authorities do not accept an application for 8 years, approve it for 10, and 

can grant a 1-year extension if a new indication is added. The system is not dissimilar to the Hatch-Waxman exclusivities of 4 and 5 years. 

Biologics, licensed under the PHA Act are already entitled to and have received 

the patent-term extensions for which they became eligible under Hatch-Waxman. 

There are no distinctions in the patent term restoration provisions for drugs or biologics, or for FD&C Act products and PHS Act products. However, biologics cannot 

benefit from the exclusivity provisions on Hatch-Waxman as these do not apply to 

PHS Act products. 

Further, I want to reiterate that I do not believe that any sponsor of a followon biologic will use the actual data of an innovator product, although they will need 

to refer to the already public prior finding of safety, purity and potency of the FDA, 

namely, the label of the innovator biologic product that they are referencing for comparability purposes. Thus, the rationale for data exclusivity is not protection against 

a subsequent sponsors’ use of the data itself, but a term that refers to a preclusion 

on the FDA approving another product as interchangeable with a future innovator 

product for a certain period—and as such has been more accurately called market 

exclusivity. That is why I used the term market exclusivity throughout my testimony, and indeed it has value to the innovator as it is a greater assurance than 

patents which may be disputed and declared invalid or unenforceable in court (but 

prior to such litigation, their status cannot be guaranteed). Clearly the potential for 

patents extend for a longer period, and as such both patents and market 

exclusivities are valuable to the sponsors of biologic products, and as an incentive 

for further innovation. 

Question 4. I understand that FDA recently approved Omnitrope as a ‘‘comparable’’ biotech drug, and that your application included clinical trials. In that application how many patients were enrolled? Could you describe the key differences 

in the approval in the United States and EU? 

Answer 4. I am happy to address what is reflected in the public record. FDAapproved Omnitrope as a 505(b)(2) NDA under FD&C Act in May 2006. As such it 

was no different from other biologic drugs that have been approved by the Agency 

using this pathway, although we were the first case of a recombinant product that 

referenced a previously approved recombinant product. In our NDA we referred to 

the prior approval of an existing product and then we provided data, including clinical trials, to show that we were comparable (albeit this is not a term that is used 

in the Hatch-Waxman statute when 505(b)(2) was created). The same product, and 

the same set of data, that included analytical, preclinical and clinical data was approved in Europe under their Biosimilars pathway prior to the U.S. approval by 

FDA. The European pathway is based on comparability (CHMP/437/04: GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS. London, 30 October 

2005). 

76 

To the extent reflected in the Summary Basis for Approval (SBA), and with the 

caveat that the studies continued for longer periods relative to the U.S. approval 

than would have otherwise been the case because of the delay in the approval, thus 

generating much more extensive data than the FDA or Sandoz anticipated. 

Question 5. Currently the Clinton-Schumer bill has a few IP provisions that seem 

to tip the balance established in current law towards the generic companies. As 

Novartis is part generic part innovator, could you discuss the balance that is established in this bill? 

Answer 5. As discussed above, in my answer to Question 3, we do believe that 

a balance of incentives for innovators will be important, as we create the new pathway that enables competing, interchangeable follow-on biologics. Indefinite monopolies for innovator products, even when all patents have expired, is not appropriate 

for biologics, any more than it was for drugs back in 1984 when Hatch-Waxman was 

enacted. Novartis believes in respect for intellectual property and competition, and 

believe that both will ultimately benefit patients through the greater availability of 

more and better medicines. Competition is the best way to ensure access to costeffective drugs after patents expire, and we believe that the time has come for the 

authority to be granted to the FDA to approve Follow-on Biologics. These Followon Biologics will compete in the free-market, and newer and better ones will continue to be created, as long as it is to the same consistent, appropriately-high, 

science-based regulatory standards that apply to innovator products, and as long as 

legitimate intellectual property is respected. To the extent that market exclusivity 

can be provided to innovator biologics approved subsequent to enactment of any proposed legislation, we would anticipate being supportive, as we believe this gives a 

greater certainty to innovators, and as such will be a stimulus to their continued 

innovation. 

QUESTIONS OF SENATOR BURR

Question 1. Do you support the Clinton-Schumer bill in its entirety? 

Answer 1. Novartis does not support the bill in its entirety, however, as discussed 

in our testimony, we support the principles of the regulatory pathway proposed. 

Novartis supports the pathway proposed in the Clinton-Schumer bill because we believe that the FDA has proven their ability to use the comparability process for evaluating differences between biologic products in a manner that encouraged upgrading 

manufacturing and the increased availability of biologics without putting any patients at undue risk. We believe that they can be granted the authority to apply 

these same regulatory principles to the evaluation and approval of follow-on biologics, including interchangeable ones. 

Novartis has not endorsed the intellectual property provisions in the bill. We do 

not believe that such provisions need to be in any way linked to the regulatory approval process—they can be as we say ‘‘decoupled’’ with the courts continuing to supervise patent disputes and FDA getting on with their job of reviewing and approving regulatory filings. Further, we think market exclusivity for the sponsors of future innovator biologic products should be included in the legislation. 

Question 2. Under the Clinton-Schumer bill, the FDA has to lay out exactly what 

is wrong with a follow-on biologic application and tell the company what they have 

to do to fix the application. The FDA does not do that for any other company submitting an application for product approval (innovator biologic, generic, brand, animal drug, etc.). Do any of you support that language? 

Answer 2. The regulatory criteria included in the Clinton-Schumer bill that form 

the basis for the rejection by the FDA of an application for a comparable product 

are derived from the Food, Drug, and Cosmetic Act Section 505 approval provisions 

for new drug approvals, albeit with tighter standards and more predictable operation and applying strict criteria and time lines. This will be to the benefit of all 

applicants for both comparable, interchangeable and second generation biologic 

products. 

Question 3. Under current law, a company cannot choose the court they want to 

be sued in. In the Clinton-Schumer bill a follow-on biologic company can decide 

where they want to be sued. Do any of you support that language? 

Answer 3. As a scientist and former regulator, I am not qualified by training or 

experience to address such a technical question of law and legal policy. Following 

receipt of the committee’s questions, I have in these responses been consulting with 

my legal colleagues, and, upon receiving their input, could submit the views of the 

Novartis Group of Companies on this issue at a later date if that would be useful. 

77 

Question 4. The Clinton-Schumer bill permits the FDA to look at and use ‘‘any 

other information available to the Secretary’’ to determine whether a follow-on biologic is comparable to the innovator biologic. So the FDA could look at the 

innovator’s biologics licensing application for the data it needs to approve the followon. The fifth amendment to the U.S. Constitution protects trade secret data from 

use by the government without compensation. With the FDA’s current budget, do 

you think that the FDA has the funds to compensate the innovator company for 

using its data to approve another company’s application? 

Answer 4. I am not a lawyer but it does not appear to me that anything in the 

Clinton-Schumer bill can or even aspires to override the trade secret restrictions 

that affect all applications to the FDA, innovator or generic, today. I think the reference to any other information to the secretary is any other public information, or 

any other information to which he already has access under the PHS Act, not any 

information that is protected and the property of another company, and simply in 

the possession of the FDA for the purposes of a regulatory review. 

As discussed in my answers above, the innovators data is neither needed nor of 

interest to the subsequent sponsor of a Follow-on Biologic. At the point at which 

the legitimate IP has expired, the innovator product has been on the market for 

many years, if not decades, and it is certain that the technology available to produce 

the Follow-on Biologic will be vastly superior to that which was state-of-the-art at 

the time the innovator product was licensed. All the necessary data comparing the 

innovator product with that of the subsequent sponsor will have been developed by 

that subsequent sponsor in their own analyses and tests of commercially purchased 

innovator product compared head-to-head with their own candidate. The innovators 

own data would not be helpful as those tests would not have been conducted with 

the samples of the follow-on biologic, and the tests themselves, as well as the reagents will often also be proprietary to the original sponsor. As such the data to 

support the subsequent sponsors application will either be publicly available or the 

property of the subsequent sponsor. The FDA will not need any funds to compensate 

the innovator as they will not be using their data. 

RESPONSE TO QUESTIONS OF SENATORS ENZI AND BURR BY SID BANWART

QUESTIONS OF SENATOR ENZI

Question 1. Thank you for your testimony. You note that you support the ClintonSchumer bill as it will provide follow-on biologics to the market quickly. I assume 

that you would support changes in the legislation that would address some of the 

concerns that you have heard today as long as they do not significantly delay competition in the pharmaceutical marketplace? 

Answer 1. Caterpillar supports legislation that would create an appropriate regulatory route for FDA review in a timely manner of biogenerics that are safe and effective. The Clinton-Schumer bill is the first measure in the 110th Congress to address this important issue. 

Question 2. Would you support other legislation that would bring follow-on biologics to the market quickly? 

Answer 2. Caterpillar welcomes the debate on this important issue and will review other legislative proposals as introduced. 

Question 3. In your written testimony you have focused on the cost of the medicines without discussing the value of these medicines to your workforce. Do you 

measure employees satisfaction with the health plans? And how do you measure the 

value you are getting for your medical purchases? 

Answer 3. Employees have an opportunity to provide feedback about our selfinsured benefits plan on the value survey we conduct on a regular basis. Caterpillar 

does extensive benchmarking with comparator companies and our benefits packages 

consistently rank among the top quartile. We conduct rigorous analysis of the value 

of medical purchasing through the 6 Sigma process. 

Question 4. Caterpillar is an innovative company and files for patents, presumably 

to prevent competitors from free riding on your Research and Development. I would 

assume you would be opposed to a law that would devalue your patents even if in 

doing so that would make mining equipment decrease in price. How would you distinguish that situation from this one? 

Answer 4. Caterpillar supports a competitive marketplace and, upon expiration of 

its patent, Caterpillar expects and welcomes competition in the marketplace by others using the previously protected Caterpillar inventions. Such post-expiration use 

78 

of the patented invention is part of the bargain made by the patentee for the limited 

period of exclusivity provided by the patent laws. 

In the area of patented biologicals, no competition exists using the patented invention after the patent expires because the FDA currently has no authority to approve biogeneric products in an abbreviated fashion. Caterpillar urges Congress to 

pass a bipartisan solution to create an appropriate regulatory pathway for FDA review of safe and effective biogenerics once a patent has expired or been held invalid. 

QUESTIONS OF SENATOR BURR

Question 1. Do you support the Clinton-Schumer bill in its entirety? 

Answer 1. Caterpillar supports legislation that would create an appropriate regulatory route for FDA review of biogenerics in a safe and timely manner. The Clinton-Schumer bill is the first measure in the 110th Congress to address this important issue. 

Question 2. Under the Clinton-Schumer bill, the FDA has to lay out exactly what 

is wrong with a follow-on biologic application and tell the company what they have 

to do to fix the application. The FDA does not do that for any other company submitting an application for product approval (innovator biologic, generic, brand, animal drug, etc.). Do any of you support that language? 

Answer 2. Caterpillar believes that the FDA should be given the authority to approve biogeneric drugs that are safe, effective, and provide additional value to the 

health of our employees. 

Question 3. Under current law, a company cannot choose the court they want to 

be sued in. In the Clinton-Schumer bill a follow-on biologic company can decide 

where they want to be sued. Do any of you support that language? 

Answer 3. Caterpillar does not have a formal position on this particular provision 

of the legislation. 

Question 4. The Clinton-Schumer bill permits the FDA to look at and use ‘‘any 

other information available to the Secretary’’ to determine whether a follow-on biologic is comparable to the innovator biologic. So the FDA could look at the 

innovator’s biologics licensing application for the data it needs to approve the followon. The fifth amendment to the U.S. Constitution protects trade secret data from 

use by the Government without compensation. With the FDA’s current budget, do 

you think that the FDA has the funds to compensate the innovator company for 

using its data to approve another company’s application? 

Answer 4. The Clinton-Schumer bill reflects language used in current law for new 

drug applications containing active ingredients (i.e., Hatch-Waxman and the Food, 

Drug, and Cosmetic Act) to create a parallel system for generic biologics. 

Regarding the FDA’s budget, Caterpillar acknowledged in both its written and 

oral testimony the need for additional funding for the FDA to assume additional responsibilities associated with generic biologics. Excerpt from Caterpillar’s written 

testimony, page 6: 

4. Increase resources for the Food and Drug Administration. 

In order to adequately assume these new responsibilities, the FDA will need 

adequate resources. We support additional resources for FDA to secure more 

staff to ensure the timely review of biogeneric applications and the safety of 

biogenerics for consumers. 

[Whereupon, at 11:50 a.m., the hearing was adjourned.] 

Æ