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REAUTHORIZATION OF THE PRESCRIPTION DRUG

USER FEE ACT

HEARING

BEFORE THE

SUBCOMMITTEE ON HEALTH

OF THE

COMMITTEE ON ENERGY AND

COMMERCE

HOUSE OF REPRESENTATIVES

ONE HUNDRED TENTH CONGRESS

FIRST SESSION

APRIL 17, 2007

Serial No. 110–29

(

Printed for the use of the Committee on Energy and Commerce

energycommerce.house.gov

COMMITTEE ON ENERGY AND COMMERCE

JOHN D. DINGELL, Michigan, Chairman

HENRY A. WAXMAN, California

EDWARD J. MARKEY, Massachusetts

RICK BOUCHER, Virginia

EDOLPHUS TOWNS, New York

FRANK PALLONE, JR., New Jersey

BART GORDON, Tennessee

BOBBY L. RUSH, Illinois

ANNA G. ESHOO, California

BART STUPAK, Michigan

ELIOT L. ENGEL, New York

ALBERT R. WYNN, Maryland

GENE GREEN, Texas

DIANA DEGETTE, Colorado

Vice Chairman

LOIS CAPPS, California

MIKE DOYLE, Pennsylvania

JANE HARMAN, California

TOM ALLEN, Maine

JAN SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

CHARLES A. GONZALEZ, Texas

JAY INSLEE, Washington

TAMMY BALDWIN, Wisconsin

MIKE ROSS, Arkansas

DARLENE HOOLEY, Oregon

ANTHONY D. WEINER, New York

JIM MATHESON, Utah

G.K. BUTTERFIELD, North Carolina

CHARLIE MELANCON, Louisiana

JOHN BARROW, Georgia

BARON P. HILL, Indiana

JOE BARTON, Texas

Ranking Member

RALPH M. HALL, Texas

J. DENNIS HASTERT, Illinois

FRED UPTON, Michigan

CLIFF STEARNS, Florida

NATHAN DEAL, Georgia

ED WHITFIELD, Kentucky

BARBARA CUBIN, Wyoming

JOHN SHIMKUS, Illinois

HEATHER WILSON, New Mexico

JOHN B. SHADEGG, Arizona

CHARLES W. ‘‘CHIP’’ PICKERING,

Mississippi

VITO FOSSELLA, New York

STEVE BUYER, Indiana

GEORGE RADANOVICH, California

JOSEPH R. PITTS, Pennsylvania

MARY BONO, California

GREG WALDEN, Oregon

LEE TERRY, Nebraska

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

SUE WILKINS MYRICK, North Carolina

JOHN SULLIVAN, Oklahoma

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

PROFESSIONAL STAFF

DENNIS B. FITZGIBBONS, Chief of Staff

GREGG A. ROTHSCHILD, Chief Counsel

SHARON E. DAVIS, Chief Clerk

BUD ALBRIGHT, Minority Staff Director

(II)

(III)

SUBCOMMITTEE ON HEALTH

FRANK PALLONE, JR., New Jersey, Chairman

HENRY A. WAXMAN, California

EDOLPHUS TOWNS, New York

BART GORDON, Tennessee

ANNA G. ESHOO, California

GENE GREEN, Texas

Vice Chairman

DIANA DEGETTE, Colorado

LOIS CAPPS, California

TOM ALLEN, Maine

TAMMY BALDWIN, Wisconsin

ELIOT L. ENGEL, New York

JAN SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

MIKE ROSS, Arkansas

DARLENE HOOLEY, Oregon

ANTHONY D. WEINER, New York

JIM MATHESON, Utah

JOHN D. DINGELL, Michigan (ex officio)

NATHAN DEAL, Georgia,

Ranking Member

RALPH M. HALL, Texas

BARBARA CUBIN, Wyoming

HEATHER WILSON, New Mexico

JOHN B. SHADEGG, Arizona

STEVE BUYER, Indiana

JOSEPH R. PITTS, Pennsylvania

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

SUE WILKINS MYRICK, North Carolina

JOHN SULLIVAN, Oklahoma

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

JOE BARTON, Texas (ex officio)

(V)

C O N T E N T S

Page

Hon. Frank Pallone, Jr., a Representative in Congress from the State of

New Jersey, opening statement .......................................................................... 1

Hon. Nathan Deal, a Representative in Congress from the State of Georgia,

opening statement ................................................................................................ 3

Hon. Henry A. Waxman, a Representative in Congress from the State of

California, opening statement ............................................................................. 4

Hon. Heather Wilson, a Representative in Congress from the State of New

Mexico, opening statement .................................................................................. 5

Hon. John D. Dingell, a Representative in Congress from the State of Michigan, opening statement ....................................................................................... 5

Hon. Steve Buyer, a Representative in Congress from the State of Indiana,

opening statement ................................................................................................ 6

Hon. Gene Green, a Representative in Congress from the State of Texas,

opening statement ................................................................................................ 7

Hon. Tim Murphy, a Representative in Congress from the Commonwealth

of Pennsylvania, opening statement ................................................................... 8

Hon. Diana DeGette, a Representative in Congress from the State of Colorado, opening statement ...................................................................................... 9

Hon. Lois Capps, a Representative in Congress from the State of California,

opening statement ................................................................................................ 10

Hon. Marsha Blackburn, a Representative in Congress from the State of

Tennessee, opening statement ............................................................................ 11

Hon. Darlene Hooley, a Representative in Congress from the State of Oregon,

opening statement ................................................................................................ 12

Hon. John B. Shadegg, a Representative in Congress from the State of Arizona, opening statement ...................................................................................... 12

Hon. Anna G. Eshoo, a Representative in Congress from the State of California, opening statement ........................................................................................ 13

Hon. Jim Matheson, a Representative in Congress from the State of Utah,

opening statement ................................................................................................ 14

Hon. Jan Schakowsky, a Representative in Congress from the State of Illinois, opening statement ....................................................................................... 15

WITNESSES

Theresa M. Mullin, Assistant Commissioner for Planning, U.S. Food and

Drug Administration ............................................................................................ 16

Prepared statement .......................................................................................... 19

Answers to submitted questions ...................................................................... 105

Alan Goldhammer, deputy vice president, regulatory affairs, Pharmaceutical

Research and Manufacturers of America, Washington, DC ............................. 60

Prepared statement .......................................................................................... 62

William Hubbard, senior advisor, Coalition for a Stronger FDA, Chapel Hill,

NC ......................................................................................................................... 66

Prepared statement .......................................................................................... 67

James Thew, patient advocate, Amyotrophic Lateral Sclerosis Association,

Machesney Park, IL ............................................................................................. 69

Prepared statement .......................................................................................... 71

Kay Holcombe, senior policy advisor, Genzyme Corporation, Washington, DC . 73

Prepared statement .......................................................................................... 75

William K. Vaughan, senior policy advocate, Consumers Union, Washington,

DC .......................................................................................................................... 78

Prepared statement .......................................................................................... 80

(1)

REAUTHORIZATION OF THE PRESCRIPTION

DRUG USER FEE ACT

TUESDAY, APRIL 17, 2007

HOUSE OF REPRESENTATIVES, SUBCOMMITTEE ON HEALTH, COMMITTEE ON ENERGY AND COMMERCE, Washington, DC.

The subcommittee met, pursuant to call, at 10:00 a.m., in room

2123 of the Rayburn House Office Building, Hon. Frank Pallone,

Jr. (chairman) presiding.

Members present: Representatives Green, Waxman, Eshoo,

DeGette, Capps, Baldwin, Schakowsky, Ross, Hooley, Matheson,

Dingell, Deal, Shadegg, Buyer, Wilson, Pitts, Rogers, Sullivan Murphy, Burgess, and Blackburn.

Also present: Representatives Markey and Stupak.

Staff present: John Ford, Jack Maniko, Virgil Miller, Bobby

Clark, Brin Frazier, Chad Grant, Ryan Long, Nandan Kenkermath,

Jesse Levine.

OPENING STATEMENT OF HON. FRANK PALLONE, JR., A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY

Mr. PALLONE. I would like to call the meeting to order. And

today we have a hearing on Reauthorization of the Prescription

Drug User Fee Act. I recognize myself for an opening statement.

I would like to initially welcome everyone to today’s hearing,

which will be the first in a series of hearings over the next few

weeks that will focus on issues involving the Food and Drug Administration, including the Medical Device User Fee and Modernization Act reauthorization, creating a pathway for FDA approval of follow-on biologics, as well as drug safety issues. But today’s hearing will focus on the reauthorization of the Prescription

Drug User Fee Act, otherwise known as PDUFA. Originally authorized in 1992, PDUFA has provided FDA with the additional resources it needs to efficiently review an application for a new drug

or biologic to enter the market.

Prior to the 1992 law, it would take FDA up to 29 months, sometimes longer, to approve a new drug application or a biologic licensing agreement. This backlog was cause for concern for both patients and drug manufacturers. Patients had to wait longer to receive new therapies for life threatening illnesses, such as HIV/

AIDS or cancer. Pharmaceutical companies were threatened by the

loss of time they would have to recoup their investments on research and development.

2

In order to remedy these problems, Congress passed landmark

legislation which established a user fee system in which drug manufacturers would provide a revenue source to the FDA to help expedite the review of new drug and biologic applications. Since its enactment, the user fee program has been viewed largely as a success. It has allowed FDA to increase the size of its work force in

order to speed up review times. As a result, the median time between when a new drug application or biologic licensing agreement

is submitted, and FDA approval has decreased dramatically.

But shorter review time should not be the only measure of success for the program. As we set out to reauthorize this important

program for a third time, we must examine a number of issues that

remain unresolved. For example, we must pay attention to the

trade-offs we make by expediting FDA’s approval process. There

are legitimate concerns, both in and outside of Congress, that in

our rush to speed drugs to market, we could be overlooking critical

safety issues and place patients at risk. We must strike the right

balance between a timely pre-market review process and a robust

post-market surveillance system to ensure patients have access to

the safest and most effective medicines.

Previous reauthorizations of PDUFA have focused more on the

pre-market side of the process and I believe it is necessary for us

to spend more time examining how we should strengthen our Nation’s post-market surveillance system this time around. Now, to

that end, the agreement reached between the FDA and industry to

increase the amount of user fees that can go towards post-market

surveillance is certainly a step in the right direction, but that is

not to say that Congress should not take any steps further.

There are a number of proposals that would improve upon the

FDA’s ability to monitor a drug over the course of its life cycle, as

the Institute of Medicine has suggested. We need to ensure that

FDA has the resources and the authority necessary to ensure the

safety of a drug once it is already on the market. And these are

important issues that are quite literally life and death for millions

of Americans; that is why this subcommittee will examine drug

safety, in part, today but more thoroughly in a separate hearing,

as well. We will have a separate hearing on drug safety, in general.

Furthermore, while I am pleased to see that the FDA and the industry have reached an agreement on direct-to-consumer advertising, I am not certain that what has been laid out will suffice.

Under current law, FDA does not have prior approval authority for

prescription drug use advertising. Rather, FDA relies on drug markets, drug makers, to voluntarily submit their ads to review. Nothing in the current proposal would change that and the program

outlined in PDUFA still relies on the industry to voluntarily subject its ads to FDA review. This type of self-policing strikes me as

something along the lines of the fox guarding the hen house and

I realize that there are constitutional or first amendment concerns

involved here, but this part of the proposal may need some work,

particularly as it relates to the mass marketing of new drugs approved by the FDA.

In the end, I will say that many of us probably wish that there

wasn’t a need for the PDUFA program and that FDA could be

funded entirely out of general revenues, but that possibility does

3

not currently exist. In the absence of that, I think that the PDUFA

program has worked well and there is strong support for its reauthorization on a bipartisan basis and that we will obviously get

more information about a number of these issues as we proceed

today and the next few weeks.

I would like to thank our witnesses for being here today and I

look forward to their testimony and I would now recognize our

ranking member, Mr. Deal, for 5 minutes for the purpose of delivering his opening statement. Thank you.

OPENING STATEMENT OF HON. NATHAN DEAL, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF GEORGIA

Mr. DEAL. Thank you, Mr. Chairman. I want to thank you for

giving the committee an opportunity to examine this important

piece of legislation. PDUFA has helped the FDA evaluate new

drugs in a timely fashion and has given patients faster access to

approve medications. I am sure our witnesses today will testify of

the many successes of PDUFA, but also to the need for changes

during this round of reauthorization to ensure that program remains effective into the future.

Since the last authorization of PDUFA, new areas of concerns

have arisen and I am certain the committee will fairly evaluate

ways to improve the program as we move forward. For instance, I

have been concerned, for a very long time, about the types of advertisements presented to consumers during recent years and I am

pleased to see that PDUFA IV, before us today, addresses this area

of direct-to-consumer advertising.

While I realize the industry has taken steps to ensure consumers

are provided with accurate information, the establishment of a separate fee program for FDA review of these ads help solidify the

FDA’s advisory role. Hopefully, companies will take advantage of

the opportunity to receive feedback on their television ads and that

this will prevent patients from being misled by persuasive commercials. Today’s patients are bombarded with information about how

best to manage their health and they should be assured that this

information is accurate.

The increased emphasis on post-market drug safety is also well

placed. As the FDA receives information about adverse effects, they

need the tools to evaluate these reports and quickly detect problems with approved medications. Allowing the FDA to continue to

monitor the safety of the drug throughout its life and providing increased resources to improve the FDA’s post-market safety efforts

helps ensure that the drugs available to consumers are safe and effective.

The original PDUFA legislation marked a dramatic change in

how the FDA funds its drug review activities to the point that today’s user fees comprise a sizable portion of the FDA’s budget. The

committee should continue to monitor this dynamic that is created

between the FDA and the industry and the original intent that

user fees only supplement FDA’s appropriations from Congress. Indeed, a variety of drug and FDA issues await action before this

committee and I look forward to the testimony of the witnesses

who will help inform us on our reauthorization efforts.

Mr. Chairman, I will yield back the balance of my time.

4

Mr. PALLONE. Thank you and recognize Mr. Waxman for an

opening statement.

OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA

Mr. WAXMAN. Thank you very much, Mr. Chairman. Our hearing

today is on reauthorization of PDUFA, Prescription Drug User Fee

bill. This reauthorization also gives us an opportunity to look at

other ways we can enhance FDA’s ability to do its job. For example,

by giving FDA the authority to approve bio-generics and enhancing

its ongoing authority to see to it that drugs are tested on children.

But perhaps, most importantly, the reauthorization of PDUFA will

allow us to address the critical issue of drug safety.

Today, the confidence Americans have long held in FDA has been

seriously shaken. I don’t need to repeat the list of recent high-profile drug safety crises that led to this decline in confidence. FDA’s

drug safety program is in serious need of repair. The Institute of

Medicine issued a high-profile report on drug safety, concluding (1)

that our drug safety system is seriously dysfunctional, and (2) FDA

cannot protect Americans from unsafe drugs unless Congress provides more resources and more legal authorities.

FDA currently lacks several critical authorities. FDA lacks authority to require post-market safety studies, even when necessary

to determine a drug’s risks. FDA lacks authority to impose necessary restrictions on the distribution of drugs shown to have risks.

FDA doesn’t have the ability to place controls on huge advertising

campaigns at the launch of new drugs, which cause excessive use

of drugs before their safety profile is clear. And finally, the agency’s

authority to require labeling changes after approval under the current system is so weak it guarantees the drug companies will be

able to delay and water down needed warnings on drugs. We simply must address this problem.

There are some positive aspects of the negotiated FDA PDUFA

package; it increases the amount of user fee dollars dedicated to

post-market drug safety activities, but the proposal does nothing to

give FDA the vitally important authorities it needs to protect the

American public from risky drugs. That is why I hope that we can

incorporate the bill that I have introduced with Representative

Markey in this legislation, just as the Enzi-Kennedy drug safety

legislation is being added to the PDUFA reauthorization in the

other body.

This reauthorization will give us a rare but critical opportunity

to take up this legislation and see it enacted. PDUFA has now become an entrenched feature of FDA’s drug regulatory system, but

it has not been without cost. Many people think that the stringent

deadlines, timelines for taking action on new drug applications may

lead to safety problems once they are on the market. Heavy reliance on user fees gives a suspicion that FDA is in the pocket of

the pharmaceutical industry. A better balance between the amount

FDA receives in user fees and the amount it receives in Federal

dollars will help move us quite a way from dealing with this problem.

Thank you, Mr. Chairman, for holding this hearing.

5

Mr. PALLONE. Thank you, Mr. Waxman. The gentlewoman from

New Mexico.

OPENING STATEMENT OF HON. HEATHER WILSON, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW MEXICO

Mrs. WILSON. Thank you, Mr. Chairman. I don’t think there is

any disagreement on this committee or in the members of the public that the prescription drug user fee has helped to speed the approval of lifesaving prescriptions. It has brought about $270 million

of revenue into the FDA, allowing them to hire more people and

has reduced the amount of time it takes to get a drug approved,

from about 29 months down to 14 months. That is a tremendous

accomplishment for this program and I think it needs to be reauthorized.

As we look at these balances between safety and access, I hope

that we don’t overemphasize or don’t wrongly emphasize what

might be a false public perception that my colleague from California just mentioned and that we focus on the things that matters,

as public servants, and that is safety and rapid access to lifesaving

treatment. I am glad to see the steps the FDA has taken in establishing new post-marketing and surveillance efforts. I look forward

to understanding the draft bill that the administration has put forward. There are some new provisions that might enhance the process for both pre-market review and for post-market surveillance.

And I look forward to working on this legislation.

I yield the balance of my time.

Mr. PALLONE. Thank you, and recognize the chairman of the full

committee, Mr. Dingell.

OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

The CHAIRMAN. Mr. Chairman, I thank you for your courtesy. I

thank you for holding this important hearing. We are here to discuss the reauthorization of a very important piece of legislation,

the Prescription Drug User Fee Act. Originally passed in 1992, this

program has provided valuable resources to the Food and Drug Administration to allow timely approval of safe and effective new prescription pharmaceuticals and biologics. Each reauthorization has

strengthened the program and we find ourselves with the opportunity to make further enhancements.

I would note that this legislation was the result of discussions

between industry, consumers, Members of Congress, and others

who were concerned about serious problems in terms of the licensing of new drugs within the FDA’s purview. And as a result of the

gross inadequacy of funds which existed with regard to Food and

Drug and the delay that this was imposing, both on consumers and

on industry, the Members of Congress decided that we would work

with industry to create a program which would carry out the very

important purpose of ensuring that prescription pharmaceuticals

came speedily to the market and that there were funds and resources made available to FDA to carry out their responsibilities.

6

The legislation has worked well. It has been expanded on a number of occasions and it will continue to work better if this committee and the Congress does what needs to be done to see to it that

it has continuing sympathetic reauthorization processes which

move it forward. I would note that I have seen some, what I regard

as, unfair criticisms of the legislation in which it is said that the

legislation does not encourage FDA independence in terms of its licensing of new prescription pharmaceuticals.

I know of nothing to support those statements and I would advise anyone who has a different view on these matters to come forward forthwith so that the committee may go into these matters

and we may find out whether, in fact, there is something wrong

when nothing appears to be wrong. As we consider PDUFA reauthorization, we have to be mindful of two fundamental goals; gaining quicker access to lifesaving products for patients and ensuring

that the products that do come to market are safe and effective.

For a cancer patient, access to a lifesaving product in 6 months

as opposed to 18 months may be the difference between life and

death. Similarly, for that same cancer patient, access to a drug that

is neither safe or effective may very well be the difference between

life and death. We are going to work to find balance between these

concerns. We look to countless Americans who depend on the development of safe, effective and accessible drugs and biologics and

speedily so. We recognize the time sensitivity of this reauthorization. The committee must act in a timely manner to prevent possible exit of scientists and other experienced officers at FDA whose

positions are funded by user fees.

With this in mind, Chairman Pallone and I have sent a letter to

the commissioner of the Food and Drug Administration asking for

a date certain by which the agency will begin issuing notices. Coincidentally, the due date of this answer happens to be today. I will

expect our witness from FDA to address this issue in her testimony

and that we will have the answers to the questions because the

continuance of an adequate staff and an adequate mechanism to

approve new prescription pharmaceuticals is an urgent matter of

concern.

I appreciate the hearing, Mr. Chairman, and the work that user

fee stakeholders have put into this proposal. I look forward to the

testimony of the witnesses and the input of our members as we discuss the PDUFA reauthorization. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you, Chairman Dingell. I recognize now the

gentleman from Indiana, Mr. Buyer.

OPENING STATEMENT OF HON. STEVE BUYER, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF INDIANA

Mr. BUYER. I would like to compliment Mr. Waxman and the

Democratic majority, back in 1992, for this legislation. I think, as

I look back, also Mr. Dingell and Mr. Waxman, your leadership has

made a difference. And so as you look back over the history and

all the reauthorizations that we have done, the words that come up

are access and safety, but I just want to lay out part of my challenge is the inconsistent use of the language, access and safety.

So as we focus here on PDUFA, I then take a look at other

things that we have done. Well, let us see. This Congress just said

7

let us repeal noninterference, so they want to choose access over

the development of new drugs because if you repeal that, I assure

you it will have a tremendous impact upon the ability to get new

drugs to market. So here the Democratic majority then chooses access over the development of new drugs. Then when it comes to

drug re-importation, the Democratic majority will choose access

over the safety that is of our closed system.

And then when it comes to the issue on advertising, I am not

surprised the Democratic majority would then choose Government

regulation or choose censorship over freedom of speech. I don’t care,

whether I look back, they did that on the V-chip or they will do

that now with regard to how we are going to regulate on advertising. I just see inconsistencies. So as I focus here on PDUFA, I am

very keen on the language that people use. They will stand up and

pound their chest and say we are going to choose safety, we are

going to be careful with regard to access; well, at the same time,

they want to take our closed system and open it up and say well,

it is all about getting drugs from China, anyway, while at the same

time are we really protecting people? No. The answer is no, flat out

no.

And so I am challenged by, and I am going to be very careful to

listen to language that is being used as we go through the reauthorization process here of PDUFA. I just ask that we be consistent

so that we can be fair in how we treat people that reside in this

country. We should look at this not only from the standpoint of the

consumer, the manufacturer, but also, in particular, the Government, as a regulatory function. What information do our scientists,

i.e. at FDA, need that is useful so that they can look at these applications? We can increase the quality of the application, reduce the

bureaucracies and therefore get that product into the marketplace.

And moving toward this ability to enhance electronic, whether it

is filing or the adverse effects, all this will go a long way. And I

want to compliment the FDA in putting together this legislation

and with that, I will yield back.

Mr. PALLONE. Thank you. I now recognize our vice chair, Mr.

Green.

OPENING STATEMENT OF HON. GENE GREEN, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. GREEN. Thank you, Mr. Chairman, for holding the hearing

on the reauthorization of the Prescription Drug User Fee Act.

While this hearing represents the first official step in the health

subcommittee’s efforts to reauthorize PDUFA, the committee has

been working behind the scenes for a long time to take a good look

at the relationship between drug manufacturers and the FDA and

how that relationship affects the FDA’s ability to ensure the safety

of our country’s drug supply. In the Oversight and Investigation

Subcommittee we investigate cases like Vioxx, antidepressants and

Ketek and uncovered a bias at the FDA towards swift approval of

new drug applications with too little attention paid toward postmarket surveillance.

There is no question that PDUFA was initially enacted to ensure

drug approval in a more timely manner. In 1992, when Congress

first authorized the user fees, patient groups joined the industry in

8

pushing for this regulatory framework so that those suffering from

disease could have faster access to potentially lifesaving drugs. At

that time, it took 27 months, on the average, for FDA to review a

standard new drug application. That timeframe has shrunk to 101⁄2

months since PDUFA’s initial enactment. Unfortunately, the use to

be authorized by PDUFA was accompanied by some serious unintended consequences.

As we have learned, over the past few years, its bias toward new

drug approval resulted in a culture problem at the FDA where scientists with objections or concerns about the drugs’ applications

were silenced. We have heard of FDA supervisors telling scientists

that their client was the pharmaceutical industry, a statement

which flies in the face of the FDA’s mission of protecting the public

health.

In addition to culture problems, the PDUFA framework has contributed to a structural problem at FDA where the resources

weighed heavily in favor of new drug approval. In fact, the Office

of Drug Safety receives only one-fourth of the resources and oneseventh of the staff dedicated to the Office of New Drugs. With no

independent regulatory authority, the Office of Drug Safety has

only few options at its disposal to ensure that drug sponsors make

good on their commitment to post-market studies. In fact, the pharmaceutical industry hasn’t even begun 71 percent of the post-market studies requested by the FDA, a sign of the industry’s lack of

regard for the post-market surveillance process in their clear understanding that FDA, can’t do much about it.

I think most of my colleagues agree we are going to change that

bias during this reauthorization. While I am pleased that the proposal worked out between the industry and the FDA includes a

dedicated funding source for drug safety, the $29 million set aside

for drug safety represents only 7 percent of the total user fee annually under the proposal. I would like to see more emphasis on drug

safety to ensure that the FDA has a workforce level to assure the

American people that our drug supply is safe and effective.

Mr. Chairman, I look forward to working with you to accomplish

these goals of the PDUFA reauthorization process and I thank our

witnesses for appearing today and look forward to their testimony.

And with that, Mr. Chairman, I will yield back my time.

Mr. PALLONE. Thank you. Mr. Murphy of Pennsylvania.

OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA

Mr. MURPHY. Thank you very much, Mr. Chairman. I appreciate

you holding this hearing today. I wanted to bring out two parts as

we proceed with this to make sure we reviewed these as we look

at issues involving drug safety. Not only should we all be concerned

about reviewing medications and making sure that medications are

brought to the market in a timely manner, but also safely in terms

of understanding the impact of their chemical components on persons, as well as their ability to treat disease.

But it is also important, as we review this, that we look at some

of the aspects of how medication is prescribed. In particular, the

area of psychiatric medications concern me. I previously raised

9

questions that emphasized that anti-depressant medication should

only be prescribed by mental health professionals and accompanied

by psychotherapy, particularly with those with depression or bipolar illness. I know, in the past, this committee and other committees have taken up the issue with regard to adolescents, who have

increased risk of suicide when they are on anti-depressant medications.

It is important to understand that such medications may change

the mood of the patient but do not necessarily change the behavior

of the patient and they certainly do not change the cognitive processes of the patient. It is important, I believe, that the FDA works

with manufacturers and with prescribers of medication to understand that all of those components are essential parts of dealing

with medications in a safe and effective way; not only what they

are made of, but how they are used.

I am also hopeful that the final PDUFA language will reauthorize the Best Pharmaceuticals for Children Act to ensure that approved drugs are also tested for practical applications for our Nation’s children. We recognize that adult medications tend to move

faster than those approved for children and yet, it is important

that we not just use adult medications and prescribe them for kids,

but really review, in a sound, scientific, reliable and valid way all

the aspects of these medications, again, in a way that moves

through safely, effectively and efficiently in a timely manner to

help our Nation’s children.

I appreciate this time and I yield back the balance of it. Thank

you.

Mr. PALLONE. Thank you. Gentlewoman from Colorado, Ms.

DeGette.

OPENING STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF COLORADO

Ms. DEGETTE. Thank you, Mr. Chairman. This is a complicated

issue to address and I think it deserves careful scrutiny. The goal

of PDUFA is to speed up the process by which drug treatments are

brought to market in the safest form possible and I think we need

to do everything in our power, as we look at reauthorization, to further improve this program to meet that goal. Fifteen years ago

PDUFA I was enacted and the original design was simply to provide the FDA with additional funds to reduce a substantial backlog

of new drug applications and to speed up the application process

to bring drugs to market. Since its inception, PDUFA has evolved

to address the ever changing nature of prescription drugs and biologics.

In PDUFA II, Congress required greater transparency in the

drug review process, better communication with industry and outside groups and expanded performance goals to activities associated with earlier phases of drug development. PDUFA III further

expanded the FDA’s role in drug review to include labeling and collecting safety information data, among other things. In spite of

PDUFA’s evolution into its current incarnation, problems continue

to persist in the drug approval process.

10

Mr. Green and I were just talking about our membership of the

Oversight and Investigations subcommittee where we can attest to

numerous hearings over the years that there remain a significant

number of problems with the drug approval process that have resulted in dismaying health problems for many Americans. Vioxx

and Ketek come to mind here. I look forward to listening to the

witnesses’ testimony today to address the issue of how we use

PDUFA to ensure the health and wellbeing of those who take pharmaceuticals and biologics every day.

As we approach the authorization of PDUFA IV, I would like to

stress several issues that are important. Because of the problems

that have occurred with a number of drugs over recent years, as

we have heard, the public has lost confidence in the FDA to protect

it from the negative effects of some pharmaceuticals and biologics.

The FDA must regain its trust from the American public and show

the public that it is truly an independent agency interested only in

the public’s health. This will mean increased transparency with the

drug approval process and more intensive post-market drug review.

Safe and effective drugs are what people expect from the drug

approval process and we need to show that such a process exists.

As with any situation in which regulators are working closely with

entities that are regulated, there are oftentimes people who see

that relationship as too cozy. I am interested in hearing from the

two panels today about how we might better make clearer distinctions between industry and regulators to further restore the

public’s confidence.

Mr. Chairman, as with past iterations, this process is an opportunity to improve on the foundation of PDUFA and I look forward

to working with you, the committee and those here today to make

sure that the health and wellbeing of our country is preserved.

Thank you.

Mr. PALLONE. Thank you. The gentleman from Texas, Dr. Burgess.

Mr. BURGESS. Thank you, Mr. Chairman. I am going to submit

for the record, in the interest of time. We have got many witnesses

who have come quite a distance, far away as northwest Washington, so I will reserve my time for questions.

[The prepared statement of Hon. Michael Burgess follows:]

Mr. PALLONE. Thank you. The gentlewoman from California,

Mrs. Capps.

OPENING STATEMENT OF HON. LOIS CAPPS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA

Mrs. CAPPS. Thank you, Chairman Pallone, and thank you to our

witnesses for their testimony today at this important hearing. And

as we begin our discussion about Prescription Drug User Fee Act

and its reauthorization, we undoubtedly will be opening the door

to a whole slew of issues related to Food and Drug Administration

function. As we discuss each of these issues, we need always to be

keeping uppermost in mind the most important issue of all and

that is ensuring a safe and affordable drug supply to all Americans

within effective timelines. The progress has been made; unfortunately, we have not yet reached this goal.

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I understand that my colleagues in other subcommittees and

committees have already held hearings on the barriers to ensuring

that safe and affordable drug supply that we desire. I hope that

today we can build on some of the lessons already learned and the

bottom line remains, I believe, two of the barriers are: one: the failure to provide FDA with adequate appropriated funds to fulfill its

mission, and second, a system vulnerable to and indeed, plagued by

conflicts of interest.

There is something very wrong when the Institutes of Medicine

concludes that the drug safety system is impaired. And the General

Accounting Office concludes that ‘‘FDA lacks a clear and effective

process for post-market drug safety issues.’’ Clinical trials are an

important component of evaluating drug safety, but they cannot be

the only one. We must be more rigorous in monitoring those drugs

once they reach the public. Quite frankly, I fear that the failure to

properly invest in post-market safety is a result of inappropriate

industry influence in the process.

I am also deeply concerned with staffing and structural issues at

the FDA that impede optimal results for timely and safe approval

of drugs. We simply must do more to attract and retain qualified

scientists and then give them the tools to properly monitor drugs

continuously through the process of pre-market approval through

post-market surveillance. I certainly recognize the impetus for creating PDUFA and for needing additional revenues to get lifesaving

drugs out on the market as quickly as it is safely possible.

But unfortunately, we do not have the best possible system in

place, even though we are quite aware of what improvements are

necessary. As we move through the PDUFA reauthorization process, I hope we can succeed in making the improvements necessary

to serve our Nation’s public health interests. We have an obligation

to do so. I yield back.

Mr. PALLONE. Thank you. The gentlewoman from Tennessee,

Mrs. Blackburn.

OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF TENNESSEE

Mrs. BLACKBURN. Thank you, Mr. Chairman, and I want to welcome our witnesses who are here. We look forward to hearing from

you. Four quick points from me on the issue before us. As we look

at the reauthorization, I will say it is nice to see a program that

has shown some success and we look forward to hearing about the

successes and then also some of the stumbling blocks that may be

there.

Second, it is nice to see a program that has a revenue string and

then applies it back into its mission. Number 3, that mission of expedited review and safety monitoring, safety of product to the marketplace, Dr. Mullin, I will say it is nice that that is still on the

radar, the agency hasn’t lost sight of that. And No. 4, I think it is

imperative that we realize money does not solve every problem and

just giving more money in a budget is not going to take care of any

of the obstacles or burdens that are there.

I hope that we will keep our focus on looking at regulation, at

duplication, at paperwork, at the burden of bureaucracy that may

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be a hindrance—that may be continuing to slow the process and

keeping drugs that need to be in the pipeline and to consumers

who need to get them. And with that, Mr. Chairman, I thank you

and I yield back.

Mr. PALLONE. Thank you. I recognize the gentlewoman from Oregon, Ms. Hooley.

OPENING STATEMENT OF HON. DARLENE HOOLEY, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF OREGON

Ms. HOOLEY. Thank you, Mr. Chairman. The Prescription Drug

User Fee Act has played an important role over the last 15 years

in getting drugs and biologics to patients more quickly. Patient access to potential lifesaving drugs was unreasonably delayed before

this act was passed. On average, it took over 30 months for a drug

to get approved in 1992, before PDUFA. Fortunately, the median

time between submission of an application and approval has decreased to less than 14 months as a result of funding provided by

PDUFA. However, it is not perfect.

The high proportion of FDA drug review funding provided by

user fee is not ideal. Given current budget constraints, user fees

are an important and necessary source of funds to get lifesaving

drugs to market as quickly and safely as possible. Along with ensuring adequate funding for review of new drugs, it is critical that

reauthorization of PDUFA improve post-market safety reviews.

As Dr. Mullin notes in her written testimony, reports of serious

and unexpected side effects increased by more than 65 percent in

the 3 years between 2002 and 2005. That is an alarming increase

and we must ensure that FDA has sufficient resources to analyze

adverse events and take action when a pattern of adverse events

is recognized.

The FDA recommendation to eliminate the restriction of postmarket surveillance to only 3 years after approval is a positive

step. There is no good reason why FDA should not review drugs

for adverse side effects as long as they are on the market. Larry

Kirkwood, a constituent of mine from Molalla, came in to my office

last month to share his story about the debilitating stroke he suffered. He believes his injuries were caused by a prescription drug

that FDA failed to learn had unexpected side effects until after it

was too late for him.

I want to make sure that FDA has sufficient funds to ensure that

no one has to wonder, like Larry, whether an adverse health event

could have been avoided if they had knowledge of potential side effects learned through more rigorous post-market surveillance. I

look forward to discussing the direct-to-consumer advertising provisions recommended by FDA. The FDA is correctly taking an increased oversight role with DTC advertising. However, I want to

make sure that the voluntary system envisioned by FDA is sufficient to protect the public health.

Finally, I think it is important to pass PDUFA in a timely manner so that FDA does not lose its best scientists because Congress

fails to act before their employees received reduction in force notices. Thank you, Mr. Chairman. I look forward to the hearing.

Mr. PALLONE. Thank you. I recognize the gentleman from Arizona, Mr. Shadegg.

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OPENING STATEMENT OF HON. JOHN B. SHADEGG, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF ARIZONA

Mr. SHADEGG. Thank you, Mr. Chairman. I thank you for holding

this hearing. The Prescription Drug User Fee Act was originally

enacted in 1992 in order to expedite the approval process for drug

and biologic applications and drug safety monitoring and I believe

we should work together in a bipartisan fashion to reauthorize it.

To accomplish its goal, PDUFA requires pharmaceutical companies

to pay application fees for each new product, annual manufacturing

fees and annual product fees. These user fees have contributed to

a 42.5 percent of the FDA’s human drug program budget in 2006,

roughly $517.5 million.

Prior to the enactment of PDUFA, FDA review for a new drug

or biologic averaged 29 months. By 2003, that approval time had

dropped to less than 14 months, meaning it had been cut more

than in half. The benefit to consumers of speeding up this process

is immense in terms of lives saved and health improved. The latest

reauthorization, commonly referred to as PDUFA IV, aims to enhance pre-market review of human drug applications, ensure the financial footing of the human drug program and modernize the

post-market safety system.

To accomplish these goals, the proposal would increase the overall user fee by $87.4 million above the current levels. I believe

these are worthy goals and that it is important for us to steward

this legislation through bipartisan passage as quickly as possible.

Mr. Chairman, I look forward to working with you and to hearing from the experts before this committee and to approving reauthorization of a straightforward legislation as quickly as possible

and I yield back the balance of my time.

Mr. PALLONE. Thank you. The gentlewoman from California, Ms.

Eshoo.

OPENING STATEMENT OF HON. ANNA G. ESHOO, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA

Ms. ESHOO. Thank you, Mr. Chairman, for holding this important hearing on reauthorizing PDUFA. I am proud to have worked

with former Congressman Jim Greenwood to enact the most recent

reauthorization of this legislation and I can’t believe how time flies,

that we are here again. This is always an important opportunity

to not only review what Congress put into place, but the time to

review how well it is working. And I think it is one of the most

important pieces of legislation that our committee is going to undertake this year.

Prescription drugs and biologics have really changed healthcare

as we know it and they continue to improve patient care and to extend lives. Prior to the initial passage of PDUFA, it often took

years; not months, but it took years for drugs and biologics to be

reviewed by the FDA. They were then strapped for financial and

human resources and they were unable to devote enough time and

energy to the review process. PDUFA, I think, has come a long

way, so that the FDA has the staffing and the expertise to ensure

that drugs are safe and reach the patients that really need them.

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But there are always tensions in the two undertakings, that it

is a timely process so that the most important and the best products move into the marketplace, obviously, to patients, but also

that there is the efficacy that the American people have come to

not only appreciate, but demand of the FDA. So I think that

PDUFA has worked and that it has worked well, but it is not without its problems and the program is not perfect. In fact, I think

anything human beings devise is a reflection of our humanity. It

is less than perfect.

What I would like to say in this is that I hope, Mr. Chairman,

that we will have a clean bill. The whole issue of follow-on biologics

or biosimilars is one that is being examined in the Senate and I

know that Mr. Waxman is planning to raise here. I do not think

that it should be part of PDUFA. There are many complexities to

what is being talked about and offered. I think that the committee

needs to review that kind of legislation on a stand-alone basis.

I am not so sure what you plan to do with the pediatric legislation. I was Democratic lead on that. I think that that has worked

well. I also think that that should be discussed, maybe, in its own

hearing, whether you plan to make that part of the reauthorization

of PDUFA. I would like to talk to you about it so, I am glad that

we are having this hearing. I look forward to hearing from the witnesses. I want to reiterate my support for PDUFA and the user fee

program. I think it is a good combination both what the industry

does and the funding for FDA and if we need to do more, we need

to examine it and make that decision.

Certainly, the American people should have full confidence in

FDA and there have been some products that have had to be removed from the market. We need to examine that, why that has

happened and I hope that when we come through the other side

of this process, that the American people will have even more confidence in the FDA. So thank you for holding this hearing. I look

forward to the testimony of those that are going to be here. We

have individuals that were a part of our team. Thank you for holding the hearing.

Mr. PALLONE. Thank you. I recognize the gentleman from Oklahoma, Mr. Sullivan.

Mr. SULLIVAN. I waive, Mr. Chairman.

Mr. PALLONE. And the gentleman from Utah, Mr. Matheson.

OPENING STATEMENT OF HON. JIM MATHESON, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF UTAH

Mr. MATHESON. Thank you, Mr. Chairman. Thank you for holding this hearing. As we will learn today from our panel of experts,

new drugs are now available in this country faster than anywhere

else in the world. In fact, since its inception in 1992, PDUFA has

helped enable FDA to improve more than 1200 new medicines and

reduce review times for innovative drugs and biologics, providing

patients and doctors with access to breakthrough treatments. And

this is an important achievement. It shows that the PDUFA program is meeting its primary goal. I do think we should make every

effort to ensure that people have access to effective new medicines

as quickly as possible, but with thorough and compliant safety

guidelines.

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In light of recent adverse drug examples brought before Congress, I look forward to hearing recommendations from our witnesses on how best to achieve the balance between innovation and

public safety. As a new member of this committee, I am looking forward to the discussion and recommendations for the reauthorization of this program. And with that, Mr. Chairman, I yield back.

Mr. PALLONE. I recognize Mr. Pitts of Pennsylvania.

Mr. PITTS. I will waive.

Mr. PALLONE. And next is the gentlewoman from Wisconsin, Ms.

Baldwin.

Ms. BALDWIN. Thank you, Mr. Chairman. Thank you for holding

this hearing and I, too, will waive my opening statement this morning.

Mr. PALLONE. And then we go to Ms. Schakowsky, gentlewoman

from Illinois.

OPENING STATEMENT OF HON. JAN SCHAKOWSKY, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF ILLINOIS

Ms. SCHAKOWSKY. Thank you. Since its enactment 15 years ago,

PDUFA has made a significant difference in the time it takes to

get lifesaving prescription drugs into the hands of patients who

need them. For many years this has, for many, literally meant the

difference between life and death, as the FDA’s new drug approval

process has been streamlined from 29 months in the 1980s to just

12 months for standard application and 6 months for priority application. This made possible by funding collected by the user fee,

which has enabled the FDA to literally double its staff and make

major improvements towards technology.

But as I am sure most of us know by now, this user fee is the

farthest thing from free money. Coming in at just under 43 percent

of the FDA’s funding for human drug programs, there is no pretending that the source of this funding plays a small impartial role

in policy and procedure at the FDA, far from it. In fact, it is no

secret at all that the pharmaceutical industry has been granted a

statutory role in directing where the collected user fees will be allocated within the FDA.

Behind closed door with no public input, the industry decides

how the FDA will spend this money, speeding up the approval

process at the cost, sometimes, of important safety measures. With

a fourth PDUFA authorization proposal, including an additional

$87.4 million in user fees over the current base, it is well past time

for us to start examining what needs to be in place to protect consumers. We need better transparency, better oversight of direct-toconsumer marketing and additional resources allocated to postmarket surveillance.

Without these measures, we may only see additional tragedies,

like the unacceptable cases of Vioxx and Ketek. The drug industry

cannot continue to be given a carte blanche at the FDA. They must

be held accountable and we must enable the FDA to increase their

authority and transparency throughout their drug approval process. I look forward to what should be a very productive hearing

today and I am eager to hear from our witnesses. I yield back.

Thank you.

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Mr. PALLONE. Thank you. And that concludes the opening statements by members of the subcommittee, so we will now turn to our

witness.

I want to welcome Dr. Theresa Mullin. Dr. Mullin is the Assistant Commissioner for Planning with the Food and Drug Administration, and we will now have a 5-minute opening statement from

Dr. Mullin. I just want to mention that, in the discretion of the

committee, you can submit additional brief and pertinent statements in writing for inclusion in the record. And I will now recognize you for an opening statement. Thank you for being with us

today.

STATEMENT OF THERESA MULLIN, ASSISTANT COMMISSIONER FOR PLANNING, FOOD AND DRUG ADMINISTRATION

Ms. MULLIN. Good morning, Mr. Chairman and members of the

committee. I am Theresa Mullin, the Assistant Commissioner for

Planning at the Food and Drug Administration and I am pleased

to be here today to talk about the Prescription Drug User Fee Act,

known as PDUFA. As a Director of Planning, I played a lead role

in the coordination of implementation of PDUFA III and the ongoing analysis of PDUFA performance and resource requirements.

And most recently, I served as the lead FDA negotiator in the discussions with industry related to the reauthorization of PDUFA.

I would like to begin by discussing the successes of PDUFA and

FDA’s implementation of PDUFA, and also describe some of the

challenges that we have tried to address in our recommendations

for reauthorization. I will also summarize the highlights of our proposals for PDUFA IV. I would also like to emphasize the importance of a timely reauthorization before the expiration of this program in September of this year.

Let me start by saying that FDA considers the review of safety

and effectiveness of new drugs to be a central part of its mission

of protecting and promoting public health. As you know, Congress

enacted PDUFA in 1992 and its been reauthorized twice since

then. The law provided added funds that made it possible for us

to hire additional reviewers and update our IT systems to support

drug review. At the same time, we committed to providing a complete review in a faster and more predictable timeframe. But prior

to that, our drug review process was understaffed and slow and it

delayed access to new medicines for patients in the United States.

PDUFA enabled us to increase the speed of the application review without changing our standards for safety and effectiveness.

And this has also led to a shorter time to marketing approval for

those drug applications that have met the standards. The median

time for approval for priority drugs and biologics has been reduced

from a median of 15 months in 1993 to a median of 6 months in

2006. And a priority designation means that it is a new drug that

offers a significant advance over existing treatments. Earlier access

to new drugs has provided important benefits for patients.

Since the enactment of PDUFA, FDA has approved over 1,200

new drugs and among those approvals, 76 new drugs for cancer,

178 new anti-infective drugs, 111 new drugs for metabolic and endocrine disorders, 115 new drugs for neurological and psychiatric

17

disorders, 80 new drugs for cardiovascular and renal disease,

among many other new medicines.

PDUFA has been successful in speeding access to new drugs, but

the program has also faced challenges and I would like to talk

briefly about the challenges. First, program costs, including payroll

and rent related cost, have really outpaced the funding. And second, the review workload has grown significantly, particularly review activities that are not accounted for in the current workload

adjustor. There has been an increasingly dramatic growth in the

number of consultation meetings requested by companies during

the drug development phase.

For example, in the year 2000 meetings scheduled at the request

of drug sponsors grew by 72 percent and now we are up to, last

year, 2,288 meetings requested by companies for consultations.

That translates into more than nine industry meetings per business day. And the same people who are doing those meetings are

doing drug reviews and all the other work. These meetings are very

useful. They basically help to improve the drug development program and it is a benefit to the patients who are then going to be

participating in the clinical trials in that program. But they are

also very labor intensive.

The third challenge is the growth in the volume of post-market

safety work and our system hasn’t kept up. For example, the number of serious and unexpected adverse events grew by over 65 percent between 2002 and 2005. We need the capacity to review and

respond in a timely manner. PDUFA currently allows for fee supported post-market activities, but it is only for up to the first 3

years after approval and only for those products approved after October 1 2002. Our analysis of the timing of safety related labeling

changes has found that the majority of those changes occur after

the first 3 years that a product is on the market.

In our most recent reauthorization, PDUFA III, Congress directed FDA to consult key stakeholders in developing our reauthorization recommendations. We began with the public process in November 2005. We had a public meeting on PDUFA and asked

stakeholders to tell us what they thought should be changed and

what should be retained in the program the following year. In

2006, we had meetings with the patient groups, consumer groups

and health professionals to, again, follow up and find out what they

thought we ought to be doing to improve the program.

Now, in these meetings, some stakeholders felt concern that we

rely on user fees at all, but most felt that we really needed to have

strong support to keep the review program strong and adequately

staffed. Nearly all expressed the view that we ought to be spending

more on post-market safety in PDUFA and many thought we

should be expanding our capacity for the review of direct-to-consumer advertising. In our discussions with industry and in development of recommendations, we have tried to address those concerns,

as well as our own.

I would now like to highlight the four key recommendations that

we have for PDUFA IV. The first is to put the new drug review

program on a sound financial footing. User fees have provided substantial resources to FDA, but they haven’t kept up with the increasing cost of the program due to inflation and this expanding reVerDate 11-SEP-98 10:35 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00022 Fmt 6633 Sfmt 6633 Q:\DOCS\110-29 SCOM1 PsN: SCOM1
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view work load. And so we are proposing changes to the financial

provisions of PDUFA that would correct for these shortcomings.

Second, we are recommending enhancements in two areas of premarket review; first, to expand our work in the good review management principles for efficient and effective pre-market review

and second, to conduct some initiatives so that we can enhance the

science base and upgrade the science base of our review process

and also develop guidance to improve and expedite critical drug development.

And third, we are recommending changes to modernize the postmarket safety system. We are recommending increased funds and

the removal of the date limitations on the use of those funds for

post-market safety and we are recommending increased funds to

first conduct studies to be sure we are applying the most effective

tools for collection of adverse events. We also want to expand our

access to better patient population databases for epidemiology.

Training for the post-market safety area, our standards for epidemiology studies, evaluating what really works in risk management

post-market. And finally, direct-to-consumer advertising. We are

proposing a separate user fee for direct-to-consumer advertising because stakeholders expressed concerns about this and we are proposing a separate program for that and so that we can conduct a

more timely review of the ads submitted to us for comment, for advisory review so we can weigh in on whether those ads are accurate

and adequately balanced and adequately supported. My final point

is just, and I have heard it many times, about the need for reauthorization and that we want to work with you in whatever way

we can to support that. Thank you. I will be happy to answer any

questions.

[The prepared statement of Ms. Mullin follows:]

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Mr. PALLONE. Thank you. Thank you very much and now we will

take some questions and I will recognize myself for 5 minutes for

that purpose.

My first question relates to what Chairman Dingell said and you

mentioned, the need for timely reauthorization. A few weeks ago,

Chairman Dingell and I wrote to Dr. von Eschenbach asking for a

day certain as to when he would be forced to send a reduction in

force or RIF notice to FDA employees should the user fee program

fail to be authorized before September 30. Under part 351 of title

5, Code of Federal Regulations, the commissioner would have at

least 60 days to issue a RIF notice and that would put us at the

end of July that we would have PDUFA reauthorized or on its way

to the White House.

We are asking this so as to understand the timeframe, we can

ensure that there is no personnel disruptions with the program, so

my questions really are first, do you have that date for us with regard to the RIFs and second, would there be any reason to move

the date up to the end of June or sooner? This is all for the purpose

of getting this done in a timely fashion, obviously.

Ms. MULLIN. Well, as you said, the regulations require that we

give individual employees 60 days notice. Substantial planning has

to go into identifying the employees and putting that RIF into effect. The union would also need to be notified of it and it is a fairly

complex process. We would like to submit the longer description of

what has to be done in order to carry out that process, but I guess

the larger point for us, as you say, is that when employees become

aware that a process is underway, we are concerned that they may

begin to look for something else to do.

Mr. PALLONE. But are you going to give me a date because Mr.

Dingell insists on regular order around here and we want to be orderly.

Ms. MULLIN. I wish I could give you a specific date. I do have

one and I would like to go back and have the longer description of

what has to be done provided to you. I do know that reauthorization in June or at least mid-July would be most preferred, I would

say.

Mr. PALLONE. OK. Well, that is helpful. Thank you. Second question. The PDUFA IV proposal is a result of a compromise between

FDA and stakeholder groups. What are some of the items that

were included in the initial discussions that were left out of the

final proposal?

Ms. MULLIN. Well, in terms of the safety package that we have,

we essentially have gone into the package, it is all of our priorities

FDA identified for drug safety and the entire package was supported. FDA, in its own, looking at other programs, for example, in

the DTC area, has focused on TV advertisement as a place where

we can really sort of have a great impact, we think, and we actually have the data to actually structure and go in there and start

a program data on the workload that is there today so we can estimate what it would take. I would have to say that in terms of

resourcing for what we wanted to get that we really did come out

of it with the things that we went in and wanted to have.

Mr. PALLONE. So you don’t think there are any items that were

in the initial discussions that were left out, for the most part?

33

Ms. MULLIN. No, I don’t think we really got the things that we

were hoping to get.

Mr. PALLONE. OK. Now, you mentioned, in your written testimony, that the number of reports of serious and unexpected adverse events has jumped by more than 65 percent in 3 years. In

your opinion, is there a correlation between those reports and the

fact that user fees are becoming a larger and larger portion of the

FDA budget?

Ms. MULLIN. In my opinion, there is no relationship between

those two things.

Mr. PALLONE. OK. And then I wanted to ask you, finally, according to the data analyzed by Harvard professor, Daniel Carpenter,

drugs approved just before PDUFA deadlines are far more likely

than those approved at other points in the review cycle to cause

safety problems after they are in widespread use. Do you agree

with that assessment?

Ms. MULLIN. I had heard about that finding. I haven’t read his

paper and I really don’t feel I can comment on it. I just really don’t

think I can make a comment on it.

Mr. PALLONE. What I am trying to get out is whether there is

any indication that PDUFA timeliness and PDUFA timelines compromise the safety of new drugs and biologics. If you don’t think

that is true, do you have——

Ms. MULLIN. Well, we don’t believe that there is a problem. We

don’t think that the timelines have any effect on the safety or the

issues that he points out by, like I said, I don’t really know what

is in his paper, but that has not been our experience. We don’t

think there is a relationship there.

Mr. PALLONE. Do you have any evidence you could submit to us

in writing that would contradict what the professor is saying?

Ms. MULLIN. I think we would be happy to provide a more

thoughtful and to go back and look at that paper response to that

for the record.

Mr. PALLONE. I would appreciate it. Thank you. Mr. Deal.

Mr. DEAL. Thank you. I would like to ask you if you could elaborate on the whole issue of health information technology. Let me

couch it in two particulars. Last year, as we were trying to pass

an expanded health information technology bill, one of the things

we were trying to promote was non-identifiable health information

that could assist in a variety of areas; further development in research, et cetera. And I guess my concern is what is the current

situation with regard to your ability for data mining through

health information technology to determine adverse events and to

what extent could that be expanded and to what extent would the

funding that is in this proposed legislation assist in that regard?

Ms. MULLIN. Our current post-market safety system relies primarily on a passive reporting approach and we receive information

through passive surveillance. I believe what you are describing is

moving more toward what is called an active surveillance system

and the proposals that we have for post-market safety in PDUFA

IV would move us and position us to be ready to begin, but be

ready to be a part of that kind of system which is often described

and I think, envisioned as a consortium or partnership with many,

34

many parties participating is how I think the department has conceived it, as well.

We have talked about a sentinel system, for example. But to do

that, we need to have the infrastructure that can allow us to link,

have access to linked databases, these kinds of population databases that we are talking about and so we need to have that. We

would need to have better tools, analytic tools, for mining appropriately using those kinds of data and as I mentioned, in our packages, best epidemiology practices so the people’s methods for looking at these very complex data sets are consistent to well-understood, so people aren’t arguing about the findings because they

don’t agree on the methods. So we want a process where we involve

academics and industry and other members of the public in trying

to identify and discuss that so we can identify best practices for

using those kinds of data sets, as well. And we have put in some

resources for moving toward that kind of approach in PDUFA IV.

Mr. DEAL. I think one of the things that we all have concerns

about is that we have some overall and overarching policy considerations as we deal with a variety of issues, and I think the information technology gathering process is very important, especially as

we deal with things like follow-on biologics and the pharmaceuticals associated with all of that entire area.

I know this is not exactly within the scope of what you are here

to testify about today, but I would hope that FDA would provide

this committee with your points of view as it would regard how we

would structure this non-identifiable information that would be

most beneficial to you. For example, I know that in the projects

that are ongoing now with reporting of information by physicians

and others and moving toward perhaps they pay for performance

arrangement. I would hope that we would have the information

that is being gathered there in a format that would be compatible

with FDA utilizing that information.

Sometimes I think we do things in little categories of their own

and do not have concern for how they could interact with and impact on other areas of what the Government is doing in different

agencies. So I don’t think it necessarily requires a response from

you here, but I would hope that as we move forward looking at

these areas such as health IT, that FDA could give us some insight

as to what, if anything, we could do that would facilitate your activities, particularly as it relates to the post-approval adverse event

categories. Thank you, Mr. Chairman.

Mr. PALLONE. Did you want to respond?

Ms. MULLIN. My comment there would be that the department

is undertaking an effort to look at, certainly under the AHIC, as

it is called, under Secretary Leavitt and the Office of National Coordinator, are focusing on interoperability standards to be sure that

we do have the kind of capabilities you are describing and FDA is

fully participating in that process.

Mr. PALLONE. Thank you. Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman. Dr. Mullin, thank you

for your testimony. The industry/FDA proposal would expand the

use of the user fees to some important post-market safety activities

and this is a positive development. I want to ask you more about

this. The proposal specifies that FDA may apply user fees to things

35

like (1) collecting and reviewing post-market safety information; (2)

developing improved adverse event data collection systems; and (3)

expanding FDA’s analytical tools to assess potential safety problems, including access to external databases.

And yet, under the proposal, only $29 million would be devoted

to these activities; the remaining $360 million would continue to be

spent on review activities. In its report, the IOM set forth some

rough estimates for how much funding it would take to conduct enhanced drug safety activities, including many activities described

in the industry/FDA proposal, they came up with something more

in the range of a $100 million to $200 million. So I am deeply concerned that $29 million is just not going to be enough. At the outset of the FDA and negotiation with industry, how much did FDA

request for drug safety activities?

Ms. MULLIN. At the outset of our discussions, we, as I mentioned

a minute ago, wanted the set of items that we proposed and we

have a base amount of spending already in the post-market area,

although it has the time restrictions on it, and it is on the order

of about $15 million a year that we currently have from user fees

that we spend on post-market safety, as opposed to the broader

drug safety, of course, which a great deal of which happens in premarket. But $15 million, 30, 29.3 is added to that and this is again

focused on these post-market activities. But we focused on the set

of things that are post-market safety.

Mr. WAXMAN. You thought this amount of money is sufficient?

You didn’t ask for more.

Ms. MULLIN. We thought it was sufficient to cover the things

that we thought were our highest priority. It would certainly not

cover everything that is recommended in the IOM report.

Mr. WAXMAN. Let me ask you this. If all you asked for was an

additional $29 million, would this create an optimal drug safety

system? If not, what else is needed?

Ms. MULLIN. I think it doesn’t create the system mentioned in

the IOM report, which is a much more expansive effort, but it gives

us a very strong safety system that we think is a significant improvement and will provide a very strong capability for us.

Mr. WAXMAN. One of the recommendations that the IOM made

was to do something about FDA’s lack of authority to require drug

manufacturers to take certain critical actions with respect to drug

safety. For example, FDA is unable to require manufacturers to

conduct post-market studies. Under the current law, FDA could ask

a manufacturer to conduct the studies and then hope that they are

actually done when the manufacturer has agreed to FDA’s request,

but if later they don’t do the studies—and most of them appear not

to—FDA’s only option is to remove the drug from the market,

something that FDA has never done and isn’t likely to do, given

the significant patient populations that come to rely on these

drugs.

I know that one of the performance goals contained in the industry/FDA PDUFA proposal is develop standard operating procedures

that would clarify FDA’s policies and procedures with respect to requesting voluntary study commitments, but this obviously does

nothing to address the very critical fact that FDA is entirely unable

36

to require that these studies be done in the first place or that they

be completed. This is not, of course, just a theoretical problem.

According to FDA’s own data in 2006, there were 1200 open or

ongoing commitments to conduct post-marketing studies, but manufacturers ended up completing only 11 percent of these studies

that year; 71 percent of these studies hadn’t even started. Do you

think this is acceptable? Do you agree the PDUFA package does

nothing to change the fact that FDA lacks the authority to require

post-market studies because FDA would need Congress to act to

address that problem?

Ms. MULLIN. Well, I will go back and begin with the IOM report

and I know those recommendations were in there. The IOM report

had recommendations——

Mr. WAXMAN. Well, I am not talking about the report. I am asking specifically on this issue, on this recommendation that you be

able to require these studies to be done.

Ms. MULLIN. I will begin, if I may, just saying that the recommendations that they made were for FDA, some recommendations for the department and some for Congress and regulatory authority recommendations were directed at Congress and my role in

doing these PDUFA discussions has been to focus on getting better

resourcing for the current authority and so we can do a better

job——

Mr. WAXMAN. Well, don’t you think in addition you ought to have

that authority to require the manufacturers do the study?

Ms. MULLIN. I can’t really speak to that, but I can say that what

we have in the PDUFA that we are recommending is additional resources so that——

Mr. WAXMAN. Well, I know you are satisfied with what you have,

but don’t you think you ought to have more, given your experiences

at FDA in this area?

Ms. MULLIN. I am really not an expert on that and I can’t really

speak to that.

Mr. WAXMAN. Thank you. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you, Mr. Waxman. Mr. Buyer from Indiana.

Mr. BUYER. I would like to follow up where, on Mr. Waxman’s,

but take a different course on the post-market review. I noticed,

over the years, the FDA has been very concerned with regard to

the number of counterfeit drugs that are coming into our country.

So here we can focus on the perfection of a closed system, while at

the same time we have cracks in that closed system. So the Internet has exploited this and so we have many of our citizens think

that they are getting drugs from Canadian pharmacies when, in

fact, the FDA, in cooperation with United States Customs and Border Protection, you have been conducting surveillance.

So whether it has been in 2001, 2003, 2004, 2005, you have been

going to different ports of entry, examining parcels that come in to

the hubs and you have been determining that many, each one,

there are different percentages; 60, 70, 80, now it is 90 percent of

the drugs that they examine are non-FDA approved drugs. So if we

are going to look at this post-market review and how you are able

to come up or perfect a particular system, I look at this and say

my gosh, if we have got so many unapproved FDA drugs, obviously,

37

there would be then a lack of assurance with regard to safety, effectiveness, quality and purity.

And if the FDA cannot assure the safety and efficacy of a drug

product line that is coming through these types of sources, because

you have not been able to review or you didn’t review or approve,

nor have you had accessibility to monitor the manufacturing and

quality control of a particular facility from a particular country.

And if they are coming from 27 different countries through these

types of sources, I don’t know how you can sit here before us and

say well, we are going to have a wonderful monitoring system here.

We go to page 8 of your testimony. On page 8 of your written

testimony in discussing the post-market review of drugs, it says the

FDA intends to use additional resources ‘‘to improve our tools for

detection of adverse events.’’ My question, now, is knowing that we

have this exploitation that is occurring from other countries to gain

access to our system and there are people even sitting here in this

panel before you that think that will this get access to people? To

heck with safety. Let us go with a populist issue. So to what extent

has the FDA factored in counterfeit drugs and what effects will

FDA pursue to combat counterfeit drugs in this post-market review?

Ms. MULLIN. The post-market compliance issues that you refer to

are currently outside the scope of what is defined as human drug

review in the statute and our recommendations for PDUFA IV

would still not include post-market compliance issues in the area

that you are talking about.

Mr. BUYER. Time out for just a second. We are going to reauthorize this. If I had a particular drug that is on the market and if,

oh, take a step back. A manufacturer puts a drug on the market

and the doctor has prescribed this particular drug to the patient.

The patient begins to take that drug and then thinks that well, I

can get that drug cheaper, so I will get it through a Canadian

source and what we have happening is, is that there are adverse

effects that don’t even end up being reported. So my question to

you is how can we have an effective system if we have this

prevalency occurring with regard to the number of unapproved

FDA drugs and many, many drugs that are coming onto the marketplace? How can we improve this detection system?

Ms. MULLIN. Well, some of the adverse event reports we may be

getting now may be the result of the use of counterfeit medications

and we are going to continue to monitor adverse events and try to

understand the context of the care in which they occurred so we

can identify what the source of harm was.

Mr. BUYER. Do we know that of the 60 percent increase of adverse effects over the last 3 years, do we know the impact of the

counterfeit drugs are having upon that number?

Ms. MULLIN. I don’t think we do, but I have to say we are really

outside of the scope of my expertise and if you would like, we can

certainly go back and talk to the experts who focus on the counterfeit drug issues at FDA and provide you an answer for the record.

Mr. BUYER. I just don’t know how we can have, how we can best

protect the American people and give them the assurances of a

drug’s safety if we are going to permit this exploitation and damage

to our drug supply and then in turn, beat up the manufacturer. I

38

would like to work with you on figuring out how we can expand

the scope and go after these counterfeiters. I yield back.

Mr. PALLONE. Thank you. The gentleman from Texas, Mr. Green,

our vice chair.

Mr. GREEN. Thank you, Mr. Chairman. Again, welcome, Dr.

Mullin. Former FDA Commissioner Mark McClellan has advocated

for a more robust system to monitor post-market risk. In testimony

delivered to the Senate Health Committee and in a recent New

England Journal of Medicine article, he writes the problems in the

current adverse events reporting system are spontaneous and by

design, can only capture a small fraction of the problem. To improve surveillance, Dr. McClellan proposes that risk information be

gathered through an electronic and active surveillance system network.

We know that data exists already through private health insurers and within the Medicare and Medicaid programs. In fact, I

know at least one pharmacy benefit manager that thanks to its

electronic data, knew about the Vioxx problem and pulled Vioxx before even the FDA took action. Can you comment on Dr.

McClellan’s proposal to what additional funds would be needed to

implement it and how it could complement existing surveillance

systems at the FDA to catch these problems sooner?

Ms. MULLIN. Well, we think that the active surveillance approach that Dr. McClellan is describing is really the way of the future. We think that is the way we want to go in the future. I think

that what we have in our package of proposals for PDUFA IV, as

I am saying, it really helps us to move and be positioned to be able

to work effectively with that kind of pooled population data. The

scope of such a system that is envisioned is not there yet today.

Those electronic health records are definitely beginning to become

available, so we are moving in that direction.

What we are doing, to be ready for that kind of system which I

have often heard described as perhaps something where there will

be multiple parties involved, shared resources and so forth, in the

future where we want to be ready for that, to be participating in

it and so the tools and moving the infrastructure, our IT infrastructure, that way is critical for our being ready to be participants in

that, as well.

Mr. GREEN. So whatever we reauthorize under PDUFA, we need

to make sure the resources are there so the FDA can do their job

with that——

Ms. MULLIN. I think FDA would want to participate and want to

be involved in that.

Mr. GREEN. OK. I would like to explore the new user fee for the

direct-to-consumer advertising. As you mentioned in your statement, companies currently have the option of submitting ads before

public hearing. To your knowledge, what percentage of drug advertisements are submitted to FDA for pre-screening?

Ms. MULLIN. Our data suggests that about a third of those direct-to-consumer advertisements that are broadcast on TV are currently submitted for pre-review.

Mr. GREEN. OK. I understand that the new user fee would be

sufficient to hire 27 additional staff to review the ads. Is it true

39

that the review would still be voluntary for industry in the proposal?

Ms. MULLIN. Yes. Under our proposal, which is the current authority, it would be a voluntary review.

Mr. GREEN. What element of the proposal, if any, would provide

additional incentives to submit their ads?

Ms. MULLIN. We think that companies would—well, first of all,

we arrived at this proposal and I think it received the support and

endorsement of the industry, including, I would assume, the companies that would be participating in such a program. But we think

the incentives would be that if you are going to put out a new ad

and spend a great deal of money on broadcast, TV broadcast ads,

that it would be certainly advantageous to participate in this and

get FDA’s views before you run the ad about whether or not we

consider it to be compliant rather than having to say have it pulled

later. And so that is a reason and also the extra people would allow

us to have these reviews in a much more timely way than we can

do today and we think that the timely review plus just the value

of having that FDA advisory review would encourage participation.

Mr. GREEN. In your opinion, is there a public health benefit or

safety, drug safety, benefit on direct-to-consumer advertising for

newly approved drugs?

Ms. MULLIN. Well, I am not an expert on that. I am certainly not

a lawyer. But it is my understanding there are first amendment

concerns related to that.

Mr. GREEN. Well, I guess I have some concerns in using Vioxx

and I know when it was first developed, I actually had relatives

wanting me to get them some because they thought it was getting

prescription, because their illnesses and so the market was created

for it. And I guess, maybe, if we are going to create this market,

which is what advertising is for, we ought to make sure that that

pharmaceutical does not have these side effects that we now know

and of course, the civil justice system took care of some of that because we had this untold number of lawsuits on Vioxx. I would

much prefer the FDA to do that and the pharmaceutical industry

before people have to go to the courthouse. Mr. Chairman, thank

you for the time.

Mr. PALLONE. Thank you. Mr. Murphy.

Mr. MURPHY. Thank you, Mr. Chairman. Just a couple of quick

questions. One relates to the issue of dealing with the statutory

time limit that restricts user fee funding for drug safety, I believe

it is 3 years. How long do you think this should be extended? What

would the cost of that be if it went beyond 3 years?

Ms. MULLIN. We are basically recommending that the time limit

be altogether removed because I think, we believe when a safety

issue comes up, you don’t want to have an artificial restriction on

what products can be included in the study, for example, that you

might want to use user fee funds to support the work that is going

into that analysis and you wouldn’t want to leave products out of

the analysis because of a date restriction. We have accounted for

the removal altogether in the proposed amount of additional fees

that we are talking about here.

Mr. MURPHY. Would this, then, allow you, for example, if a drug,

drug X is used and it has begun to be prescribed for different purVerDate 11-SEP-98 10:35 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00044 Fmt 6633 Sfmt 6633 Q:\DOCS\110-29 SCOM1 PsN: SCOM1
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poses, say, 3, 4, 5 years after it was first approved, this would

allow you to go into other trials and other reviews of those medications once new discoveries would come up for those drugs?

Ms. MULLIN. Absolutely. We would continue to follow the product

through the whole life cycle, as we say.

Mr. MURPHY. Thank you. And another area, this agreement, it

establishes a new user fee for reviewing direct-to-consumer advertising. Now, some members would like to require review of all advertising, including print, Internet, television, et cetera. How would

this work? Would the fees be sufficient to cover all levels for the

FDA to review all advertisements and on all media?

Ms. MULLIN. No, the amount of money we are talking about here,

the $6.25 million, was specifically to address the staffing that we

thought would be needed to deal with just the more timely review

of direct-to-consumer TV ads and we assumed that we would get

more than today. We assumed that there would be about 150 submissions of such ads per year, that was a ballpark number we used

to come up with the resources. It was not and did not include anything, any scope of work beyond that.

Mr. MURPHY. But we have to know that there are many levels

of ads that, through print and magazines, there are multiple pages

of ads; there are things, pop-ups on the Internet that also cover

those. How will we review those direct-to-consumer ads and determine if they are appropriate?

Ms. MULLIN. We have a staff that review ads more generally will

still be there. I mean, we will still be reviewing those ads as well

as we can, all of the other materials.

Mr. MURPHY. I hope so, because it is an area that certainly many

constituents are concerned about, with regard to the amount of

funding that is spent on direct-to-consumer ads. If they influence

a patient’s decision when they come to physicians’ offices and demand to be prescribed certain drugs, it is important that those ads

do depict, in an accurate and truthful way, all those claims and I

mean, I certainly understand the value of letting people know that

there are medications available and they do have some benefits in

terms of helping people understand that they may even have an illness that they are not aware of and that it is treatable.

However, we also want to make sure that they are not increasing

unnecessarily prescription drug and healthcare costs in doing that,

so I don’t know if this is enough money to cover that. I am very

concerned about all the other areas that are going on. I mean, if

this is just television, it doesn’t even cover radio, which there are

several levels here. So I am very concerned and I hope that your

efforts can be expanded to look carefully at all those areas.

Ms. MULLIN. Well, we will continue to look at those other areas,

but this program, you are right, only focuses on, that we are proposing, only focuses on the direct-to-consumer TV ads for pre-review.

Mr. MURPHY. Thank you very much. Mr. Chairman, I yield back

the balance of my time.

Mr. PALLONE. Thank you. The gentlewoman from Colorado, Ms.

DeGette.

Ms. DEGETTE. Thank you, Mr. Chairman. Dr. Mullin, I have a

concern that, as I said in my opening statement, that the public

41

has lost some of its faith in the FDA’s ability to regulate the drug

industry because of some of these high-profile problems that we

have had and they believe, as a result of these problems, that the

FDA has too cozy a relationship with the pharmaceutical and

biotech companies. So to that end, I am concerned about these recent PDUFA negotiations that the FDA and drug industry have

been having and the fact whether they were made available to the

public. Can you talk to me about the negotiating process and what

kind of public disclosure there was?

Ms. MULLIN. Our process, certainly. Our process began with a

public meeting in November 2005 and we had a panel of consumers, a panel of patients’ advocacy groups, a panel of healthcare provider professionals and academic researchers and also a panel from

industry to begin with and to hear, sort of, the opening sort of view

of the program and what needed to be addressed. We also undertook a lot of analysis within FDA to understand and sort of document what are the real issues to separate impressions that we may

have from what the actual data suggest by way of the issues.

We followed it up with meetings with, a separate meeting with

patient advocacy groups, a meeting in May with patient advocacy

groups and a meeting in May with consumer advocacy groups and

in June with healthcare professionals to further understand what

their concerns were and hear about it. And they provided us with

very helpful, I would say, kind of a big picture guidance about the

areas of their concern. At the same time, we were having more detailed discussions with industry about things like rent and——

Ms. DEGETTE. And if you will excuse me, we only have 5 minutes. But those meetings were held privately, correct? With the

meetings with industry. I mean, I know you had a couple public,

opportunities for public input, but the meetings with industry were

held privately, as I understand it.

Ms. MULLIN. Well, they were private in the sense of just industry

people were involved in those discussions.

Ms. DEGETTE. Right. And so the question is in theory, those

meetings could be held in public, similar to FDA advisory committee meetings? I am wondering, if you did that, is there confidential

or trade secret material of individual companies that has been discussed in those private meetings with the companies? Is there

some reason not to have more, to have the availability of the public, at least, sitting in on those meetings?

Ms. MULLIN. There is nothing confidential, commercial or trade

secret, anything of that type discussed in such meetings.

Ms. DEGETTE. So what would be, given some of these issues and

all of our concern that we restore the public’s confidence, to the extent that it has been diminished, in the FDA, what would be the

legal or policy decision to not have those meetings open to the public?

Ms. MULLIN. I don’t know. I don’t know how well that would

work, but it is certainly worth looking at. I guess I feel that the

most important thing we can do to restore public confidence is to

get the program strengthened and so that is really, again, the sort

of getting the resources needed. I mean, the workload I mentioned

is a very difficulty reality and I think it——

42

Ms. DEGETTE. Right. Yes. And that is my next question, is the

strengthening of the program that the FDA announced on January

30, I have got the press release here, talked about 41 separate activities, eight of which the FDA proposed to be funded out of

PDUFA IV, and 18 as it described is recently initiation and 15 to

be started. I am wondering how the FDA is going to find the resources necessary. I think it is a really ambitious and good strategy, I am just wondering how you are going to find the resources

to fund it?

Ms. MULLIN. Some of these efforts involve better collaboration

between pre- and post-market safety and that is one of the things

that the program, overall, will be able to fund and in addition to

the resources that we are talking about for PDUFA, we requested

additional appropriated dollars and the president’s budget includes

$11.2 million in additional appropriated dollars.

Ms. DEGETTE. So the president’s budget, the $11.2 million,

would, if Congress appropriated that, would it be adequate to fund

all of these improvements?

Ms. MULLIN. The ones that we described in our January response

to the IOM report.

Ms. DEGETTE. Thank you very much.

Mr. PALLONE. Thank you. Dr. Burgess.

Mr. BURGESS. Thank you, Mr. Chairman. Dr. Mullin, thank you

for being here and providing us with your testimony. The Food and

Drug Administration is probably, when I think of Federal agencies,

it is the Federal agency that I was very first aware of back in either the late 1950’s or early 1960’s, as a small child, reading the

stories in Life magazine about the tragedy of phylitimite in Europe

and whether it was because of bureaucratic inefficiency or scientific

curiosity, phylitimite was prevented from being sold on the American market and we were spared that tragedy, so I am not sure

that I can say that I was aware that it was the FDA that did that,

but I was aware that there was a regulatory agency in the Federal

Government that was looking out for the citizens in this country,

but then that kind of morphed.

As a physician in the 1980’s, I became very resentful of the FDA

because it seemed like there were all these great things that were

happening around the world and we could not get them for our patients. I didn’t know that it was PDUFA that came along and allowed that process to be speeded up and allowed that backlog to

suddenly begin to move forward, but is now the United States,

where do we rank in terms of being a country that is able to get

breakthrough pharmaceuticals to our patients in a timely fashion?

Are we near the top, are we still in the middle or near the bottom?

Ms. MULLIN. We are definitely near the top. I think we are considered to be still the gold standard in terms of getting products

to market and including safe, effective products to market. I think

there is a recently considerable interest in Europe in trying to improve their support for new product development, to sort of work,

you have probably heard the term we have used, critical path, but

they have become very interested in that because of wanting to be

more competitive, but we are still considered to be a world leader.

Mr. BURGESS. So have we, in a sense, traded places, then, with

Europe since the 1980’s where it seemed to take us so long in the

43

1980’s to get new drugs to market and Europe could have them,

essentially, as soon as they were off the laboratory branch, Europeans physicians had access to medications where we would have

to wait, it seemed like, years. Have we now switched positions with

Europe?

Ms. MULLIN. I believe we have. I haven’t seen the most recent

data, but it is my understanding that we are definitely a country

that is often the first place in the world where a new product may

be introduced and patients in the U.S. may have first access.

Mr. BURGESS. So largely because of the efforts that Congress

made many years ago, 15 years ago, with the first PDUFA, with

PDUFA I, that was able to alleviate some of that backlog and begin

to break that log jam, was that?

Ms. MULLIN. We think that is a factor. We think that is an important factor.

Mr. BURGESS. Well, I agree with you and I think it would be a

mistake to see it go away. Now, let me, you were asked a question

about Dr. McClellan’s comments on the use of information technology to speed the process or to essentially speed the learning

process for drugs after they have gone on to market. Do you, at the

FDA, now currently have the architecture, the infrastructure in

place to allow you that sort of rapid learning environment from an

information technology standpoint?

Ms. MULLIN. We don’t have that infrastructure today and part of

our proposal here includes some funding to improve the infrastructure for adverse event collection and also to link, to access linked

databases, which are the type that are being referred to in that active surveillance concept.

Mr. BURGESS. And is that through PDUFA or is that through

part of the general appropriations process?

Ms. MULLIN. Well, certainly in PDUFA we have tried to include

that. Overall, we are trying to improve our IT infrastructure at

FDA and generally trying to do that for all medical products and

other products, as well, so I have to say that it is part of our larger

budget effort, as well.

Mr. BURGESS. Am I correct in the assumption that that part of

information technology infrastructure that is purchases through

any funding available through PDUFA will not have any strings attached to it so that it has a particular drug’s name on it as a product goes through?

Ms. MULLIN. There are no strings attached to it in that way and

I also think it is an understanding, in terms of getting resources

for drug and biologics infrastructure that with the same infrastructure is one we will want to build on for medical devices and other

medical products. It doesn’t make sense to have many separate systems.

Mr. BURGESS. I would agree with that philosophy wholeheartedly. Now, just for my own edification, what is the process for

review? A new drug comes to market, is approved by the advisory

panel and approved by the whole FDA, it becomes generally available to clinicians and patients throughout the country. Is there a

defined period for look-back as to problems that might be surfacing? What are the procedures that are in place now for a new drug

that comes to market?

44

Ms. MULLIN. Well, the new drug review process actually begins

much sooner than when we get that marketing application; that actually marks sort of the end of the development phase. The first

time FDA sees a drug is actually when an investigational new drug

application is submitted, really is drug begins clinical trials in humans and we continue to get information about that product over

the years of development. We have meetings with companies.

Mr. BURGESS. That database is then built upon by data that

trickles back in after it becomes generally available to the local

medical doctor and the patients in the community?

Ms. MULLIN. Right. Yes.

Mr. BURGESS. Did we used to just get a form to fill out, to say

that if you have had a problem with a drug in the past year, fill

in this form and do the best you can to recollect all the particulars

and send it back to the FDA postage paid? I don’t recall ever receiving any information or maybe it was just because I was inattentive and curious, but I don’t ever recall receiving any information that said now we have got this up on the Internet and you can

simply go to a secure Web site and record the same information.

Somewhere along the line I stopped getting the prepaid envelopes,

so again, maybe I just wasn’t paying attention. Has that process

been in place?

Ms. MULLIN. We are right now working on really simplifying and

streamlining our med watch reporting process so that it is one

entry point straightforward.

Mr. BURGESS. So can I still get those envelopes in the mail once

or twice a year?

Ms. MULLIN. I actually don’t know if you still get those in the

mail, but we are trying to make the Internet based reporting much

more straightforward.

Mr. BURGESS. I am about to run out of time. I will say I have

never been a fan of direct consumer advertising. As a physician, I

was always insulted when a patient would come, carrying a 3-yearold magazine and an ad and say I want this, Doctor, and I realize

I shouldn’t have left them in the waiting room so long that they

had a chance to do that, but I am grateful that you are spending

some time and effort to monitor that. I am grateful that there is

going to be a pre-approval process. Of that one-third that now does

not voluntarily pre-approve, I think you mentioned a number of

one-third that doesn’t go through the process, to what extent are

you finding problems in that one-third that is self-unregulated?

Ms. MULLIN. Actually, it is one-third that do submit today for

pre-review and advisory review.

Mr. BURGESS. Oh, OK.

Ms. MULLIN. And I actually don’t know the percentage where we

would recommend to them that they make some changes because

we feel that the ad is not a fair and balanced representation of the

benefits and risks. I do know, I have been told the top five reasons

why ads are considered to be violative and they sort of are the

overstatement, the understatement or the minimization or omission of risk information.

Mr. BURGESS. With the disclaimers they have to put on the television, I don’t know why they even do it in the first place, but it

is America and they are allowed free speech rights and I don’t

45

think we, at least right now, if there was a way, finally, on the offlabel use of medications, are you going to look at compiling a database for the off-label use of compounds, some of which is extremely

valuable to clinical practice, some of which borders on quackery,

but are you going to be watching and is that going to be something

that is generally accessible to clinicians and providers?

Ms. MULLIN. I think, as we move toward this approach of active

surveillance, which is what we intend to do through PDUFA IV, we

are going to have the ability to look at the population database and

how the drug is used and of course, that is going to include its use

off-label, so it is going to give us a much more complete picture of

how drugs are going to be used and we will be able to do a much

better job of analyzing the ways in which they are off-label used.

Mr. BURGESS. Even if the manufacturer has no interest in pursuing the off-label——

Mr. PALLONE. We have got to move on here.

Mr. BURGESS. Let me give you that one in writing, because that

is important. Some drugs do actually have a black box warning and

for all the good they do, we go around that in clinical practice, but

thank you.

Mr. PALLONE. Thank you. Mrs. Capps.

Mrs. CAPPS. I want to congratulate you, Dr. Mullin, for your recommendations to modernize your post-market review capabilities

and shore up your work force for post-market safety work, but I notice that you only discuss how user fees would be used to achieve

this. Now, I, along with several of my colleagues, are going to be

urging for greater congressional appropriations for the FDA and for

lessening the percentage of revenue that is relied upon from the industry.

I do take seriously the recommendations of the four former FDA

commissioners who agreed that we would be better served through

a greater direct appropriations which would give the FDA more

independent authority and would lessen the reliance on constraining agreements with the industry. So I want to get on the record

and ask you if you agree, and it can be a yes or a no, that if a

greater percentage of FDA funding came from appropriations, from

us, from the taxpayers, if you will, the agency could better provide

for an independent drug review system?

Ms. MULLIN. Well, I have to say that I don’t think that the share

of resources that come from fees versus appropriations really has

any effect on the regulatory decision process. There is no evidence

of that. I wouldn’t want to imply that we don’t welcome more appropriations, but I don’t see any impact on the regulatory decision

process.

Mrs. CAPPS. Excuse me. No matter what the percentage is from

the private sector?

Ms. MULLIN. I don’t think that it affects the review process. I

don’t think that our reviewers, while the people who work in my

kind of job, who are aware of budget and where the money is going

and the financial analyst types may pay attention to that. We work

in planning and budget offices. The people who actually do the reviews are in another part of the organization; they are focused on

the review. And so I don’t see that it matters to that process.

46

Mrs. CAPPS. I guess you can tell I am aligned with the four

former FDA commissioners. But I will move on because I believe

that the public understand that we need to be taking an effort to

ensure that FDA retains independence when we have heard about

so many instances of undue influence by industry, so whatever the

percentage, surely there are concerns about undue influence and I

want to ask you what steps you will be and perhaps already are

taking to ensure independence?

Ms. MULLIN. Well, as I said, the appropriations side, the user fee

side of the program has been adjusted over the years for inflation

and workload and the same mechanisms haven’t been there for the

appropriations side, so that is why I think we have seen this continuing growth of difference between them. The people who do the

reviews are in different parts of the organization. They are in the

drug centers, they are in review divisions and they really are not

aware of whether the money that is supporting them comes from

user fees, appropriations. That is something that is actually determined after the fact. We figure that out at the end of the fiscal

year what percentage we have had from user fees or appropriations.

Mrs. CAPPS. So the understanding that I have had, that there is

a plan to exclude individuals from an advisory panel if they hold

$50,000 or more in financial ties to the company or its competitor,

that is only determined after the year?

Ms. MULLIN. The advisory committee issue that you are mentioning is not one in my area of expertise and it is really a separate

issue, but I would be happy to get any questions you have about

advisory committees answered by the people at FDA who are experts.

Mrs. CAPPS. I would like to have that. I understand that that is

a plan and I am kind of disheartened to have read just last week

about an advisory for Arcoxia, which did, even those this proposal

is under say, that particular panel included scientists with financial ties.

Ms. MULLIN. Well those are not FDA reviewers. Advisory committee members are not FDA staff reviewers.

Mrs. CAPPS. No, but advisory panels are very influential, is that

not true?

Ms. MULLIN. They give FDA advice and I think they are important and I would really want to take your question back and have

it properly addressed in writing for the record.

Mrs. CAPPS. I was assuming that it was under your jurisdiction,

but so I would really appreciate a response to this. I think there

is some concern that I have held about the importance, and maybe

that could be part of my question that you will get back to me or

somebody will, about the role that the advisory panel plays, then,

in determining the approval. Is it just advice and to what degree

is it advice. Thank you. I appreciate that. And with that, I will

yield back and wait for an answer.

Mr. PALLONE. Thank you. Recognize Ms. Blackburn.

Mrs. BLACKBURN. Thank you so much. Let us see where I want

to start. Let us go back to Dr. Burgess’ question where we were

talking about the drugs that are approved in the country and how

often in the U.S. we are first approved with new drugs that are

47

coming to market and we look at other areas around the globe and

how often those drugs are first to market and available to our consumers here. I would like for you to expand on that just a bit and

give us, if you can, percentages where we are first to market with

new drugs or maybe even raw numbers and you can do this in

writing.

You don’t have to do it right now, but I think that that would

be helpful for us and knowing how often that was the case prior

to PDUFA so that we can look at some apples to apples comparisons, if you will. And then another thing I would like to know and

maybe you can expand on this just a little bit. If PDUFA were not

reauthorized, then the amount of time, the length of time that you

would expect that review process to increase and delaying the patients’ access to new therapies and new drugs. What kind of delay

would we expect to see? And you may be able to answer that or

you may want to submit that in writing.

Ms. MULLIN. I think we need to submit it in writing. The program currently is supported by actually, get the right number here,

of more like 58 percent of the funding of PDUFA today comes from

user fees; 58 percent from fees, 42 percent from appropriations. So

as you can imagine, that would have, probably, a fairly devastating

effect on the program. Fifty-five percent of the FTE support, slightly different, comes from user fees. So more than half of the people

in the program, almost 60 percent of the funding of the program,

which covers other things related to costs of the programs, so if

that were to go away and rather abruptly, it would cause a lot of

dislocation.

Mrs. BLACKBURN. Another thing I think would be helpful to us

is to know specifically what policy changes, and you have talked a

little bit about this in your testimony, but specific policy changes

that would impede your success or your continued success and as

you all talk about different things, throw that in as you write your

response, just the specific actions in those policy changes.

One thing I do want to highlight. In reading your testimony and

then listening to your answers, as we look at the reauthorization,

I think it is important to all of us that, and it certainly is important to me, that any funding that you have, and we need to know

if FDA is going to ensure that the funding reaches its intended targets and is not just used to increase the bureaucracy. PDUFA came

about because of an unresponsive bureaucracy and I think that it

is an imperative to constituents that we deal with that are dealing

with your agency, that the funding reach those intended targets

and I hope that that is not lost.

Ms. MULLIN. Speaking as someone in the office of the commissioner, who might be viewed as part of the bureaucracy part of

that, we have actually tried to reduce the administrative overhead

of the program to make sure we are hiring more reviewers with the

money and really putting it where it is needed most in the premarket and post-market safety reviews.

Mrs. BLACKBURN. My time is going to run out and I have got two

more questions for you. One, on your IT improvements, the infrastructure that you are building, are you doing that in-house or are

you outsourcing that work?

Ms. MULLIN. Most of our IT work is done through contract work.

48

Mrs. BLACKBURN. Through contract, so it is outsourced. Do you

consider it on-schedule or is it lagging behind?

Ms. MULLIN. I think it is on schedule and I think that we are

paying a great deal of attention, because resources are tight, to

making sure that those contracts are very well managed.

Mrs. BLACKBURN. And then I will just highlight your DTC program and the advertising review. I think we are all going to be

watching very closely on the type expansion that you are looking

for, the direct-to-consumer advertising is something that a lot of

complaints come in about and as you move forward with a framework with basically your expectations, a clear definition of that, I

think it is going to be something that we are going to be watching

closely to see and I yield back.

Mr. PALLONE. Thank you. Ms. Hooley.

Ms. HOOLEY. First of all, thank you so much for testifying and

taking all of our questions and sometimes I think we forget what

an awesome responsibility you have, how important it is to get new

drugs on the market, what it does for people’s lives, how important

it is to make sure when they come on the market they are safe and

that you do that follow up. So I have some questions in regard to

some of the follow-up. And thankfully, you are removing the 3-year

time limit for post-market review. That means that you will obviously have a lot more work to do in your surveillance office.

In your written testimony you stated that the recommendations

for PDUFA would permit the hiring of 82 additional staff for postmarket safety activities. How many employees do you currently

have working on that post-market safety? And what I am trying to

do is get a better sense of how much this additional funding for

post-market surveillance will get you; how many of the new hires

in the post-market safety division would you estimate will be used

in maintaining the existing level of post-market surveillance out

past that current 3-year window versus engaging in new and more

comprehensive surveillance activities. So that is sort of my first

question. Let me ask the second and you can answer both of them.

It is my understanding that the Office of Surveillance and Epidemiology has little or no enforcement authority of its own. The Office of New Drugs has that authority. Do you think the Office of

Surveillance and Epidemiology should be given more authority to

act when it uncovers post-market safety concerns? If the expertise

on post-market safety is within their office, doesn’t it make sense

for that office to have enforcement authority?

Ms. MULLIN. I think that, in FDA’s view, it is FDA that has the

authority and that we really work as a team and if we are talking

about benefit and risk and you can’t separate benefit and risk; instead of pre-market/post-market, we think you have got to combine

the information you obtained about the drug pre-market with the

further experience post-market and look at, again, benefit versus

risk of a product and see whether the balance of benefit versus risk

is adequately served by the current labeling and whether the drug

should be on the market, but really, we like to think of it as we

are trying to create a team here.

Talking about a culture of safety, we think the way, the best way

to address this is to create a strong team across pre-market and

post-market and not further look at divisions there. So I think that

49

we view it as benefit versus risk, life cycle of the product and let

us keep focusing on learning and bringing the new information

that we get into our overall assessment of the product. So that is

kind of, I think, the approach we are trying to take and use the

best science, also, in trying to update the information that we have.

You asked about numbers and I have—at least, I don’t have the

whole office here, but I do have some information about, at least,

the fee supported part of post-market safety staff today and the fiscal year 2005, I have the actuals in front of me. We don’t have the

actuals yet available for 2006. That year just closed out last September.

Ms. HOOLEY. All right.

Ms. MULLIN. And the total FTE for post-market risk management funded by fees was 62 staff.

Ms. HOOLEY. So you would get an additional 82 over the 62?

Ms. MULLIN. That is correct.

Ms. HOOLEY. OK.

Ms. MULLIN. And that 62 is spread across the——

Ms. HOOLEY. And then how are you going to use that additional

funding? You are going to hire 82 additional, so——

Ms. MULLIN. Well, first of all, you were saying a minute ago that

taking the time limit away would create more work. And actually,

the work, we think, will be the same. I mean, the workload is one

thing; having the resources that we can apply to the workload is

what we are going to be able to do now that we got the elimination

of the what we can support with the fees, so we are going to be

able to use those fee dollars to support the work that is there already. And we are going to spend about $5 million a year of contract epidemiology studies and we are going to be using about a

few million dollars to do the IT upgrades that I have been talking

about and the balance of the resources would be used for training

our staff that are on board today, conducting a few public processes

that we described in the testimony that I provided in writing and

basically hiring more epidemiologists and safety experts so we can

beef up our capacity. We need more people to do that work, as well

as giving them better tools. So that is how we would use the resources.

Ms. HOOLEY. Thank you and I yield back my time.

Mr. PALLONE. Thank you. Mr. Pitts.

Mr. PITTS. Thank you, Mr. Chairman. Thank you, Dr. Mullin, for

your testimony. A couple of things. As I understood your testimony,

is the United States now the country where most new drugs are

first approved?

Ms. MULLIN. The data that I have is not the most recent and the

last thing I saw on this, and I think it is a couple of years old, so

I would rather go back and get the latest analysis from our economists and provide that for the record.

Mr. PITTS. But we are certainly near the top?

Ms. MULLIN. We are certainly near the top.

Mr. PITTS. Now, was this the case prior to PDUFA?

Ms. MULLIN. No, it wasn’t. Actually, there has been something

of a reversal, if you look at the data going back.

50

Mr. PITTS. If PDUFA is not reauthorized, could we expect to see

review times increase and thus delay patients’ access to new therapies?

Ms. MULLIN. Yes, I think it would be safe to say that you would

see that.

Mr. PITTS. Now, a goal of PDUFA IV is to accelerate the move

towards automated drug review and improve health IT infrastructure at the FDA. How will that help reviewers analyze applications?

Ms. MULLIN. I think having better access to population databases

will be extremely helpful, certainly as you get into post-market review it will help. But also, as we get information when an efficacy

supplement comes in, that is a product that has been on the market for a while, so you have post-market experience with that as

well as the new information that you will receive in an efficacy

supplement. And so I think it would help both the pre-market reviewers and even more, the post-market reviewers in trying to get

a more complete and accurate picture of the use of the product out

there in the delivery system and trying to understand the adverse

event reports and signals that we are getting so we can appropriately respond.

Mr. PITTS. Now, as I understand your response to Congressman

Buyer, I think you said much of the 60 percent increase in adverse

effects over the last 3 years can be attributed to counterfeit drugs

on the market, is that correct?

Ms. MULLIN. No, I don’t.

Mr. PITTS. No.

Ms. MULLIN. I think I said I don’t know how much of that can

be attributed. I really don’t know how much of that could be attributed to the use of counterfeit drugs. The data on counterfeit drug

use is pretty imperfect, but I don’t know the amount. We can go

back and get the best information we have on that for the record.

Mr. PITTS. What about foreign versions of FDA approved drugs?

Ms. MULLIN. A foreign version of an FDA approved drug, I am

not expert in this area, but it is not an FDA approved drug if it

is not the version that is used and labeled by FDA.

Mr. PITTS. What could Congress do to help you deal with counterfeit drugs or foreign versions of FDA approved drugs?

Ms. MULLIN. I don’t think I can give you an adequate answer

and we have experts at FDA who can, so I would rather take your

question back to them and provide the answer for the record.

Mr. PITTS. Is there something that doctors need to do, that we

need to ask of doctors to ensure that they are getting the drug from

a supply chain which they can control?

Ms. MULLIN. Again, I would like to include that in the answer

that we provide for the record.

Mr. PITTS. All right. Thank you, Mr. Chairman.

Mr. PALLONE. Ms. Eshoo.

Ms. ESHOO. Thank you, Mr. Chairman, and thank you, Dr.

Mullin, for your testimony so far. An all-electronic drug review system at FDA, we know, is going to cut application time and decrease

or entirely eliminate paper filing. And I think that those are two

very important goals and I think that they need to be achieved. It

is also very importantly, I think, a way to eliminate medical errors

51

and in time, it could help track safety information through a product’s life cycle and it would be useful for data mining activates to

identify adverse events and compile clinical trial data. So it clearly

is a very important investment and it would produce a lot of outcomes that we need and that we are looking for.

Now, I understand that the administration’s PDUFA proposal includes $4 million to move the FDA toward an all-electronic drug review system. Now, when you compare the $4 million with something else, $6.25 million that would be generated to support the

new user fee for direct-to-consumer television ad reviews, it is a curiosity to me. So I want to ask you, in your view, is the $4 million

adequate for the adoption of an agency-wide program for an allelectronic drug review system?

Ms. MULLIN. The $4 million is not adequate, but fortunately, and

we should have made this clearer in my testimony, that that is in

addition to what we are already spending from user fees on IT systems and so——

Ms. ESHOO. What is the total amount?

Ms. MULLIN. The total amount that we are currently for PDUFA,

which we would continue to spend in going into the future and——

Ms. ESHOO. But I am asking you, what is the total amount for

the all-electronic drug review system?

Ms. MULLIN. The total amount that we are spending from

PDUFA fees would be more on the order of $34 million because we

are spending about $30 million per year now from user fee dollars.

Ms. ESHOO. So the $4 million——

Ms. MULLIN. Is added on to about $30 million.

Ms. ESHOO. And will that complete, is that complete funding to

achieve the system that I just outlined?

Ms. MULLIN. No, it is not and there are also, we are trying to

build systems that are not just siloed for human drugs and biologics, but make it a system that can also be accommodating medical devices and other medical processes.

Ms. ESHOO. So $34 million is what? For this year?

Ms. MULLIN. The $34 million would be the amount that would

start in 2008 if we had the $30 million going forward from PDUFA

III added to $4 million from PDUFA IV. In addition to that, the

$4 million that you are referring to is the pre-market component,

but as you were saying, post-market——

Ms. ESHOO. Is it going to require an additional appropriation for

Congress or are the user fees going to cover this?

Ms. MULLIN. For PDUFA and for human drug review, we are

seeking these resources for user fee support and there is, in addition, the $33.7 million for post-market proposals IT support. So for

in PDUFA, the new money we are talking about in PDUFA IV

would be $4 million for pre-market, $3.7 for post, so that is $7.7

million new IT money in PDUFA IV on top of about $30 million

a year we are spending currently for PDUFA user fees on IT.

Ms. ESHOO. I see. Now, can you briefly explain the steps that

FDA is going to take under PDUFA IV to modernize and improve

the ways that the post-market safety will be monitored and analyzed?

52

Ms. MULLIN. Certainly. We would begin by trying to improve our

IT informatics support, as you were just saying. The collection of

adverse event reports that are accessed to link databases——

Ms. ESHOO. So you are looking to have this system beef it up,

essentially? It is relying upon this?

Ms. MULLIN. The infrastructure is an important piece, but in addition to the infrastructure, we are going to look at the best way

to collect adverse event information so that we get the most information out of it, best epidemiology practices. We haven’t got a

standardized set of practices for those studies today and we want

to have access to these databases. We want to make sure we use

good methods to analyze the data once we have it, so increasing

our access to population databases to be able to conduct studies of

post-market——

Ms. ESHOO. Let me just very quickly ask, because I have 11 seconds left, what has FDA done to identify drug safety problems and

remove products from market earlier in the post-market cycle? It

is a problem for the FDA and this why the confidence, I think, of

the American people has gone down.

Ms. MULLIN. Well, what I am able to talk about today is what

we are trying to do going forward and beefing up the program and

providing more resources to do a better job under the current authority and I think as Chairman Pallone just said, we will have the

experts here for a separate hearing on drug safety and they can

help with that.

Ms. ESHOO. That is fair enough. Thank you. Thank you, Mr.

Chairman.

Mr. PALLONE. Thank you. And I recognize the gentlewoman from

New Mexico.

Mrs. WILSON. Thank you, Mr. Chairman. So a financial report,

I think it is the most recent one on PDUFA and there was a section

in it talking about people and the challenge that the FDA faces in

hiring, training and retaining qualified reviewers. According to the

report, it said that the agency’s ability to attract and retain the

best and the brightest in medicine and science is critical to maintaining FDA’s recognized gold standard in new product safety. It

also notes that a large number of FDA’s reviewers are nearing or

entering retirement eligibility and they are also, many of them

have excellent employment opportunities outside of Federal service.

Can you talk about that a little bit and the challenges that you

face and whether the legislation that you recommended addresses

this in any way?

Ms. MULLIN. Certainly. I think that it is a continuing challenge

for FDA to attract and then retain people who, by virtue of their

growing experience at FDA, become even more attractive to other

employers and so it is a challenge to us. One of the things we provided for, I haven’t said a great deal about, but in that sound financial footing piece, to try to increase the amount of inflation adjustment in which we include our payroll and payroll benefits.

And that includes that retention allowances for a lot of our very

specialized scientific and medical experts so that we can attract

people like that to come a little closer to the kinds of compensation

they might receive elsewhere and cover the healthcare costs of the

people in the program and retirement costs. So we are addressing

53

it by really catching up to and putting in a provision that will keep

us able to cover those costs going into the future so that we can

attract and retain those people.

Mrs. WILSON. What kind of retention bonuses are available for

these kind of folks and what kind of base salary levels do they, on

average, get?

Ms. MULLIN. I am not able to actually give you accurate details

on that, but I would be happy to go back to the people who keep

those numbers and provide an answer for the record.

Mrs. WILSON. Is there anything in the draft legislation that

would address this issue of recruitment and retention of qualified

personnel?

Ms. MULLIN. We address it through the change to the inflation

adjustor where we say we would like to have a provision that includes the most recent 5-year payroll costs for the agency as another possible adjustor for inflation. That number has been running

at 5.8 percent on average for us as opposed to 4.2 percent, which

is the 5-year average for just the Federal pay raise. So this will

help us to keep resources so that we can get to the numbers of

these qualified people that we want to have and retain.

Mrs. WILSON. And are you having any difficulty at this point in

keeping those positions filled or any difficulty in recruiting new

qualified reviewers when you have folks retire and move on?

Ms. MULLIN. Not if we have the resources and not if, people have

a sense that the program is going to continue, I think we will be

fine.

Mrs. WILSON. But currently, do you have a large vacancy rate or

a large mobility in your reviewer pool?

Ms. MULLIN. Well, now that we are going forward with our 2007

budget and able to move forward, I think we are going to be able

to staff up and with the increasing resources we are proposing in

fiscal year 2008 with PDUFA, we will really be able to aggressively

try to fill the positions that we need to fill to get the program adequately staffed. We have actually experienced a loss of FTE because of other costs going up. We haven’t been able to afford as

many people in the most recent years of the program, so we are

trying to address that so we don’t lose people because we are having to take the money to pay rent or rent related costs and that

kind of thing, so we think we will be in good shape going forward.

Mrs. WILSON. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. I recognize the gentlewoman from Wisconsin.

Ms. BALDWIN. Thank you, Mr. Chairman. Thank you, Dr. Mullin,

for your testimony. There has been a fair amount of discussion in

the questions about public confidence in the FDA and various ways

in which it may have been eroded and how we can bolster that.

And Congresswoman Capps asked some questions about the advisory panels and financial conflicts of interest that might exist and

you are going to refer those questions to colleagues of yours. I

would like to take a closer look at the question of political interference rather than financial conflicts of interest that might be experienced by the scientists who are employed by the FDA.

In response to a previous question, I think you were indicating

that the balance of private sector versus taxpayer dollars doesn’t

54

influence the research because they are employed in a separate division, et cetera. But you are probably aware of last year’s Union

of Concerned Scientists’ survey of FDA scientists and concerns that

were raised in their report about political interference with science

and as I reviewed just an executive summary of this, it appears

that the survey was provided to or the opportunity to fill out the

survey was provided to nearly 6,000 scientists.

About a thousand, just a little fewer than a thousand participated in this survey and there were some pretty disturbing findings. There were some open ended questions and also limited answer questions. One in five responded that, the scientists responded that they had been asked for non-scientific reasons to inappropriately exclude or alter technical information about their

conclusions in an FDA scientific document. More than three in five,

61 percent, knew of cases in which the Department of Health and

Human Services or FDA political appointees had inappropriately

injected themselves into FDA determinations or actions.

Three in five said they knew of cases where commercial interests

have inappropriately induced or attempted to induce the reversal,

withdrawal or modification of FDA determinations or actions. And

50 percent also felt that non-governmental interests had induced or

attempted to induce such changes. In another area it says nearly

70 percent of the respondents to the survey do not believe the FDA

has sufficient resources to effectively perform its mission of protecting public health and helping the public get accurate science-based

information they need to use medicines and foods to improve their

health.

On the open ended question that was posed, a couple of quotes

that I found particularly distressing. One was, and this if from a

scientist from the Center for Drug Evaluation and Research. ‘‘Scientific discourse is strongly discouraged when it may jeopardize an

approval. Whenever safety or efficacy concerns are raised on scientific grounds, these concerns are not taken seriously.’’ Another

one, this one is from the Center for Devices and Radiological

Health. This is a good quote. ‘‘In my experience, it is never the low

level reviewers in the FDA who breach the integrity of our work.

It is usually at much higher levels, such as center directors and

above. Those higher levels are so far removed from the scientific

work that we do, that politics has even more sway over their decisions. The people I work with are truly dedicated to serving the

American public and doing whatever is in their power to ensure

their safety.’’

And I have just several follow-up questions to what I have just

iterated. One is, do you take exception to these results or if you

don’t, how is this reflected in your planning and budgeting, your

response to this reflected in your planning and budgeting? And

then back to the answer you provided earlier on the separation of

the scientists from the budgeting decision making, how does that

work at the upper levels where that separation, perhaps, isn’t as

strong and a number of the people who responded to this survey

are indicating that the interference, the political interference is

higher up?

Ms. MULLIN. OK. Well, let me begin by saying that I think that

that separation goes all the way up. I don’t think that anybody at

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FDA, any scientist at FDA makes decisions based on the percentage of fee versus appropriated dollars. That is my belief. I think

that first of all, one of the findings that you mentioned was resources and certainly with PDUFA, we have endeavored to address

that as well as we can because we think that our review staff really does, they are overworked. I mean, they have a huge amount of

work to accomplish and it is extremely important complex work

and so what we have endeavored to do with PDUFA IV is really

boost the resources to give them enough people to be able to do

their job and because we fully support them and they are very

dedicated people. Everybody at FDA, I think, is very dedicated.

The other point I would make is I think Dr. von Eschenbach is

very concerned that, to the extent that people feel the way described in that survey, that that be addressed. And so I know that

on his short list of his agenda and leadership priorities is to

strengthen the environment of trust and transparency and integrity, to have everybody feel that the agency invites and we engage

in vigorous debate on issues, but that we make science-based decisions within our regulatory authority and I know that that is one

of his key elements of his agenda at FDA, so I think that our new

leadership plans to address this very aggressively.

Ms. BALDWIN. I wouldn’t ask you to speak for Dr. von

Eschenbach, who isn’t here today, but what you just indicated was

almost, it sounds like you take issue with some of the things that

I read, that there is a disbelief that the politics is actually getting

involved in the decision making and that it is all science-based and

yet your scientists don’t believe that. I guess I am asking you has

the agency decided to take issue with this study and its findings

or are you acting purposefully to root out the politicization of the

process as it may exist?

Ms. MULLIN. Well, I think we are trying to listen to what people’s concerns are. I can’t speak for the commissioner, but I would

say that from what I can tell, we are trying to listen to the concerns and be sure that we are employing the best science in our

decision making, that we have enough people to do the job and that

we provide an environment that encourages debate.

Mr. PALLONE. Thank you. The gentleman from Michigan, Mr.

Rogers.

Mr. ROGERS. Thank you, Mr. Chairman. I appreciate it. We have

a very difficult job, Doctor. We had one of the most emotional cases

I had in my office was a constituent whose wife was dying of cancer

and firmly believe that there was a drug that was going through

the final stages of approval, if they could only get that drug it

might, in fact, save his wife’s life and we worked as hard as we

could to find some legal remedy that they could go around the system to be able to use those drugs, even knowing what the risks

were and we couldn’t, unfortunately, do it in the course of time.

And on the other side, I have a constituent who is no longer able

to take a drug that has been removed from the market that

brought her extensive relief and she didn’t have the adverse effects

that allowed that drug to be removed from the market and wants

to find a way to be able to continue to access that drug for her

health and care and this is a difficult, difficult thing for all of you

to do and we appreciate how complex this issue is.

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Your position is, in the FDA, for planning, is for the safety and

efficacy, right? You come up with the system and the standard

which allows us to go through the process so that you can, with

some sense of surety, say that this drug is safe and it will do what

we say it is going to do. Is that correct?

Ms. MULLIN. No, that is actually not quite right. I work at a

much more, sort of, less close to the science level. I am in the office

of the commissioner. We deal with issues across the whole agency

in terms of budget and performance and provide that analysis that

PDUFA involves; centers for drugs, biologics. Some work in the

part of the field staff and the office of the commissioner.

Mr. ROGERS. So you are not a policy person to that degree?

Ms. MULLIN. I am a planning and analysis person and I am not

a scientist and so the kind of——

Mr. ROGERS. But am I incorrect in saying that you are, at least,

responsible for coming up with the template for how Drug A hits

the FDA and at the end of the day ends up on a pharmacist’s shelf,

the process of that, not necessarily the science of that?

Ms. MULLIN. No, I am not responsible for that. The scientific

staff within the centers of drugs and biologics really would determine what that process needs to look like. And it would be based

on the scientific information that you need the evidence of safety

and effectiveness. My job has been to try to help them figure out

what resources would be needed to have an effective process, what

kind of performance they want to specify to make the process run

as efficiently as possible.

Mr. ROGERS. So they would come to you and say we need resources for X or Y or Z in order to accomplish what we believe is

the right——

Ms. MULLIN. And they would have to detail what it is that needs

to be done.

Mr. ROGERS. OK. So you at least, you have some visual into that

process?

Ms. MULLIN. Yes, but it is, I would have to say, at a pretty high

level.

Mr. ROGERS. OK. Because what concerns me is the World Health

Organization estimated by 2003 that there were $32 billion of

counterfeit drugs in the world market, which is about 10 percent.

And in the U.S. value of counterfeit drugs seized in 2003 was $200

million, which was a sevenfold increase in the year before. So when

we look at a 60 percent increase in adverse effects between 1999

and 2003, in a sevenfold increase in counterfeit drugs between

2002 and 2003, I used to be an FBI agent and scratched my head

a little bit, but that is a clue.

There is a problem growing here and I don’t get a sense, at all,

that the FDA—and how do you go through an efficacy plan when

a doctor is writing in that gee, that drug didn’t have any affect at

all on my patient? Matter of fact, just down from my office in Lansing, Michigan, they did a raid in the Detroit area and found that

insulin was not refrigerated correctly, wrong instructions were on

the drug. This is one of those Canadian pharmacies that we found

out was not a Canadian pharmacy. And non-active ingredients. So

none of that, according to the testimony I have heard today, gets

factored in at all.

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How can we honestly say we are coming up with a system for

safety and efficacy even with post-approval, when we have no clue

where the logistics chain of those drugs are?

Ms. MULLIN. Well, counterfeit drugs are an important concern. I

think there are a lot of factors that could be cited that may be contributing to the increase in the number of serious and unexpected

adverse events and that may very well be one of them. There are

others, as well. For example, people are using a lot more drugs and

people are using a lot more combinations.

More people are using more drugs at the same time, as well as

perhaps dietary supplements and other things, so it is a complex

picture, but I think what will help here is getting to the ability to

go to these bigger population databases because we are going to be

able to take a better look at the adverse events. I mean, as you say,

some of those events could be caused by counterfeit products, but

if we try to take a better look at when those events occur, we will

get a better sense of what is driving it and the many factors that

may be driving it.

Mr. ROGERS. But that is the only thing that concerned me, and

I know my time is up, Mr. Chairman, is that that hasn’t been already ruled in and how you would make that determination. Just

in one port, they found that 85 percent of the packages they inspected, 85 percent that were labeled as Canadian drugs were, in

fact, not Canadian drugs. That is a huge problem. And if you don’t

have a plan to roll that in to make that determination, maybe it

is a 1 percent problem, maybe it is a 90 percent problem. The thing

that scares me most is that you don’t know.

Ms. MULLIN. Well, we do have a whole separate plan, if you will,

related to imported products and it is not just in the drugs area,

but across the whole range and we need a solution and informatics

is part of that solution, as well, but I hear and we will be coming

back with the answers for the record on counterfeit drugs. We will

try to address the issues that you have raised. As I said, today a

lot of the compliance work that would be involved in FDA’s enforcement of counterfeit products is outside the scope of the PDUFA

program.

Mr. ROGERS. Thank you and I yield back your time, Mr. Chairman.

Mr. PALLONE. Thank you. Mr. Stupak.

Mr. STUPAK. Thank you, Mr. Chairman, and thank you for allowing me to sit in and ask a few questions. As chair of OI, we have

had two hearings on PDUFA reauthorization. Unfortunately, we

look at the problems that continue to plague the FDA and unfortunately, I haven’t heard anything that would assure me that the

FDA’s going to do anything different to improve the drug safety. If

you take what Mr. Rogers was just asking you about, 10 years ago,

Mr. Dingell and I did a bill on Internet sales, pharmacies, where

we didn’t have a big problem like we have now. I have been to

those mail houses, as he has indicated, and for 10 years now we

have been trying to get the FDA to even comment on our legislation and they refused and have not. Are you prepared to comment

on it today, the legislation we have had on Internet pharmacy

sales?

Ms. MULLIN. No, I am afraid not. I am not able to do that.

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Mr. STUPAK. OK. You mentioned the 288 meetings you have had

with drug manufacturers that your folks at FDA do. How many of

those—were nine meetings a day, I think you said. How many of

them dealt with post-marketing issues?

Ms. MULLIN. Most of those meetings that were talked about are

dealing with issues during drug development, so they would——

Mr. STUPAK. But post-market——

Ms. MULLIN. No, they would not be post-market meetings.

Mr. STUPAK. So it sounds like you are more concerned about drug

development, but not post-marketing safety surveillance.

Ms. MULLIN. In the program to date, the funding for post-market

mismanagement work has been limited and so one of the things we

are proposing for PDUFA IV is to get rid of that limitation on how

long and how the funds can be used.

Mr. STUPAK. Well, I heard you say that and in response to Mr.

Waxman, because I have been watching this hearing up in my office, if the FDA’s primary mission is to ensure safety and efficacy

of products proposed for marketing, is it to help speed it to market

or to make sure drugs are safe and you said well, it is a dual or

equal concern of the FDA, I believe you said, right?

Ms. MULLIN. Yes. I mean, we like to prevent problems before the

products go on the market, too.

Mr. STUPAK. Then why isn’t post-market surveillance, then, receiving equal amount of resources to do the post-market surveillance? Because if you have $29.3 million, that is about 7 percent

of the user fees paid for post-market surveillance.

Ms. MULLIN. Well, the post-market surveillance piece is a little

bit larger than that because we have money we are spending today

on the order of about $15 million in the fee program today, so it

would be added on top of that.

Mr. STUPAK. PDUFA IV reauthorization proposal is $29.3 million.

Ms. MULLIN. Right.

Mr. STUPAK. And that was what you developed this in consultation with industry.

Ms. MULLIN. Right.

Mr. STUPAK. So if my figures are right, that is near 7 percent of

the user fees.

Ms. MULLIN. But those are added on to the base program that we have today and the base program we have today has about $15

million a year that goes to that purpose. The other thing I would

say——

Mr. STUPAK. Fifteen million dollars, maybe another 3 percent;

now we are up to 10 percent. Do you think 10 percent is equal to

90 percent?

Ms. MULLIN. Post-market surveillance is one component of postmarket safety and——

Mr. STUPAK. Well, let us go to another component. Let us go to

the 1,200 post-marketing studies that are pending before the FDA.

Of those, 11 percent are done. 71 percent of the post-market surveillance that are supposed to be done have never been done, 71

percent. Why isn’t the FDA demanding that the manufacturers do

the post-marketing studies that they promised to do with the approval of these drugs? That is using your authority to get them to

59

do the post-marketing things, so we can leave money out of this

equation.

Ms. MULLIN. Well, we don’t have the authority to require, under

current authority we cannot require the completion of those studies.

Mr. STUPAK. So what recommendations do you have to get the

authority to require the marketing be done?

Ms. MULLIN. We are not recommending changes.

Mr. STUPAK. You are not making any recommendations, right.

Ms. MULLIN. We are not making changes in our authority. We

are recommending that the increase——

Mr. STUPAK. So if you are not going to recommend any changes,

how is this ever going to be resolved? You don’t want the authority,

you are not asking for the authority, so how are these 71 percent

of 1,200 post-marketing studies that should have been done that

are not done, how are they going to get done if you don’t ask for

the authority and you have no intention to ask for the authority?

Ms. MULLIN. Well, we include in our proposal for PDUFA IV is

increased resources so that we can have the discussions of labeling

and post-market commitments weeks before the action date and

not what sometimes happens, days before. And we think the result

of that is going to be much better designed trial that we expect actually would be completed at a higher rate.

Mr. STUPAK. How about the 1–800 number we talked about, postmarket surveillance, and you rely upon the public, when the drug

is finally being used, the public to help you with to flag problems

with it? In the last PDUFA reauthorization, the FDA was supposed

to put a 1–800, I believe it is FDA 1088 number on all bottle of

medicine being prescribed. It has been almost 5 years. You still

haven’t done it. I have asked everyone from the FDA. They keep

telling me it is going to come soon. Are you going to do this before

the reauthorization, before September, or is this something I will

have to once again stick in PDUFA so the American people know

how to report an adverse event to the FDA?

Ms. MULLIN. I am not able to address that, Mr. Stupak. I don’t

know. We are working on a better Med Watch Plus, as we are calling it, online system.

Mr. STUPAK. I don’t care about that. I want to know about the

800 number. I mean, when something happens, people don’t know

who to turn to, how to report an adverse event. You rely upon

those adverse events to see if there is a signal out there, whether

there is a problem with the drug.

Mr. PALLONE. If you could answer that and then we are going to

move on.

Mr. STUPAK. I am sorry.

Ms. MULLIN. I would be happy to go back and to talk to the folks

who know more about that and to provide you an answer for the

record.

Mr. STUPAK. Same answer for 5 years, Mr. Chairman.

Mr. PALLONE. I understand. Thank you. And that concludes our

questions, but thank you very much. We really appreciate your

being here this morning. Thanks.

Ms. MULLIN. Thank you.

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Mr. PALLONE. I would like to have the next panel come forward,

if you would. Well, thank you for being with us, I was going to say

this morning, but it is this afternoon. Let me introduce each of the

five panel members from my left to right. Dr. Alan Goldhammer is

deputy vice president for Regulatory Affairs for PhRMA. Next is

Mr. Hubbard, William Hubbard, who is a senior advisor of the Coalition for a Stronger FDA. And then we have Mr. James Thew, who

is a patient advocate with the ALS Association. And then we have

Kay Holcombe, who is senior policy advisor for the Genzyme Corporation, former staff member for our committee. And next to her

is Bill Vaughn, who is a senior policy advocate for the Consumers

Union, a former staff member with Mr. Stark. So thank you all for

being here and I guess we will start with an opening statement by

Dr. Goldhammer.

STATEMENT OF ALAN GOLDHAMMER, DEPUTY VICE PRESIDENT, REGULATORY AFFAIRS, PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA

Mr. GOLDHAMMER. Thank you very much, Mr. Chairman and

members of the Subcommittee on Health. I am Alan Goldhammer,

deputy vice president for Regulatory Affairs at PhRMA. Having

participated in each of the four previous user fee negotiations, I

bring to the subcommittee today an historical perspective of

PDUFA and the need for expeditious reauthorization. Last year

FDA and industry representatives spent 9 months integrating comments from public stakeholders in discussing how the PDUFA program could be improved to continue to meet FDA’s central mission

of protecting and promoting the public health.

The passage of PDUFA in 1992 brought about tangible results in

a very short period of time. Drug reviews that were averaging over

30 months were shortened and the backlog of pending applications

eliminated. This added predictability to the drug review process

and provided widespread public access to important new therapies.

The 5-year sunset provision of PDUFA has been a good thing. It

provides necessary time to gauge the effectiveness of the program,

allowing all stakeholders to reflect on what can be further done

within the confines of user fees to improve the review process.

The past two PDUFA reauthorizations have increased FDA resources, improving interactions during drug development, the information technology infrastructure and also and perhaps most importantly, FDA’s drug safety operations. Throughout the past 15 years

of PDUFA, the exacting standards by which FDA evaluates new

drug applications has not been compromised. Increased resources

have allowed FDA to complete its rigorous reviews more efficiently.

The outcome of an individual review is not affected by PDUFA

funding and whether a drug is to be approved is a decision for FDA

alone to make based on information in the license application.

The PDUFA IV proposal being considered here today contains

important new provisions and resources to enhance and modernize

the FDA drug safety program, add a new user fee program for reviews and advisory opinions on direct-to-consumer television advertisements, improve drug development and provide a more stable financing for the program. We believe that the substantial new funding provided to enhance and modernize FDA’s drug safety system,

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nearly $150 million over the next 5 years, will continue to assure

FDA’s pre- and post-market safety assessment as the world’s gold

standard.

Furthermore, this PDUFA agreement substantively addresses all

relevant recommendations in the IOM drug safety report that could

be addressed through additional resources. These additional resources will be used to reduce FDA’s reliance on the spontaneous

reporting of adverse events and increase the use of modernized

techniques and resources, such as epidemiology studies on large

medical databases to identify risks more quickly and more importantly, accurately. FDA and industry also need a process to identify

risk management, risk communication tools that are effective and

work. This PDUFA agreement provides resources to accomplish

this.

A key patient safety initiative is the allocation of a portion of the

funding to improving the trade name review process. FDA will now

have resources to review trade names during drug development, reducing the likelihood of medication errors because of confusing

trade names. The proposal also includes a new user fee for reviewing the issuance of an advisory opinion on direct-to-consumer advertisements. In 2005 PhRMA issued a set of voluntary guiding

principles regarding DTC advertising. Our member companies committed to submit all new DTC television ads to FDA prior to public

dissemination to ensure FDA’s suggestions could be addressed before the ad was aired.

This proposed user fee will ensure that FDA has the resources

to review TV advertisements in accordance with our guiding principles. The proposal also suggests additional improvements to the

drug review process. By implementing the good review management principles formulated during PDUFA III, FDA will communicate to sponsors the timelines for discussing labeling and postmarket commitments in advance of the action date. This will lead

to more meaningful post-market studies that are appropriate for

the new drug.

Funding is also allocated for the purpose of expediting drug development. This will permit FDA staff to participate in external activities, such as partnerships and consortiums that are generating

data and information that will create new paradigms for drug development. In return, FDA commits to developing draft guidance in

areas related to safety assessment, clinical trial design and the use

of biomarkers. This important work will lead to earlier patient access of important new therapies.

Finally, there are a number of proposed technical adjustments to

the financing of the PDUFA program over the next 5 years. It is

PhRMA’s hope that collectively these will provide the sound financial footing needed to continue to keep FDA’s drug and biological

review program strong. And thank you.

[The prepared statement of Mr. Goldhammer follows:]

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Mr. PALLONE. Thank you, Doctor. And next we have Mr. Hubbard.

STATEMENT OF WILLIAM HUBBARD, SENIOR ADVISOR,

COALITION FOR A STRONGER FDA

Mr. HUBBARD. Thank you, Mr. Chairman. I have a written statement, but I will just make a few remarks, if I may. I am here representing a remarkable coalition of patient, consumer and industry

groups that is trying to point out to the Congress that dire shortfalls at FDA resource problems are emerging. I was at FDA for 27

years, the last 14 in which I was an associate commissioner, very

much involved in the origination of PDUFA and its most recent reauthorization.

When I came to the FDA in the 1970’s, it was clearly the biggest

problem that FDA had. Successive FDA commissioners and agency

secretaries made it their highest priority. The patient groups were

crying out for access to new drugs. Many patients were going overseas for therapy. We all remember the case of Rock Hudson going

to Paris for AL721. Industry was very frustrated and feeling the

standards might have to be lowered to get their products through

the system. Research and development for new drugs was moving

overseas to Europe and with lost jobs and lost ownership in pharmaceutical development. And then FDA was a much beleaguered

agency in terms of drug review at that time.

Many things were tried during that period by commissioners and

secretaries and others, administrative and regulatory reform

through the 1960’s and 1970’s and 1980’s and nothing seemed to

work until this committee grabbed the reins and developed the

PDUFA paradigm that exists now. So thanks to PDUFA, American

patients now get drugs. First, the review process gets them products as fast or faster than anywhere in the world. Pharmaceutical

research and development moved back to the United States and it

stayed here in the years since PDUFA was enacted. And FDA has

now had the resources to maintain the safety standards that you

told them to maintain when you gave them the additional resources.

So I believe PDUFA is arguably the most important thing this

committee has done, in the FDA context, since the 1938 Food, Drug

and Cosmetic Act was enacted. But there is a downside, Mr. Chairman, to PDUFA. While the new resources have flowed into the program, appropriated funds have not kept up. That has caused two

negative outcomes. First of all, industry fees are now an ever-increasing percentage, raising fears of undue industry influence, and

funds have been shifted because of PDUFA, from pulling FDA programs elsewhere in the agency to the Drug Review Program, thus

weakening public protection elsewhere.

I have one slide that I will ask to be put up very quickly to give

you an example, a data example. If we could put up a slide called

FDA Staffing. As you know, FDA does all of its work via its people

and so I think this slide will demonstrate to you that while the

overall FDA workforce is growing, the workforce for the programs

other than users fees have declined. Have we got that slide or

should I proceed?

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The point of the data, Mr. Chairman, is that the increase in

PDUFA has caused a concomitant reduction base programs at

FDA, so that the agency’s drug safety, food safety and other programs have lost a thousand people in the last 10 years, and we

could explain that more at another time if you like. And so if I

may, at the close, there are two big things I would hope that the

committee would turn to next. One is on the drug safety side. The

ledgers become imbalanced. All of these resources have flowed into

the drug review side but at the expense of the drug safety side.

And I have another piece of data that we can give you later that

shows the tremendous increase in adverse drug reaction reports

that the agency simply cannot look at, and I don’t believe the current new PDUFA deal will substantially affect that, because the

people that review that are not being beefed up substantially, so

there needs to be more resources overall into the drug safety side

to catch up with that huge increase on the drug review side.

And then the other thing that is going on is that while drug reviews have dropped substantially since the early 1990’s, total drug

development time still takes 10 to 12 years and there is great frustration on the patient and industry part, that these drugs are not

getting through the system. FDA has a proposal to shorten drug

development time so that from the initial synthesis in the lab to

actual availability to doctors in writing their scrip, that can be

shortened substantially. It is called a critical path. FDA has not

been able to get the funding for that program and so I believe that

there needs to be some way found to find additional funding for

drug safety and for drug development that would compliment the

progress made by the PDUFA program. So with those comments,

I will end my comments. Thank you, Mr. Chairman.

[The prepared statement of Mr. Hubbard follows:]

STATEMENT OF WILLIAM K. HUBBARD

Mr. Chairman and members of the Committee, I am William K. Hubbard. Before

my retirement after 33 years of Federal service, I served for many years with the

U.S. Food and Drug Administration, and for my last 14 years was an FDA Associate

Commissioner responsible for, among other things, FDA’s regulations and policy development. Although I have remained retired since my departure from FDA in 2005,

I have agreed to provide advice to a remarkable group of patient, public interest,

and industry groups that have recently formed themselves into a Coalition for a

Stronger FDA (whose mission is to urge that FDA’s appropriations be increased).

Throughout my career at FDA, I was deeply involved in improving one of FDA’s

most important functions—the review and marketing approval of new pharmaceuticals. Accordingly, I wish to thank the Committee for inviting me to testify on

the Prescription Drug User Fee Act that the Committee is considering for reauthorization.

BACKGROUND

As you know, the process for assessing new drugs for approval is a complex and

challenging undertaking. In any one year, FDA must oversee thousands of drugs undergoing testing, and review hundreds of applications to market the drugs that

emerge successfully from the testing process. FDA’s scientists have very little margin for error, as the approval of a new drug makes it available to millions of Americans, and often also triggers approval in many other countries, thus exposing any

given drug to a potential patient population in the billions around the globe.

When I began my career at the FDA, the review of new drugs was the most troubled program in the agency, and remained so for many years. The signs of distress

were rampant:

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• Applications to market new drugs often lingered three or more years in the FDA

review process; • Patients pleaded with FDA for more rapid access to new therapies, particularly

for serious and life-threatening illnesses, and sometimes felt compelled to travel

overseas for therapy they could not get in the United States; • Drug sponsors were increasingly frustrated that years of effort to develop new

products were put on hold while FDA reviewers labored to process a flow of drug

applications that greatly outpaced their capacity to manage a growing workload; • Investments in pharmaceuticals and medical product research and development

were moving to Europe and industry leaders decried the lost jobs and other economic detriments caused by the ‘‘drug lag’’ with Europe,

• And FDA officials proposed and developed a series of initiatives to speed the

review of new drugs, none of which managed to significantly reduce drug review

times.

Then, in 1992, this committee took the lead in drafting legislation to create a new

program for addressing the ‘‘drug lag,’’ and it has been, in my opinion, one of the

most successful statutes ever enacted for improving public health.

THE PRESCRIPTION DRUG USER FEE ACT

The drug user fee act, known by its acronym, PDUFA, has been a remarkable success story. In rapid succession after PDUFA’s creation, FDA’s time to review new

drugs dropped steadily; new, life-saving drugs flowed to patients more rapidly than

ever before; investment in medical R&D climbed steadily, resulting in yet more new

drug discoveries; and the United States seized and maintained its lead in global

pharmaceutical development. Today, thanks to PDUFA, drugs are reviewed in the

United States as fast as or faster than anywhere else in the world, with no diminution in FDA’s historically high standards for drug safety.

In essence, Congress instructed FDA that review speed mattered, but not at the

expense of safety; and mandated that FDA be given new resources to apply to drug

reviews, but would be expected to manage those resources in a documented, business-like method—with program activities closely tracked and progress carefully assessed. Drug sponsors, in turn, were given more access to FDA scientists, so that

they could better understand FDA’s requirements and design better clinical trials,

resulting in better applications that could be reviewed more easily by FDA scientists. Thanks to this remarkable program, well over a thousand new treatments

have flowed expeditiously to patients since its enactment, saving countless lives and

reducing untold suffering. For this reason, I join the many others who have urged

you to act quickly to reauthorize the PDUFA program as negotiated between FDA

and the pharmaceutical industry.

THE DOWNSIDE TO PDUFA

Despite its overwhelming success in improving the process for reviewing new

drugs, I must take note of some effects flowing from the PDUFA program that are

problematic. First and foremost, budget managers have allowed the infusion of new

user fee funds to offset appropriations, despite efforts by Congressional drafters to

utilize ‘‘triggers’’ to prevent that outcome. As a result, while total FDA resources

and staffing have increased since PDUFA’s inception, the agency’s non-user fee resources have actually declined. This is best illustrated by the attached graph, which

shows total FDA staffing growing, while staff paid by appropriated dollars have declined by a thousand over the past decade—an enormous decline for an agency as

small as the FDA. The practical effect of this has been the loss of staff for such critical FDA programs as drug safety and protection of the food supply.

A second concern raised by PDUFA is the extent to which user fees are paying

for drug review expenses. When the program was first developed fifteen years ago,

it was conceived as a relatively limited supplement to the existing drug review staff,

to enable FDA to deal with a large and growing drug application workload. By the

end of PDUFA II, in the early years of this decade, fears arose that the percentage

of the drug review program that would be paid by user fees was approaching 50

percent. FDA leaders, joined by industry, consumer, and patient groups, expressed

concern that the program not pass the 50 percent point, out of fear that over-reliance on industry fees could slowly but inexorably lead to greater industry influence

in FDA’s decisions whether to approve or disapprove a given drug. Unfortunately,

that 50 percent level was passed in PDUFA III. This has been caused by decisions

to hold down or reduce FDA’s annual appropriations. So, for example, in a given

year the PDUFA fees are adjusted to stay even with FDA’s increased costs—usually

about 6 percent per year. But FDA’s appropriations in recent years have been well

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below its inflationary costs, meaning that the portion of the drug review program

funded by fees has risen steadily. If this continues unabated, it is quite possible that

the percentage of the program paid by user fees could exceed 70 percent, a level

that raises both fairness questions for drug sponsors and concerns about industry

influence in FDA decision-making. Therefore, I urge the committee to consider ways

of ‘‘rebalancing the ledger’’ so that the original intent of PDUFA is restored.

THE NEXT CHALLENGE IN DRUG DEVELOPMENT

I will close with a final observation about FDA’s drug program. PDUFA has been

momentous for its success in improving the speed to market of new drugs. But there

are two other critical legs to what one might call the drug development ‘‘tripod.’’ The

first is one the committee will likely be wrestling with this year as well—the safety

of drugs once they are on the market. As new funds have flowed to FDA for the

drug review program, the drug safety staff that monitors drugs on the market has

not been increased, despite an ever-increasing workload. I have attached a graph

that demonstrates the enormous increase in adverse event reports being submitted

to FDA reports that are intended to give FDA early clues as to whether a marketed

drug should be relabeled, restricted, or even withdrawn. This increase in workload

has overwhelmed FDA’s drug safety function, and as a result, problems with drugs

such as Vioxx are likely to continue. FDA officials have ideas for substantially improving the drug safety system focused on using new technologies to capture drug

safety ‘‘signals’’ sooner and more thoroughly. I urge you to hear their views and to

assist them in gaining the appropriations to fund their solution to this vexing problem.

My last point relates to drug development time—the years, often a decade or

more, from the time a new drug is synthesized in a laboratory to the time it actually

starts treating patients as an approved drug. While drug review times within the

FDA dropped rapidly and substantially thanks to the PDUFA program, drug development times have remained too high. Further, drug manufacturer continue to pursue ‘‘dry holes’’ that are expensive and shift focus away from successful therapies

(the vast majority of drugs making it to the human testing phase ultimately fail).

Also, the number of submissions of new drugs for approval by the FDA has flattened

out, suggesting that the next wave of new drug discoveries will be harder to find

and develop. Indeed, there is substantial evidence that the current ‘‘path’’ to new

drug development is increasingly challenging, inefficient, and costly. FDA has made

a proposal to decision makers that it calls ‘‘The Critical Path.’’ It is offering to bring

to bear its considerable experience in drug assessment to the development of powerful new scientific and technical methods (such as computer-based predictive models,

biomarkers for safety and effectiveness, and new clinical evaluation techniques), to

help drug manufacturers become more efficient and more successful in their decisions about which therapies to pursue and bring to market—with the expectation,

of course, that the public will ultimately benefit by having more and better drugs

made available for their treatment as rapidly as possible. But FDA has been unable

to secure funding for this initiative, despite widespread expressions of support for

the concept. I urge you to consider the Critical Path program an important part of

your mission to improve the FDA’s drug program and to impress upon your Appropriations colleagues the importance of funding that initiative. Indeed, Mr. Chairman, an increase of just $40 million a year for five years, for

a total increase in appropriations of $200 million annually by the fifth year, would,

in my opinion, both ‘‘fix’’ drug safety and provide the necessary funding for the Critical Path initiative. I believe that such relatively modest sums would be repaid

many, many times over in the development of new therapies and the successful

treatment of our citizens and, as such, would be an investment of tremendous value

to our society.

I again applaud the Committee for its groundbreaking work in enacting PDFUA

and thereby successfully addressing a major national problem. And I thank you for

letting me express my views today on its reauthorization.

Mr. PALLONE. Thank you. Sorry about the slide. I don’t know,

maybe we can get it passed out later. Mr. Thew.

STATEMENT OF JIM THEW, PATIENT ADVOCATE,

AMYOTROPHIC LATERAL SCLEROSIS ASSOCIATION

Mr. THEW. Good afternoon, Mr. Chairman and Congressman

Deal and the members of the subcommittee. My name is Jim Thew

70

and I am from Machesney Park, IL. I appreciate the opportunity

to speak with you this afternoon on behalf of the ALS Association

and the people living with ALS across the country. I was diagnosed

with ALS in July 2004. At the time, I had no idea what ALS was.

But when doctors say I am sorry, you don’t have cancer, you know

that is not good news.

ALS is better known as Lou Gehrig’s disease. It is a neurological

disease that destroys a person’s ability to control their muscles.

You can see what the disease has done to me. I can no longer stand

or walk without assistance. I spend most of my time in this wheelchair. You can hear the disease in my voice. It has taken away my

ability to speak. At night, I am in need of assistance of a machine

called a bipap to help me breathe. That is what this disease has

done to me so far, but it will continue to progress as it gets worse.

I call ALS the monster. That is because it is the scariest thing

I have ever faced. I met a young man by the name of Eric Oberman

from Alabama when I was in DC last year for the ALS Association’s advocacy days. He was 24 years old, his whole life ahead of

him, but the only thing he could move was his toes. He could not

speak. He could not breathe without a ventilator. He could not

even nod his head or wink his eyes. But he was alive; you could

see the life within his eyes; that he knew exactly what was happening and that is why I call ALS the monster. I know that this is

what ALS will do. It can strike anyone regardless of their age, gender or race. It is not discriminative. And it is fatal. Usually the average lifespan is 2 to 5 years.

What bothers me is that we don’t know enough about this disease. We know it strikes military veterans like myself at about

twice the rate as the general population, but we don’t know why.

That is why we need to have more funding for ALS research at the

Department of Veterans and the VA. We know ALS is a rare disease, but we don’t know how many may strike. That is why we

need a national ALS registry and why I hope Congress will pass

the Registry Act, which is expected to be introduced soon by Congressman Engel. Mr. Chairman, I also want to thank you for cosponsoring the bill last year and I hope you will do so again.

We also don’t have an effective treatment for ALS and that is

why PDUFA is so important, because we need encouragement and

a speedy access to new drugs that will benefit people like myself.

There is currently only one drug approved to treat ALS. However,

Rilutek, which was approved in late 1995, prolongs life by just a

few months and only in a few patients.

PDUFA includes a number of important provisions and goals

that the ALS Association strongly supports. First, PDUFA provides

needed resources to the FDA; second, PDUFA will help speed drug

development and drug reviews; third, PDUFA would improve the

use of technology to fight ALS; and PDUFA includes important provisions that will promote the collaboration between industry and

the agency.

I hope that I have given you a better understanding of why

PDUFA is so important to people like me. I also hope that you will

view this from our perspective; that you recognize the urgent need

to act; that you not delay passing PDUFA by adding provisions;

and that issues like drug safety must not hinder access to new

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treatment. It may be a matter of policy for you, but it is a matter

of life and death for me. Earlier, I told you about what ALS is

doing to me physically. What you don’t see is the real impact of the

disease. I want to watch my son graduate high school, who is only

10 years old. I want to be able to walk my daughter down the aisle

on her wedding day. I want to grow old with my wife. I want to

see my grandkids. To do all of that, I need a treatment for ALS.

I hope that you will act quickly and reauthorize PDUFA and help

me fight against this monster. Thank you for inviting me here

today.

[The prepared statement of Mr. Thew follows:]

TESTIMONY OF JIM THEW

Good morning Chairman Pallone, Congressman Deal and members of the subcommittee. My name is Jim Thew and I am from Machesney Park, Illinois. I appreciate the opportunity to speak with you this morning on behalf of The ALS Association and people living with ALS across the country. I hope that by hearing my experience living with this disease, you will gain a better understanding of the needs

of people with chronic and life-threatening conditions and why it is so important

that Congress act swiftly to reauthorize the Prescription Drug User Fee Act.

I was diagnosed with ALS in 2004. At the time, I had no idea what ALS was.

Amyotrophic lateral sclerosis meant nothing to me, as I’m sure it means nothing to

thousands of others when they are first diagnosed. But when doctors say ‘‘I’m sorry,

you don’t have cancer,’’ you know it’s not good.

ALS is better known as Lou Gehrig’s disease. It is a neurological disease that destroys a person’s ability to control their muscles. You can see what the disease has

done to me. I can no longer stand or walk without assistance. I spend most of my

time in this wheelchair. You can hear the disease in my voice. It’s taking away my

ability to speak. At night, I need the assistance of a bipap machine to help me

breathe. That’s what the disease has done to me so far. But, it will continue to

progress. It gets worse.

I call ALS ‘‘the monster.’’ That’s because it’s the scariest thing I’ve ever faced. I

met a young man from Alabama when I was in Washington last year for The ALS

Association’s Advocacy Day. He’s 24 years-old. His whole life ahead of him. But the

only thing he could move was his toes. He could not speak. He could not breathe

without a ventilator. He couldn’t even nod his head or wink an eyelid. But he was

alive—you could see the life in his eyes. That he knew exactly what was happening.

And that’s why I call ALS the monster.

I know this is what ALS will do. It can strike anyone, regardless of their age, gender, or race. It does not discriminate. And it’s fatal; usually in an average of two

to five years.

What bothers me and why I am here today is that doctors and researchers don’t

know enough about this disease. We know it strikes military veterans like me at

about twice the rate as the general population. But we don’t know why. That’s why

we need more funding for ALS research at the Department of Defense and the VA.

We know ALS is a rare disease. But we don’t know how many it strikes. That’s why

we need a national ALS registry and why I hope Congress will pass the ALS Registry Act, which is expected to be introduced soon by a Member of this subcommittee, Congressman Engel. Mr. Chairman, I also want to thank you for cosponsoring

the bill last year and hope you will do so again.

We also don’t have an effective treatment for ALS. And that’s why the Prescription Drug User Fee Act is so important because we need to encourage innovation

and speed access to new drugs that will benefit people like me. There currently is

only one drug on the market specifically approved to treat ALS. However, Rilutek,

which was approved by the FDA in late 1995, has demonstrated only modest effects,

prolonging life by just a few months and only in some patients. Unfortunately, I’m

not one of them.

PDUFA includes a number of important provisions and goals that The ALS Association strongly supports.

FDA RESOURCES

First, PDUFA provides needed resources to FDA. When I learned that the FDA

receives less funding than what some school districts get, I didn’t believe it. As

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someone whose life depends on the FDA’s ability to quickly review new drugs and

promote drug development, I strongly believe the FDA needs additional resources

to do its job and help people like me. The ALS Association believes that the PDUFA

plan put forth by the FDA will provide a much-needed increase in staff and resources and will help the Agency ensure that people have timely access to safe and

effective medicines.

DRUG DEVELOPMENT AND REVIEW

Second, PDUFA will help speed drug development and drug reviews. As I mentioned, people with ALS currently have only one treatment option. And it’s not a

great one. However, we hold onto the hope that our Nation’s scientists and researchers will develop new treatments for the disease that can slow its progression, improve quality of life and, ultimately cure and even prevent the disease from arising.

That’s why it is so critical that PDUFA promote drug development and expedite

drug reviews and approvals, including for products not specific to ALS. After all,

people with ALS can benefit from advances in the treatment of other neurological

conditions such as MS, Parkinson’s and Alzheimer’s.

The Association supports the timelines and goals outlined in PDUFA concerning

the prompt review of drugs. Delays in drug reviews mean denied access to potential

life-saving therapies for people like me—to withhold a drug in order to obtain an

unreasonable amount of data could cause patients to suffer or die due to the lack

of access to new treatments.

ENHANCED TECHNOLOGY

Third, PDUFA would improve the use of technology at FDA. I spend a great deal

of time on e-mail and on the internet. For people with ALS, information technology

is our window to the world. It helps us to easily communicate and interact with others especially as the disease robs us of the ability to move and to speak. It’s also

how we learn about new ways to fight this disease. It’s clear to me that the FDA

also can use information technology to fight ALS by streamlining the drug development and drug review process. It allows the agency to rapidly collect, analyze and

understand the enormous amount of information gathered throughout the lifecycle

of a drug, during development and after it is approved. The ALS Association is

pleased that the PDUFA plan submitted to Congress is an important step forward

in using technology to find treatments and cures for diseases like ALS.

COLLABORATION

Fourth, PDUFA includes important provisions that will promote collaboration between industry and the Agency, helping to expedite drug development. This collaboration builds on efforts underway with the Critical Path Initiative. I first heard

about the Critical Path Initiative when The ALS Association invited the FDA to

speak at our Public Policy Conference last May. I am encouraged that the Agency

is making additional efforts to help improve clinical trial design and provide other

guidance that enable us to speed the development of new drugs and decrease their

cost to develop. I am also encouraged that for the first time FDA has recommended

that fees be used to hire additional staff that will make it easier for the agency to

collaborate in the scientific research leading to new treatments and to streamline

the regulatory process. What is really important to me about this plan is that it is

not just focused on the drug review process. It also is designed to speed drug development. The ALS Association is pleased that PDUFA would provide full-time permanent staff and funding for this much needed collaboration that surely will benefit

people with ALS and other life-threatening diseases.

I hope that I have given you a better understanding of why PDUFA is so important to people like me. I also hope that you will view this from our perspective—

it may be a matter of policy for you, but it’s a matter of life and death for me.

Earlier I told you about what ALS is doing to me physically - what you can see

and hear in my voice. What you don’t see is the real impact of the disease. I want

to be able to watch my son graduate from high school. I want to be able to walk

my daughter down the aisle on her wedding day. I want to grow old with my wife

Kumi and play with our grandkids. To do all of that, I need a treatment for ALS.

I hope you will act quickly to reauthorize PDUFA and help me in the fight against

this monster. I don’t have time to wait.

Thank you again for inviting me to be here today.Summary of Key Points

PDUFA includes a number of important provisions and goals:

FDA Resources. PDUFA provides needed resources to FDA. As someone whose life

depends on the FDA’s ability to quickly review new drugs and promote drug develVerDate 11-SEP-98 10:35 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00077 Fmt 6633 Sfmt 6633 Q:\DOCS\110-29 SCOM1 PsN: SCOM1
73

opment, I strongly believe the FDA needs additional resources to do its job and help

people like me. The ALS Association believes that the PDUFA plan put forth by the

FDA will provide a much-needed increase in staff and resources and will help the

Agency ensure that people have timely access to safe and effective medicines.

Drug Development and Review. PDUFA will help speed drug development and

drug reviews. People with ALS currently have only one treatment option, which prolongs life by a few months only in some patients. It is critical that PDUFA promote

drug development and expedite drug reviews and approvals, including for products

not specific to ALS. After all, people with ALS can benefit from advances in the

treatment of other neurological conditions such as MS, Parkinson’s and Alzheimer’s.

The Association supports the timelines and goals outlined in PDUFA concerning

the prompt review of drugs. Delays in drug reviews mean denied access to potential

life-saving therapies for people like me—to withhold a drug in order to obtain an

unreasonable amount of data could cause patients to suffer or die due to the lack

of access to new treatments.

Enhanced Technology. PDUFA would improve the use of technology at FDA. FDA

can use information technology to fight ALS by streamlining the drug development

and drug review process. It allows the agency to rapidly collect, analyze and understand the enormous amount of information gathered throughout the lifecycle of a

drug, during development and after it is approved. The ALS Association is pleased

that the PDUFA plan submitted to Congress is an important step forward in using

technology to find treatments and cures for diseases like ALS.

Collaboration. PDUFA includes important provisions that will promote collaboration between industry and the Agency, helping to expedite drug development. This

collaboration builds on efforts underway with the Critical Path Initiative. The Association is encouraged that the Agency is making additional efforts to help improve

clinical trial design and provide other guidance that enable us to speed the development of new drugs and decrease their cost to develop. The Association also is

pleased that for the first time FDA has recommended that fees be used to hire additional staff that will make it easier for the agency to collaborate in the scientific

research leading to new treatments and to streamline the regulatory process. This

collaboration surely will benefit people with ALS and other life-threatening diseases.

The ALS Association encourages Congress to promptly reauthorize PDUFA this

year.

Mr. PALLONE. Thank you so much, Mr. Thew, for being here

today and you remind us about the need for timeliness and why we

have to act quickly and I appreciate that. Thank you. Ms.

Holcombe.

STATEMENT OF KAY HOLCOMBE, SENIOR POLICY ADVISOR,

GENZYME CORPORATION

Ms. HOLCOMBE. Chairman Pallone, Ranking Member Deal and

members of the subcommittee, thank you for the opportunity to testify today about the reauthorization of the Prescription Drug User

Fee Act.

Genzyme Corporation, my company, chairs the PDUFA committee for the biotechnology industry organization and today I am

speaking on behalf of BIO. Like Genzyme 25 years ago, most biotechnology healthcare companies currently are working to bring

their first product to market. A strong, effective and efficient FDA

is critical to these BIO members. Mr. Chairman and members of

the subcommittee, my most important message to you is thank you.

This subcommittee and this committee have been instrumental

from day one in enacting and overseeing the PDUFA program and

in ensuring its reauthorizations. PDUFA is credited with helping

enhance FDA’s capacity to evaluate the effectiveness and safety of

new drugs and biologics, without reducing the agency’s high standards or commitment to empirically-based and thorough product

evaluation. But a successful program is not a perfect program and

additional improvements can help address FDA’s increasing workVerDate 11-SEP-98 10:35 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00078 Fmt 6633 Sfmt 6633 Q:\DOCS\110-29 SCOM1 PsN: SCOM1
74

load and provide 21st century tools to evaluate prescription drug

products pre and post-market. You have received a full description

of the recommended PDUFA IV modifications from FDA and I will

not repeat them. BIO supports these recommendations.

I want to focus specifically on a few things associated with the

increased user fees dedicated to modernization and enhancement of

FDA’s post-market safety activities. The PDUFA IV recommendations, if enacted, will provide an increase of nearly $150 million

over 5 years, for a variety of activities, many of which were those

kinds of activities recommended in the recent report of the Institute of Medicine. For example, the new funds will allow FDA to improve its IT infrastructure for more efficient and sophisticated postmarket monitoring and analysis, and to enhance the analytical

skills necessary for an up-to-date post-market surveillance system

based on health information technology.

FDA also will be able to utilize large medical databases to mine

for potential safety signals and to evaluate them. FDA will be better equipped to identify and characterize adverse events that may

not have been seen in clinical trials, to continue to assess product

benefit risk profiles, in light of new data, and to provide physicians

and patients with useful updated information. The additional funds

also will allow the agency, with its own and outside safety experts,

to evaluate post-market risk management plans to identify the

most successful strategies and disseminate them.

Mr. Chairman, BIO joins FDA and others in supporting the

PDUFA IV recommendations, including funding for FDA’s critical

path activities to help expedite drug development, continued improvements in pre-market review, including improved processes to

achieve the best drug labeling, and to develop post-market studies

mostly likely to provide useful information for doctors and patients,

and as I mentioned briefly, to make significant post-market safety

improvements.

The PDUFA IV proposals include substantial new resources for

FDA. However, Mr. Chairman, FDA also needs adequate appropriations for its human drug review activities. PDUFA fees are intended to be additive to, not a substitute for a sound base of appropriations. But user fees now account for more than 50 percent of

the cost of human drug review and that percentage is rising. Unless appropriations increase substantially more than they have

over the last 10 years, user fees will account for more than twothirds of the cost of human drug review activities at the FDA by

the end of PDUFA IV. This imbalance of fees versus appropriations

creates an unseemly misperception that FDA must be or will become beholden to the industry it regulates. This perception is not

in the best interest of the FDA, it is not in the best interest of the

regulated industry, and it is not in the best interest of consumers.

BIO is working with the Administration and Congress to seek

needed appropriations increases for FDA. We strongly urge this

subcommittee to continue your activities, as well, in this regard.

In conclusion, Mr. Chairman, BIO urges timely reauthorization

of this successful program. We also respectfully request and urge

that the PDUFA IV reauthorization be passed unencumbered by

unrelated, complex and contentious issues that could slow or jeopardize its passage and enactment. I want to thank you again, Mr.

75

Chairman and Ranking Member Deal, on behalf of BIO and myself,

for inviting us to participate in today’s hearing. It is a great honor

for me, personally, to appear before you. Thank you.

[The prepared statement of Ms. Holcombe follows:]

TESTIMONY OF KAY HOLCOMBE

Chairman Pallone, Ranking Member Deal, and members of the Health Subcommittee, thank you for the opportunity to testify before you today on the success

of the Prescription Drug User Fee Act (PDUFA) and the proposed enhancements for

PDUFA IV.

My name is Kay Holcombe and I am Senior Policy Advisor for Genzyme Corporation. As one of the world’s foremost biotechnology companies, Genzyme is dedicated

to making a major positive impact on the lives of people with serious diseases.

Founded in Boston in 1981, Genzyme has grown from a small start-up to a diversified enterprise with more than 9,000 employees in locations across the United

States and spanning the globe. Genzyme is a leader in the effort to develop and

apply the most advanced technologies in the life sciences to address a range of

unmet medical needs. Over the past two decades Genzyme has introduced a number

of breakthrough treatments and diagnostics in the areas of inherited disorders, kidney disease, orthopaedics, transplant and immune disease, and cancer, which have

provided hope to patients who previously had no viable treatment options.

Today I represent the Biotechnology Industry Organization. BIO represents more

than 1,100 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States. BIO members are involved

in the research and development of healthcare, agricultural, industrial and environmental biotechnology products. Like Genzyme at its start, most biotechnology companies are currently working to bring their first innovative product to market. A

strong, credible, and efficient Food and Drug Administration (FDA) plays a critical

role in enabling BIO member companies’ success in creating the next generation of

biotechnology medicines.

PDUFA HAS BEEN A SUCCESS

The PDUFA program has been widely credited as an innovative program that has

strengthened the Food and Drug Administration’s (FDA’s) capacity to evaluate the

safety and effectiveness of new drugs and biologics, thereby expediting the availability of needed new therapies for patients. Congress enacted PDUFA to provide FDA

with additive, consistent, multi-year resources to increase its review capacity, including new medical and scientific expertise, so the agency could become more efficient without reducing its commitment to the highest standards of empirically based

product evaluation. In fact, since its inception in 1992, PDUFA has helped enable

FDA to approve more than 1,200 new medicines and reduced review times for innovative drugs and biologics, providing patients and doctors with earlier access to

breakthrough treatments.

While the program is successful, additional improvements can help address FDA’s

increasing workload and provide the agency with 21st century tools to evaluate prescription drug products. The recommended PDUFA IV improvements will enhance

both FDA’s post-market safety capacity and review infrastructure. BIO played a role

in the consideration of these proposals and fully supports these recommendations.

We urge Congress to adopt this framework in reauthorizing PDUFA in a timely

manner prior to its expiration.

A LIFECYCLE APPROACH TO DRUG SAFETY EVALUATION

BIO endorses the PDUFA IV proposals because they underscore our commitment

to patient well-being and safety by supplementing the Agency’s resources to enhance

and modernize the drug safety system in the United States. Safety is an integral

and paramount part of companies; considerations during research and development,

FDA’s deliberations during application review, and as part of post-market monitoring by the agency and by companies. When considering improvements to the Food

and Drug Administration’s safety evaluation system, the following principles should

be taken into account.

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BIO PRINCIPLES FOR CHANGES TO DRUG SAFETY EVALUATION AND MONITORING

• FDA Should Continue to Lead in Evaluating Safety and Efficacy. In the United

States, the FDA is, and should remain, the government reviewer of benefits and

risks of regulated products. FDA’s scientific knowledge and expertise is essential for

evaluation of safety and efficacy of medicinal products and FDA must have sufficient resources to complete its mission. Also, the Agency should be provided with

the flexibility to distribute its resources to maximize efficiency and value. FDA’s

current organizational structure, which deals with drug and biologic safety pre- and

post-approval in an integrated way, is appropriate for the comprehensive and systematic evaluation of safety throughout the lifecycle of medicines. • Benefits and Risks Must be Considered Together: All drugs and biologics carry

both benefits and risks that should be carefully weighed by patients and their doctors.— The balance between the benefits of treatment and the risks of potential

side-effects will differ based on many factors, including the nature of the treatment

and the condition, and each patient’s unique medical profile. Efforts to improve safe

use of medicines should support and inform medical decisions made by patients and

their physicians, rather than limit the ability of physicians to prescribe a particular

medicine to a particular patient. This will help to ensure that patients continue to

have access to medications they and their physicians believe they need. • Patients and Practitioners Benefit from Timely, Accurate, and Relevant Information: Patients and physicians need timely, accurate, and relevant information

about the benefits and risks of a drug or biologic so they can make well-informed

choices about therapy. FDA’s assessment and communication of emerging information regarding a treatment’s benefits and risks, both before and after approval, provides a needed integrated system of medical product evaluation. Safety information

collection, communication, and regulatory action should be informed by the best

available scientific data and expert advice. • Safety Systems Should Support and Reflect Innovation: The most beneficial policies and actions with respect to drug safety are those that continue to enhance patient health and that promote innovation and the development of novel medicines.

Biotechnology companies are on the leading edge of scientific advances in biomedical

science and bioinformatics. The public and private sector should work collaboratively to harness and use these advancements to enhance, optimize, and modernize the system of drug and biologic safety evaluation.

BIO believes the negotiated PDUFA IV reauthorization proposals are fully consistent with these principles and should be implemented. Additionally, these principles would support the establishment of a private-public partnership to conduct

routine, active surveillance through the use of population-based medical databases.

Such a system could identify safety signals and analyze the findings, so meaningful

information can be communicated to the public to support individual medical decisions. In addition, based on the information gleaned from such a 21st Century active

surveillance program, FDA can determine what, if any, additional risk mitigation

steps might be appropriate. Certain other drug safety proposals, such as a separate

office of drug safety, conditional product licensure, one-size-fits-all risk management

strategies for all drugs, or restrictions on a physician’s ability to prescribe an appropriate treatment to a patient, would not be in accordance with these principles.

MODERNIZED APPROACHES TO POST-MARKET SURVEILLANCE

PDUFA III provided FDA with $71 million to ensure efficient risk management

after a product was approved, and the PDUFA IV recommendations would build on

that commitment. The PDUFA IV post-market safety enhancements would provide

FDA with nearly $150 million over five years to establish a foundation of epidemiological expertise, IT infrastructure, and programmatic skill sets necessary for an upto-date post-market surveillance system based on 21st century advances in science

and health information technology. With this funding, FDA would be able to further

its public health mission while continuing to enable access to safe and effective medical products. Along with modernizations to current adverse event collection systems, FDA would have the capacity to utilize large medical datasets to mine for potential safety signals actively and to subsequently facilitate the testing of those signals. With this capacity, FDA would be better equipped to identify adverse events

that might not be evident in clinical trials.

Based on these recommendations, FDA would establish its vision for a 21st century drug safety system based on a five-year plan developed with the input of the

public, academia, and industry experts. FDA would establish best scientific practices

for conducting analyses of medical data sets, validate post-market risk management

and minimization plans to identify the most successful strategies and disseminate

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information about such strategies, and study how to maximize the value of adverse

event reporting and analysis during a product’s marketed life.

EXPEDITING DRUG DEVELOPMENT

Additionally, these PDUFA proposals would provide FDA with the resources necessary to draw on recent advances in genomics and biomedical science to develop

information to help improve drug development through earlier ability to predict

risks and develop appropriate ways to manage them. For example, FDA would release several guidances to expedite drug development. These guidances would outline the agency’s latest thinking on how to predict certain toxicities more accurately

and how to enhance the quality of the information developed through clinical trials.

FDA and stakeholders would work together to develop tools necessary to further

work in personalized medicine, such as new validated safety and efficacy biomarkers

and new ways to measure variation in patient response.

IMPROVED PROCEDURES TO ENSURE TIMELY AND VALUABLE PRE-MARKET REVIEWS

FDA also would improve the processes for developing clear and concise product

labels and scientifically appropriate post-market commitments. Often, discussions of

product labeling and phase IV trials occur near the end of the review period with

limited time for meaningful dialogue and few standardized procedures. The PDUFA

IV recommendations include that FDA would plan for adequate time in the review

process for these critical discussions, usually 30 days before the user fee date. Allotting this time for meaningful discussion will lead to enhanced safety information

emerging from post-market trials and clearer label information for patients and physicians.

Reducing Medication Errors. In addition, the PDUFA IV recommendations include

a program under which FDA would improve the process for review of prescription

drug product names, to minimize the potential for medication errors caused by

name confusion. According to the Institute of Medicine (July 2006), 1.5 million preventable medication errors occur each year in the United States and some of these

mistakes are caused by confusion over the drug’s name. The PDUFA IV recommendations improve the process for evaluating proprietary drug names so that

concerns can be identified earlier, before a product goes on the market.

Information Technology Enhancements: PDUFA IV provides FDA with additional

resources to establish an automated standards-based information technology environment for the exchange, review, and management of information supporting the

process for the review of human drug applications throughout the product life cycle.

These IT enhancements will lead to more efficient, higher quality evaluation of new

and marketed drugs.

The PDUFA IV recommendations, in conjunction with the new safety initiatives

FDA announced in response to the Institute of Medicine report (Sept. 2006), allow

FDA to establish a modern, comprehensive, life-cycle approach to drug safety based

on 21st century information technologies, biomedical advances, and efficient risk

management strategies.

SIGNIFICANTLY ENHANCED FUNDING BASE FOR PDUFA

From its inception, the PDUFA program has been about efficient review of applications for new prescription drug products. The PDUFA IV recommendations include significant new resources—more than $50 million—to reinforce the program’s

financial base and ensure that the program can continue to meet its goals. These

new funds allow FDA to respond to inflationary pressures, unanticipated work volume and intensity, facilities-related costs, and increased need to meet with sponsors

and to review special protocol assessments (SPAs).

PDUFA Cannot Succeed Without Strong Appropriations for Human Drug Review

While we applaud the new recommendations in PDUFA IV, BIO notes that

PDUFA fees are intended to be additive to a sound base of appropriations for FDA’s

core activities. However, BIO is concerned that FDA has become over-reliant on

these user fees to meet the core mission of the human drug program. For instance,

appropriations funded 150 fewer reviewers in 2005 compared to the start of the program in 1992. In 2005, fees funded more than half of the cost of human drug review,

compared to 7% at the start of the program. Unless appropriations increase substantially more than they have over the last 10 years, user fees could account for more

than two-thirds of the cost of human drug review by the end of PDUFA IV. BIO

is concerned that FDA’s over-reliance on industry fees creates an unseemly

misperception that FDA is beholden to the industry it regulates. In the long-term,

this perception is not in the best interest of patients, biopharmaceutical innovators

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or FDA. The fee increases proposed under PDUFA IV are necessary for FDA to implement the new proposals which will enable them to continue to make needed new

medicines available to patients, but BIO believes that FDA also needs increased appropriations to continue its mission of protecting patients as it faces a revolutionary

new era of scientific innovation and advancement.

BIO is a founding member of the Coalition for a Stronger FDA, a group of trade

associations, patient groups, consumer advocates, and individual companies whose

goal is to ensure a strong, consistent public commitment to resources for the FDA.

In addition to user fees, it is important that FDA receive a reasonable balance of

appropriations for human drug review. BIO and the Coalition for a Stronger FDA

will continue to work with the Administration and Congress to seek needed increases in appropriations for human drug review activities at FDA over the next five

years.

PDUFA SHOULD BE REAUTHORIZED IN A TIMELY MANNER

It is important that Congress complete this reauthorization in a timely manner

to avoid program interruptions, the initiation of a reduction in the FDA workforce,

and slow-down in regulatory reviews that will reduce patient access to new therapies. PDUFA should not be slowed or unencumbered by unrelated or scientifically

contentious issues. BIO looks forward to working with members of the committee

to ensure that this PDUFA package is reauthorized expeditiously and well in advance of the statutory expiration of PDUFA III on September 30th 2007.

In conclusion, BIO believes that the PDUFA program has been highly successful

and is a direct contributor to increased patient access to life-saving, breakthrough

therapies. The proposed enhancements for PDUFA IV would provide FDA with tools

and resources to modernize the post-market surveillance system, evaluate more efficiently each product’s unique benefits and risks, and continue to support the timely

development and availability of new medicines to patients.

Thank you and I would be happy to answer any question from the committee.

Mr. PALLONE. Thanks so much. Mr. Vaughan.

STATEMENT OF WILLIAM VAUGHAN, SENIOR POLICY

ADVOCATE, CONSUMERS UNION

Mr. VAUGHAN. Thank you all for inviting Consumers Union, the

publishers of Consumer Reports, to testify today, and I guess I will

have a little bit different tone but similar outcome on all of this.

We think there is a lot of wisdom in the old saying, who pays the

piper calls the tune, and that is why we oppose funding a vital consumer protection agency out of industry user fees that are essentially really a tax on people who take medicines. It would be far,

far better if the entire FDA budget were funded by the progressive

tax system. The user fee system is damaging to the image of the

FDA, as Kay just indicated, and morale of the staff and to the public because it compromises drug safety.

On the image issue, Consumers Union has just conducted a national poll. It found the public overwhelmingly wants stronger drug

safety protections, but 84 percent feel the industry has too much

influence over the regulators, with two-thirds concerned about the

user fee system. And on morale, Representative Baldwin cited the

Union of Concerned Scientists survey. I put some of those quotes

in my written testimony, which I ask permission to be put in the

record, please, and I hope you could look at them because they are

truly frightening. And recently, as Representative Capps noted,

four former FDA commissioners spoke in favor of appropriations

over user fees. So our dream is to see the FDA totally funded out

of appropriations. Well, as you said, Mr. Chairman, it isn’t going

to happen, not in this budget climate and these tough budget days.

But we hope that you might work for this in the long run, because

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it really would be helpful. Or achieve the same purposes of improved image and morale and drug safety by keeping the user fees

but breaking the strings that the industry has put on the agency.

Those strings were the main concern about users fees in the Institute of Medicine’s report. We urge you to consider Representatives

Hinchey and Stupak’s bill of the 109th that would keep user fees

but break the strings. Whatever happens, whatever happens, it is

vital that Congress give the agency more resources, as Mr. Hubbard has said, and greater authority to conduct post-market approval safety activities. We do not want to take resources away

from or in any way slow down the approval of possibly lifesaving

drugs. We so strongly agree with the ALS witness on that. As we

see it, nothing in the FDA reform bills, Grassley-Dodd, Enzi-Kennedy, or Waxman-Markey slows down the approval of new lifesaving drugs. But the agency desperately needs more resources and

authority to match the high speed of approvals with a high speed,

post-approval system that makes sure the drugs on the market

really are safe and effective. PDUFA calls for a safety increase of $29 million. That is a start

but woefully inadequate. Therefore we congratulate Senators Kennedy and Enzi, who are marking up a bill tomorrow that increases

PDUFA safety fees by $50 million per year above the $29 million

that has been talked about, dedicating the money to their new safety initiatives and particularly to an exciting new proposal to use

huge medical databases, such as Medicare’s, to do epidemiological

studies to detect safety programs. Congressman Deal, I think that

Senate bill really takes a big step forward towards the IT problems

you were talking about.

And the other issues. We urge you to look hard at the proposed

voluntary advertisement user fee proposal. I am not sure it works.

You should legislate that the companies get more than a slap on

the wrist for bad ads so they will want to pay a user fee for preclearance. And then another issue. Since PDUFA triggers general

Treasury appropriations and now involves safety, when you consider PDUFA V in 2012, and I hope you are all here, patients

should get to participate in the real negotiations. Today, consumers

are consulted while the others, several others at the table here, get

to do the actual negotiating and I feel we are sort of at the kid’s

table. I would trade 10 hours of consulting for 1 hour of negotiating

any day and I think you would get some better public policy out

of it.

And finally, it is absolutely essential that safety legislation, like

Waxman-Markey’s H.R. 1561, which we strongly endorse and we

hope you will all cosponsor, be included in whatever PDUFA legislation you enact. If FDA reforms that could save us from future

Vioxxes are not included in that must-pass PDUFA package, we

will miss the best chance in 5 years to protect the American public.

Thank you very much.

[The prepared statement of Mr. Vaughan follows:]

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Mr. PALLONE. Thank you all for your opening statements and

now we will start with questions and I will yield myself 5 minutes.

I wanted to start with Mr. Vaughan. A number of the committee

members talked about Vioxx and you, in your written statement,

use Vioxx as sort of the poster child, I guess, if you will. I wanted

to use that by reference and ask you this question. You heard the

testimony today. We are concerned about the timeliness of passing

PDUFA reauthorization. But on the other hand, the issue is out

there about whether to add drug safety or even throw in biologics

or whatever. And of course the concern is, how far can we go with

this and not jeopardize the timeliness of the reauthorization? You

were using Vioxx as sort of an example about—I think you used

it in two respects. One, you said that if you have better data collection or larger data collection, that was certainly an answer. You

mentioned Mr. Waxman’s bill, as well, in this context. So just give

me a comment on what you think led to the Vioxx situation and

what, if any, were the failings of the FDA by reference to this? I

know we could talk all day, but if you could kind of summarize.

Mr. VAUGHAN. Basically not having enough information out there

on the clinical trials that were done on that drug, so that it was

hard for the world’s researchers to really say there is a problem

here, but a lot of people saw some warning signs. The VA didn’t

use Vioxx much. Kaiser didn’t. Several State Medicaid programs

avoided it. Then when there were some studies that caused the

FDA to say, ‘‘hey, let us redo the label’’ they had to negotiate with

the company for 14 months. They couldn’t say, ‘‘excuse us, it is

very clear to us, we want a label change tomorrow morning and by

the way, you ought to cool the advertising.’’ They couldn’t do that.

The legal authorities weren’t there. Dr. McClellan has testified on

the idea of monitoring large epidemiological databases, that the

Vioxx problem probably could have been picked up in about 3

months instead of the 3 to 4 years that it took for a general consensus that, hey, this drug is trouble. To add that to PDUFA, like

Kennedy-Enzi is doing could save, in a future case, thousands of

lives, millions of dollars, free up research for other stuff instead of

law cases. So we hope that you will expand on PDUFA and include

some of these safety ideas.

Mr. PALLONE. I appreciate that. And then my second question,

which I guess can be for Ms. Holcombe or Dr. Goldhammer. With

regard to the direct-to-consumer advertising and we heard the testimony from the FDA representative about—that this would continue to be a voluntary system. There have been proposals for

moratoriums. Of course, I worry about the constitutionality of a

moratorium because of commercial speech. Are there ways of having a system that has some kind of better controls without having

a moratorium? In other words, not just relying on a voluntary system because of the concern that the bad actors may not participate? But without going to 2- or 3-year moratorium which I guess

I would be concerned might be thrown out by the courts on the free

speech grounds, is there something in between that could be done?

Mr. GOLDHAMMER. Well, unfortunately, I am not a lawyer and

can’t opine on the constitutionality.

Mr. PALLONE. Yes. I am not asking you to do that. I am just asking practically.

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Mr. GOLDHAMMER. There is a ‘‘but’’. But I will say that, since the

principles were adopted by the PhRMA board a couple of years ago,

we have seen a marked difference in enforcement. I think our statistics from 2006 pointed out, at least in the first 9 months, there

were zero enforcement actions taken by FDA against broadcast advertisements, whereas the previous year there were 17. So we have

seen a marked shift in the way the ads are submitted to FDA.

They are taking that very seriously. So it may very well be that

the voluntary action of industry has largely solved the problem out

there.

Mr. PALLONE. I am questioning that and I am asking if there is

any kind of limits on advertising other than a moratorium, that

could be put in place. And I am not trying to stop you, but I am

going beyond the voluntary. Maybe Ms. Holcombe or Mr. Vaughan

would respond to that.

Mr. VAUGHAN. I would strongly, strongly urge pre-clearance. This

is an example of talk of the pharmaceuticals. Last fall, in a backto-school campaign, pushing sleeping pills on little kids last September. They ran the ad for a few days in September. The FDA

sends them a letter in March saying, gee, please don’t run that ad

anymore, because this drug has no proof that it works in kids and

it is probably harmful to little kids. And in March, they send the

letter, nothing else. No penalty, no requirement to run ads to correct the impression that parents should pump their kids full of

sleeping pills. We have got to have a better system. This voluntary

system doesn’t work. I assume they are not members of your

PhRMA.

Mr. PALLONE. When you talk about pre-clearance, how do you do

that and move away from the voluntary system?

Mr. VAUGHAN. You submit all ads and they are pre-cleared by

FDA staff who reviews them for accuracy and honesty, that we are

not pumping poison, if you will, into our Nation’s children. Or, if

you don’t want to do that, how about this? Civil monetary penalties

are in Waxman-Markey. Make it very clear that if you are out

there with a misleading ad that doesn’t list side effects, doesn’t

give warnings, then you pay a CMP and if you do it twice, you pay

a fortune. Clariton got cited 11 times. How can people who are so

smart to make a pill like that, not get the ads right?

Mr. PALLONE. OK.

Mr. VAUGHAN. I mean, this is crazy.

Mr. PALLONE. I thank you. I know my time has run out. I yield

to Mr. Deal.

Mr. DEAL. Thank you, Mr. Chairman, and I want to thank all of

you for being here today and Mr. Thew, especially for your efforts

to be here and to testify. You certainly underscore the importance

of getting drugs on the market and research that is necessary and

hopefully speeding the process up for lifesaving drugs that would

be important to you and to many other people.

While we are talking about the advertising, I have had a problem

for a long time, understanding the reason why we would advertise

something that requires a prescription to obtain. But that, nevertheless, I have been told does pay dividends, apparently, for those

who choose to go that route. Mr. Goldhammer, I believe you said

in your testimony that, in 2005, your association issued voluntary

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standards that would say that every member of PhRMA would submit their ads for pre-approval. Can you tell us to what degree that

guideline has been successful?

Mr. GOLDHAMMER. We will have to get back to you in writing.

I believe that most, if not all, of the members of PhRMA have

signed on to those principles, but I am not the one who is in charge

of that program, but we will be happy to go back and get the exact

percentage to you.

Mr. DEAL. One of the concerns that I have heard expressed, and

I think the reason for the add-on to provide funding for reviewing

the ads, is the delay time in getting approval under the current

system and this would generate revenue that hopefully would provide personnel to be able to give a quicker approval for ads. Is that

everybody’s general understanding as the motivation?

Mr. GOLDHAMMER. Yes, that is correct. While we were negotiating, we got extensive statistics from the FDA about how long it was

taking them to review the ads and render an advisory opinion and

we have seen just, I think, over the last 3 years it has gone from

about 35 days to over 80 days. And that represents a real disincentive, I believe, for companies to submit an ad for getting this advisory opinion back, if they are going to be sitting in a queue waiting

and waiting and waiting for that opinion. On the other hand, companies want to get these opinions. To run a broadcast ad is not an

insignificant amount of money to go through and do that and I

think companies want to get it right before the ads actually air on

television.

Mr. DEAL. I think all of us are concerned about this ongoing balance or mix, if you will, between industry-funded testing and certification versus Federal general taxpayer revenue, and several of

you touched on that from a variety of points of view. Mr. Vaughan,

I am a little interested in your survey that showed that 67 percent

of Americans are concerned that funding comes from the industry.

My first reaction to that is that I am surprised that 67 percent of

the public even knows that fact. I presume that is because you

have informed them in a previous question, is that right?

Mr. VAUGHAN. No. Of course the question asks, if drugs are approved and if partly paid by—yes, of course, sir.

Mr. DEAL. Yes. OK.

Mr. VAUGHAN. But it was a good poll. About thousand folks.

Mr. DEAL. One of the concerns that you expressed, Mr. Vaughan,

was that you felt that PDUFA has compromised the safety component and you quote in your written testimony. I presume these are

researchers or people employed within FDA, expressing their concerns and you have categorized them in a variety of ways. I presume that the safety issue relates to the feeling of being under a

time limitation to get the work done. Is that generally it?

Mr. VAUGHAN. Yes, sir, that seems to be it. I have not worked

at the FDA, but also in the testimony, there is this Harvard Professor Carpenter, who, I believe, the chairman referred to earlier, that

actually tried a very sophisticated mathematical analysis and I

couldn’t attest to his math, but basically, things approved just before the PDUFA due date have a lot of trouble afterwards, like four

or five times as many adverse events and label changes. Whereas,

when the FDA takes a little bit longer and it slips a bit past the

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PDUFA due date, the drugs seem to be safer or don’t have as many

troubles on the market. Now, we wouldn’t want to slow up lifesaving drugs. If we have the cure for ALS or we think we do. For gosh

sakes, bring it to market. But for the 20th kind of statin or the

40th kind of antihistamine, what is the rush that it has to be on

the 10th month?

Mr. DEAL. Well, my comment to that is that FDA is a bureaucracy like many. Deadlines and time limits have good effects many

times, because they don’t just let you bury something within the

system, but I think we all acknowledge that it is a very delicate

balancing act that we have try to achieve. And my time has expired. Thank you, Mr. Chairman.

Mr. PALLONE. Mr. Waxman.

Mr. WAXMAN. Thank you very much, Mr. Chairman. Balancing

is something we have to do in this legislation. In one area, of balancing, is the amount of revenues that goes into drug approval that

is paid for by the user fees as opposed to appropriations. One of

the things we insisted on when we adopted PDUFA is that the user

fees not replace the appropriations. Rather than improving our system, we would end up in worse shape and I am just alarmed to

learn about the prediction that the percentage of user fees could exceed 70 percent if we don’t act to stop this ever-increasing reliance

on user fees. Mr. Hubbard, what is your view of the optimal balance? What percentage of FDA’s drug review funding should come

from user fees as opposed to Federal dollars? And what impact has

this perception had, that FDA is in the pocket of the pharmaceutical industry had on the agency and its culture?

Mr. HUBBARD. I recall that, in the late 1990’s, when the percentage approached 50, then Commissioner Jane Haney and the industry folks and the consumer patient groups all felt it should not pass

50 percent. And Dr. Haney put in a large budget for appropriations

that year to prevent that and to increase the appropriated dollars.

However, it never came and subsequent commissioners have done

that as well. So it has clearly been an effort at the FDA to try to

say let us hold it down, but that has not been done. The perception

certainly is that as those percentages go up to 60, 70, perhaps even

80 percent someday, that industry could be into FDA saying to the

scientists, we are paying your salaries and we need our approval,

and that would not be a good thing to happen. So I would urge you

to do whatever you can do to increase FDA appropriations so that

the percentage will stay where it is or even go down.

Mr. WAXMAN. Another imbalance, as I see, is that the amount of

the PDUFA funds that will go for FDA’s review of the drug compared to its drug safety program. So while PDUFA dollars are flowing freely to the drug review program, and that is increasing the

speed with which new drugs enter the market, which is something

we all find desirable, FDA’s post-market drug safety system appears to be starving. Can you talk more about how this has occurred and the impact it has had?

Mr. HUBBARD. Absolutely, Mr. Waxman. That has undeniably

happened. The post-market system at FDA has not been strengthened in the way the pre-market system has, so the imbalance has

grown and grown and grown. And this gets somewhat, I think, to

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Mr. Stupak’s point. I will show you this chart we tried to show earlier.

[Chart shown.]

This is the increase in adverse drug reports that come to the

agency. As you can see, they have increased exponentially. There

were 30 people to review them in 1990 when there were 200,000,

or 20,000. There are 30 people now to review them and they are

200,000.

Mr. WAXMAN. Do you think that the proposal that the FDA has

presented to us that they negotiated with the industry is a good

balance in this regard?

Mr. HUBBARD. Well, certainly, I very much support the negotiation that occurred, but the catch-up needs to be, in my view, on the

appropriations side. I think the fact that the industry is paying

more now for post-market surveillance is a good thing, but in the

end, you need to have the appropriations catch up, I believe.

Mr. WAXMAN. Dr. Goldhammer, I noted that you support the limited funding for FDA to conduct certain post-market drug safety activities, as set forth in the industry/FDA proposal. I am sure you

are aware of the Institute of Medicine in its very well-regarded report says that far more is needed to give Americans confidence that

marketed drugs are safe. They recommend a number of significant

reforms that would give FDA several new authorities, including, for

example, the ability to require that post-market studies, safety

studies, be conducted, to require labeling changes and to place

moratoriums on DTC ads for new drugs if it is going to increase

sales at a time they are not sure about the safety of it. Many of

these recommendations are in the Kennedy-Enzi bill and the Waxman-Markey bill. What is your position or your view on these recommendations?

Mr. GOLDHAMMER. We were empowered during the PDUFA discussions to only focus on what could be done through PDUFA and

the recognition was, when the IOM report came out in mid September, we needed to take a hard look and see, did we address what

we could have addressed through the PDUFA process? And I think

what FDA said and what we have said in our statement is the answer to that is yes. In terms of what could be done through more

resources, we have done that. The rest of the IOM report and I

think the major things, as you have noted, are, I think, issues that

IOM has thrown back to Congress for——

Mr. WAXMAN. Well, what is the position of PhRMA, let us say,

on the issue of whether FDA should be able to require a post-market review by the company rather than simply requesting?

Mr. GOLDHAMMER. Well, we don’t have a position on any of——

Mr. WAXMAN. Well, what is your best professional judgment on

that point?

Mr. GOLDHAMMER. On?

Mr. WAXMAN. On requiring the studies to be conducted post-market rather than simply requesting it and then finding it is not

done.

Mr. GOLDHAMMER. Well, as we have looked at the statistics that

FDA publishes on a yearly basis, only 3 percent are delayed. The

vast majority of them are proceeding according to schedule. Now,

I think there is a misperception in that regard, because people look

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at this large number of pending studies and believe the pending

studies are not on schedule, but that is not, in fact, what the FDA

regulation says. If a study is pending, it means it is not delayed.

Mr. WAXMAN. There is no end date set for them. Don’t you think

the FDA ought to have the authority to require it?

Mr. GOLDHAMMER. Well, I think, certainly for subpart H, drugs

approved under subpart H, they do have that authority today.

There are end dates in almost all of the post-market——

Mr. WAXMAN. So your answer is no or your answer is yes?

Mr. GOLDHAMMER. Well, I am saying I don’t have an answer, as

PhRMA right now.

Mr. WAXMAN. And I don’t have anymore time.

Mr. PALLONE. Thank you. Thanks a lot. OK, next is Mr. Buyer.

Mr. BUYER. Thank you, Mr. Chairman. Mr. Thew, I want to

thank you for being here, but when you leave today, I would like

for you to bring a point up with the leadership of ALS and other

patient advocacy groups, that these groups were pretty silent during the Democratic majority’s effort to repeal the noninterference

language that would have had a detrimental impact upon many

narrow-targeted drugs that help many different narrow-disease

groups. So I just want you to take that back with you. I appreciate

you being here to testify on this issue, but their silence on this

other issue was painful to me. And so I appreciate you being here

today and take that up with them and tell them don’t play politics

when it comes to your friends who are similarly situated.

With regard to PhRMA and BIO, let me ask this question. The

witness on behalf of FDA did not do a very good job, I don’t think,

answering questions that I had or Mr. Pitts or Mr. Rogers, relative

to this question of the prevalence that we have right now on the

drugs that are coming into our ports of entry through these imported parcels. And so when the FDA and Customs do these blitzes

and do the inspections, the prevalence of FDA unapproved drugs

and biologics is shocking. And so from a curious standpoint here,

as we talk about PDUFA IV and modernizing with regard to postmarket review and we have got this escalation of adverse reports,

how do we nail this one down? I mean, if I’m a manufacturer out

there, I have got some pretty strong concerns with regard to these

adverse reports and whether or not it is my drug or not. I mean,

you could have Dr. Burgess here prescribe something for me, but

then if I go, well, I am just going to get from a Canadian source

and I come back and see him and say I don’t feel any better, he

may or may not report. Mr. Pitts asked a really great question.

What more should we require of doctors to ask of the patients,

where did you get that prescribed drug from? Did it even have

proper labeling? Did it come from an approved source? I am curious

about your impression of all of our questions. What do we need to

add in this legislation, if anything, to nail this down?

Ms. HOLCOMBE. Well, I don’t know if there is something that you

specifically can add into this legislation. But alliteratively, I would

like to share your shock. We have been strong opponents, for years,

of efforts to reduce FDA’s ability to track imported products that

are not approved by the agency, to go after these products, prevent

them from reaching consumers in the United States, prevent counterfeit drugs from coming in. And most of the products that BIO

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member companies produce are products that are injected and so

they come in vials. Mostly they are clear liquids. So if you get a

clear liquid in a vial and you take a syringe full of it out and inject

into a patient, there is no way for you to know, is it the thing? Is

it not the thing? Is it clean, dirty? And we have had very well-publicized incidences exactly as you have described, where patients

have taken the drug over and over and they are not getting better.

We believe the wrong message has been sent to FDA by attempts

to legalize the importation of prescription drugs and that this is

something that we find shocking and appalling, that this should go

on. This is dangerous, it is absurdly dangerous and yes, from the

innovative company’s perspective, we do wonder how many when

we see these escalations of adverse reports. Is this our product? Or

is this something that someone else is shaking up in a garage

somewhere and sticking into our bottles? So I am shocked.

Mr. BUYER. Thank you.

Mr. GOLDHAMMER. Yes. And I think our other major disappointment, in addition to what Ms. Holcombe said, is with FDA’s inability to finalize the pedigree regulations that is called for under the

Prescription Drug Marketing Act that was introduced by Congressman Dingell some years ago, because this would then provide the

assurance of completely keeping the supply chain within the

United States closed. We have tried doing as much as we can,

through a variety of media opportunities, to make sure that patients purchase drugs through established pharmacies or Internet

pharmacies that are verified by the National Association of Boards

of Pharmacy, to make sure that they are not getting something

through some kind of phony Canadian Web site.

Mr. BUYER. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. Chairman Dingell is recognized for 5

minutes.

Mr. DINGELL. First, thank you. I would like to welcome our distinguished panel here and tell them that we very much appreciate

their assistance. I want to express my particular affection and respect for Ms. Holcombe, who did such valuable work when she was

a very fine member of the staff of this committee, particularly on

matters like PDUFA. Welcome back, Ms. Holcombe. We are honored that you are with us. Thank you, Mr. Chairman.

Mr. PALLONE. Mr. Stupak.

Mr. STUPAK. Well, thank you and again, thank you for allowing

me to ask questions. Mr. Goldhammer, in your testimony, you stated you believe that ‘‘PDUFA agreements substantially addresses all

relevant recommendations made by the IOM.’’ However, a very

quick glance at the IOM report, I am unable to see where the proposal, where in the proposed recommendation by IOM, that there

should be specific safety-related performance goals in PDUFA. That

is not in there. Also, I cannot find where IOM’s recommendation

that CDER review teams, regularly and systematically, analyze all

post-market results and make the public aware of their assessments or the significance of the results with regard to risk and

benefit information. Don’t you believe those two goals should be

part of PDUFA IV?

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Mr. GOLDHAMMER. I think you asked some very good questions

that probably are better directed towards the FDA, in terms of

what kind of internal management changes they are going——

Mr. STUPAK. Well, I can tell you that they don’t know and you

are at the table, so that is why I was asking you guys.

Mr. GOLDHAMMER. OK. Well, again, I am not an FDA employee

and I would be loathe to comment on what are essentially FDA

management issues.

Mr. STUPAK. No. But you were there. Weren’t you guys there?

PhRMA was at the table negotiating PDUFA IV with FDA. Don’t

you think these two goals should be in there, specific to safety-related performance goals?

And also post-marketing results that would be made available to

the public so they can assess the risk benefit analysis of a drug

they are taking.

Mr. GOLDHAMMER. Well, with respect to post-market study results, we already took the initiative on that several years ago when

we set up a database for clinical study results and we have got

data on over 350 drugs in that database.

Mr. STUPAK. Those are only the studies you want to put on. They

are not all the studies. It is the only one that PhRMA and the manufacturer puts on. It is not the ones that may find an adverse

event. You control the information that is going on there. What we

are asking for is all the reports be made available so the American

public can decide. Don’t you think that is a good idea?

Mr. GOLDHAMMER. Well, again, I think those are questions that

Congress should deliberate and there should be a thorough consideration of those as you move forward.

Mr. STUPAK. Mr. Vaughan, do you care to comment on that?

Mr. VAUGHAN. We desperately need those, sir, and we find it is

strange that we complain about the high cost of developing drugs

and bringing drugs to market and yet people don’t want to provide

information on what trials were done and what the results were so

that as a result, people keep repeating dead-end efforts of other

companies. Not only that, but it hides safety features, so we desperately need a reform of the clinical trial registry and results

database, sir.

Mr. STUPAK. Mr. Vaughan, I had asked Dr. Mullin, the last panel, about the $29 million, and Mr. Waxman mentioned a little

bit about it, too, which I see represents a mere 7 percent of the

user fees paid by industry to FDA to be put in post-marketing surveillance. Do you feel this is enough?

Mr. VAUGHAN. Not at all. There is good news in this KennedyEnzi bill being marked up tomorrow. As introduced last week, it

was $70 million more. The version they put out tonight is $50 million more, but that is a good deal. That is better than the $29 million. We think even more is needed, sir. In fact, in the written testimony, we have a list of a bunch of projects that if you all would

care to consider and legislate and help fund, we would have not

only the fastest approval system in the world, we would have the

safest drugs in the world.

Mr. STUPAK. Now, Mr. Vaughan, you also mentioned Rozerem

and that was a sleeping pill ad that ran in September 2006, where

Rozerem would remind you that it is time to go back to school. This

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ad was complete with visuals of chalkboards, school books, school

bus, laptop computers, school-age children with their backpacks. It

is my understanding that it took the FDA more than 6 months to

ask this drug maker to cease these ads that suggest sleeping pills

are indicated for children. I find that simply outrageous and indicative of the problems that plague the FDA. Yet, in the Administration’s newly released PDUFA reauthorization proposal, FDA recommends creating a separate user fee program to collect fees from

companies that seek FDA advisory reviews of their direct-to-consumer television prescription drug advertisements. Do you expect

a voluntary program that allows drug makers to decide if they

want their advertisement clear will have any major effect?

Mr. VAUGHAN. That is what baffles me and I hope you all can

dig into that a bit, because if you don’t get anything more than a

letter 6 months later saying please stop or tell us when you are

going to stop—and of course they had stopped in early September—

why would you bother with this volunteer program. And Consumers Union and Consumer Reports magazine, we have documented

a major decline in penalty letters. So they are telling companies

that they are not doing as good a job monitoring these ads. There

is no penalty when there is a violation. Why would you pay a user

fee? I am just not sure that idea works, and I hope you all can kind

of dig into what brings you to the table to use this service to get

an honest ad out there.

Mr. STUPAK. So would you support IOM’s 2-year moratorium,

then, on direct-to-consumer advertising until we can try to

straighten this out?

Mr. VAUGHAN. On drugs where there is some background chatter

or it is a new drug, wherethere might be a problem? Absolutely. I

keep this pinned to my wall. It was an ad that was done in a newsletter, not you and I, but to executives of drug companies and it

says, ‘‘how many prescriptions...how many weeks in market...until

you are confident that your drug is safe’’ Why do we want people

out mass advertising when this is what the businessmen themselves are saying. ‘‘I don’t know, but maybe once 10 million people

use it we will know.’’ If they are going to advertise, there ought to

be a little sign up there that says, and you are participating as a

human guinea pig. Call 1–800-FDA if there is an adverse effect.

Mr. PALLONE. Thank you.

Mr. STUPAK. Thank you.

Mr. PALLONE. And I apologize for missing you, Dr. Burgess. I recognize you for 5 minutes.

Mr. BURGESS. That is OK, Mr. Chairman. It has been a long day.

I appreciate everyone staying with us through all of this. Dr.

Goldhammer and Mr. Hubbard, I was so glad that you are here to

give the perspective of what life was like before PDUFA, because

some days I wonder if I really remembered it accurately. But as a

clinician during the 1980’s, it just seemed like we were constantly

running behind trying to get new therapeutics to our patients. In

fact, we had a whole course of medical school called developmental

therapeutics for cancer drugs, which was designed to how do you

get around the FDA? I guess I shouldn’t go into that too much now.

But let us talk about the direct consumer advertising. Again, I am

not a fan of it. We heard testimony in the previous panel that twoVerDate 11-SEP-98 10:35 Oct 06, 2008 Jkt 000000 PO 00000 Frm 00102 Fmt 6633 Sfmt 6633 Q:\DOCS\110-29 SCOM1 PsN: SCOM1
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thirds of the direct consumer advertising, there were two-thirds

that did not go through the voluntary. Dr. Goldhammer, do you

have a sense of that two-thirds, in retrospect, how much of that advertising would seem to be a problem, that is if a company did not

self-refer of the two-thirds that did not self-refer, what segment of

that two-thirds of the population ended up doing something that

perhaps shouldn’t have gotten on the airwaves?

Mr. GOLDHAMMER. Well, a number of those may not have been

self-referred. It may have been just minor changes to an existing

ad campaign, and the PhRMA principles don’t call for those to be

submitted for pre-clearance if they are minor changes, because it

is up to the company to make that decision. Again, I think the

most telling is the FDA statistics that point out that there have

been very few enforcement actions against television ads and we

like to think that is because of the PhRMA principles being put

into place. The other thing that the PhRMA principles call for is

in the case of a new drug that has just been approved, is that no

direct consumer advertising take place until the company has had

a chance to go out and do an educational campaign with physicians, so physicians don’t end up getting blindsided by drugs out

on the market and patients are coming in holding the ad.

Mr. BURGESS. Yes, you assume we are paying attention and of

course the practice of medicine has changed in the 21st century

and patients aren’t the same patients that were there in the 1990’s

and the 1980’s, and as much as I don’t like direct-to-consumer advertising, there were times where patients brought me information

of which I was not aware and after further research decided that

this would indeed be an appropriate therapy for them. And again,

it may not have crossed my mind or I may not have been as up

on it as I should have been.

Let us talk just a little bit about the user fee/appropriation ratio,

and this is really for everyone on the panel. We have Mr. Thew,

whose primary goal in being here today is that we do not obscure

a therapy or delay a therapy that could come his way and for people who are similarly afflicted, and I share his prayer in that regard. But I don’t recall anything, Mr. Chairman, and maybe I am

wrong, but we passed a big budget here a few weeks ago and I

don’t recall anything in there that had a big increase in the

amount of money we were going to give the FDA. Now maybe I

missed it. Maybe it was in one those vaunted reserve funds, but

to the best of my knowledge, those reserve funds were not funded

with actual dollars. They were more like, well, let us send a get

well card to SCHIP and maybe we sent a get well card to the FDA.

But if we are really serious about it and if that is going to be

the point of the discussion today, then, clearly, people on this committee need to pay attention when we go through our Labor, HHS

appropriation bill, and if the Appropriations Committee has not

done its work that we offer, the appropriate amendments under an

open rule, and I know that means we stay up here all night, but

that is OK, to see that you get the funding in the appropriations

process to balance the money that you are going to get in the

PDUFA process. And I have heard various figures, but the proportion that I am going to take away from here is a 50/50 mix. Is that

about the right number or do other people feel differently about

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that? Mr. Vaughan doesn’t want any, but again, I remember the

1980’s. I am not going back there. I know Mr. Thew doesn’t want

us to go back there, and you are about 15 years too late for that

and I would respectfully suggest that it was a Democratic Congress

that was here 15 years ago. So when you lost that battle, actually,

your friends were in charge here. But am I correct on that, that

it should be a 50/50 mix on the appropriation PDUFA funding?

Mr. HUBBARD. Well, may I comment, Dr. Burgess?

Mr. BURGESS. Please.

Mr. HUBBARD. When the 2007 budget was passed a few weeks

ago, FDA needed $90 million just to keep even from where it was

in 2006. They got $88 million. So they basically stay flat and that

was the best budget they have had in recent years. So the environment is such that a flat budget that says you can do no more is

good, because they have been actually losing money every year for

the last decade.

Mr. BURGESS. Well, we have level-funded our doctors for the last

5 years, so I know it seems appropriate that we do the same to the

FDA. Well, I appreciate everyone being here. I know my time has

expired, Mr. Chairman, and I appreciate your indulgence. Just one

last thought. Mr. Hubbard, the comments that Mr. Buyer was making, do you have any sense as to what this—if you recall, he called

it an exponential rise. Do you have any sense as to whether or not

any of those adverse drug reactions are because of corruption of the

supply chain from foreign interference?

Mr. HUBBARD. No. As you know, Dr. Burgess, the counterfeiting

is endemic around the world. The United States has been relatively

free but it is increasing in the United States, both by people wanting to sell large volumes of counterfeit drugs, as well as these imported drugs supposedly from Canada and elsewhere. But because

these drugs are not supposed to be here and they are not legal

drugs, the healthcare system doesn’t have a way to track them, because there is no way of knowing that they are even here and how

to track them. And of course, FDA has no resources to go to doctors

and medical centers and develop a tracking system for these drugs

that shouldn’t even be here to begin with.

Mr. BURGESS. So these adverse drug reports could include——

Mr. PALLONE. We are over our minutes, so wrap it up.

Mr. BURGESS. Yes, but you ignored me, so I am taking it out on

you now.

Mr. PALLONE. That is true. That is why I am being good.

Mr. BURGESS. This graph could include counterfeit but it may

not, so we have really no way of evaluating that.

Mr. HUBBARD. It could. It probably doesn’t. These are so-called

manufacturer reports where a doctor reports to the drug sponsor

and then they report to the FDA.

Mr. BURGESS. So we should accept this at face value?

Mr. HUBBARD. Well, most of them, I think.

Mr. BURGESS. All right, thank you.

Mr. PALLONE. Thank you and that is the end of our questions,

but I really thank you all for being here. I thought it was—oh, I

am sorry, Mr. Dingell. I apologize. Go ahead.

Mr. DINGELL. I have just one other question I would like to ask

of the panel here. And if you would bear with me, Mr. Chairman,

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I would be very appreciative. Mr. Hubbard, your statement, I

thought, was a very helpful one and I thought your comments on

the success of PDUFA were very beneficial. Just to give us a little

history several years ago, we found that there were severe problems related to the FDA prescription drug program. This committee

had to run an investigation, which led to the indcitment of a fair

number of individuals at the Food and Drug Administration. One

of the things we found was that the Agency didn’t have the money

that it took to process prescription pharmaceutical applications by

the pharmaceutical manufacturers. We found that people were

coming to the judgment that they were going to favor this applicant

over that applicant and sort of play god. Gratuities were passed

and all kinds of bad things happened.

So we had two problems here. We had a terrible climate inside

FDA. As I mentioned, it resulted in a few good individuals going

to jail. We also had the problem that there was not enough money

to process new drug applications in a timely manner. So there were

several things that flowed from that. The first was that the applications were not approved and as a result, drugs that could have

helped people were kept off the market. The other thing was that

manufacturers could not get decent service. So we began a process

of negotiating with the manufacturers and we said, look, we are

going to get you a system whereby you pay for the service, and

they found that this was a very good buy, because of what they received in return. They made a huge amount of money by shortening the time of waiting for approval by the Food and Drug Administration. It worked so well that we were able to engage over-thecounter drug manufacturers. Because they found that this was important to them. And then, after a long period of negotiations, we

engaged medical device manufacturers and we found that all of

this worked. We gave a commitment to the manufacturers that we

would protect their user fee money so it would not be diverted.

Now every time this committee writes legislation to put in the

trust fund, and I don’t care if it is us or the Public Works Committee or any of the other committees around here, we find that the

appropriators in the Office of Management and Budget and the

budgeters try to divert those user fee monies. Your comments indicated that PDUFA has been a tremendous success, but you also indicated that because more than 50 percent of the FDA drug approval budget comes from manufacturers for the licensing process,

that there is some kind of corruption, at least that is the impression I come away with. I want to know, is there some dishonest

practice? Is there corruption at FDA? Is there something going on

down there that this committee needs to look into? Now, tell me.

Mr. HUBBARD. Well, you will recall, Mr. Chairman, you are referring to a generic drug scandal that occurred in the late 1980’s, in

which you and your committee uncovered that. There have been examinations of the new drug approval process, to look for that. It

has never been found. And one of the advantages of the new drug

approval process is there are so many physicians and pharmacists

and others involved at FDA, that one person can’t have much influence. So fortunately, that program has been free of taint, at least

that is widespread perception.

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Mr. DINGELL. Well, if there is wrongdoing down there and if this

is tainting the system, we will change it. And I am asking you, is

this creating a problem in terms of the integrity of the system, in

terms of the protection of the consumers, in terms of the integrity

of the Food and Drug Administration?

Mr. HUBBARD. It has clearly been a concern on the part of FDA

leaders and staff that the fees should not continue to go up because

it could potentially lead to a problem.

Mr. DINGELL. Is that a statement supported by evidence of misbehavior and wrongdoing? Or is that statement based on a theory

of how good government should really work?

Mr. HUBBARD. I think the latter. There is no evidence of wrongdoing, but certainly the perception, as Mr. Vaughan and others

have pointed out, when the industry starts paying 70, 80 percent

of the fees——

Mr. DINGELL. Well, let me express one of my concerns. We investigate and analyze and check out the safety of less than 1 percent

of the foods coming into this country. We import about 50 percent

of our foods. Customs charges for the review by Customs agents at

the point of entry. They have numerous agents, so the process is

expedited. The Food and Drug Administration currently does not

provide the same reviews for food at the points of entry. FDA fails

to inspect the foods we import. Now what is coming in? Fruits and

vegetables contaminated; dog food or cat food with melamine in it;

a significant problem in terms of bacterial and viral contamination

of food stuffs coming in; tremendous amounts of counterfeit and illegal pharmaceuticals are being imported into the country. No way

of stopping it; no way of dealing with it. The good hearted people

at the Office of Management and Budget believe food inspections

are not needed. We have a leaner, meaner Food and Drug and they

do a splendid job on this. And then I go back and talk to Food and

Drug and they say, well, how many of these things are you connecting, and how many cats and dogs got killed just recently by

bad stuff coming in from China? And so they have to admit, well,

we aren’t doing so good.

Now what are we going to do about this? You live in a system

where money is like this or diverted and we have had—time preserving and protecting the monies that have to go to see to it that

PDUFA is properly implemented. Now, if PDUFA is not being

properly implemented, if there is dishonesty, misbehavior, bribes,

or special preference being afforded, I want to know about it. If

there is not, then I have to say, if we are going to continue this

system and we are going to try and do the best we can about making it work, in the broad interest of the public and the broad interest to the industry and the broad interest to the consumers and in

the broad interest of good government. Now is there rascality and

if so, who is doing it and what is doing it? What is happening?

What do we have to do about it?

Mr. HUBBARD. Mr. Chairman, I remember that you were sitting

in that chair 21 years ago, 1986, and I was on this side and you

said imports are a scandal and FDA was inspecting 10 percent at

the time. Today, they are inspecting less than 1 percent. The oversight of imported foods is a catastrophe and I will agree with you

all day long on that. In terms of PDUFA, I don’t see the kind of

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scandal you are raising in that program. They are very hardworking, dedicated people, but they do need more resources.

Mr. DINGELL. And this committee spends a huge amount of time

trying to get it for them and I must say, only with modest success.

Now, I want to thank you, Mr. Hubbard. I have asked you some

hard questions. If you come upon any wrongdoing, I want to be the

first to hear about it, and the committee wants to hear about it.

We will have the appropriate individuals before the committee to

answer questions about what they are doing that isn’t right.

Mr. PALLONE. Thank you.

Mr. DINGELL. Mr. Chairman, I thank you.

Mr. PALLONE. Thank you, Mr. Chairman. Mr. Markey is recognized.

Mr. MARKEY. I thank you, Mr. Chairman, very much and I thank

you for your courtesy. Could we just go down yes and no on this?

The question is, should the FDA have the authority to require postmarket studies, as recommend by the Institute of Medicine and by

the Government Accountability Office? Just go down. Should the

FDA have the authority to require post-market studies? Mr.

Goldhammer?

Mr. GOLDHAMMER. Yes, I think, again, I will have to give the

same answer.

Mr. MARKEY. Could you just answer yes or no?

Mr. GOLDHAMMER. We are not prepared to answer that question

yes or no.

Mr. MARKEY. You are not prepared to answer it. Yes, Mr. Hubbard?

Mr. HUBBARD. Speaking for myself and not for the group I am

representing, yes.

Mr. MARKEY. Yes. Thank you. Mr. Thew?

Mr. THEW. I would say yes.

Mr. MARKEY. Yes. Thank you. Ms. Holcombe?

Ms. HOLCOMBE. Speaking only for myself, yes.

Mr. MARKEY. Yes. Thank you.

Mr. VAUGHAN. Absolutely, yes. And for Consumers Union, absolutely, yes.

Mr. MARKEY. Thank you. And I thank each of you for that. Mr.

Vaughan, would anything in this Bush administration proposal

prevent selective disclosure of clinical trial results and ensure that

the public has access to all clinical trial information by creating a

mandatory registry of a clinical trials and results database?

Mr. VAUGHAN. No, sir.

Mr. MARKEY. What is the problem with that?

Mr. VAUGHAN. We are absolutely for it and it is in your bill with

Mr. Waxman, and Kennedy-Enzi, but correct me if I am wrong, but

the PDUFA draft bill up from the Administration doesn’t do anything in that area.

Mr. MARKEY. Why is it important that it do something in that

area?

Mr. VAUGHAN. Well, we would know what people have found

about the safety of a drug and even more, I think, sometimes what

they like to hide is whether it is any better than a placebo.

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Mr. MARKEY. OK. Again, Mr. Goldhammer, would you support

having mandatory language that all clinical trials have to be on a

list?

Mr. GOLDHAMMER. Again, that was not the province of what we

were permitted to discuss during PDUFA. I understand there

would be a subsequent hearing in this subcommittee on drug safety

and that would be part of it and I am sure we would be happy to

come back to you with an answer. But my answer right now is we

have stepped up to the plate and created such a database, which

is already being utilized.

Mr. MARKEY. But your database, Dr. Goldhammer, is a voluntary

registration.

Mr. GOLDHAMMER. That is correct.

Mr. MARKEY. Yes. Now, if a company doesn’t want to voluntarily

provide all clinical tests, what is the penalty which you impose

upon them?

Mr. GOLDHAMMER. Well, you hit it right on the head, it is voluntary and we, as a trade association don’t have an enforcement

mechanism.

Mr. MARKEY. So there is no penalty?

Mr. GOLDHAMMER. Correct.

Mr. MARKEY. Right. So the effect of that is that they can, like

I would have liked to have done when I was a boy, bring home the

good marks I got and not have to bring home the bad marks to my

mother and father. But the world really doesn’t work that way or

the world doesn’t work well that way. We can hide the tests that

you fail. The only way in which there is any accountability is if all

of it is disclosed. So let me go over to you, then, Mr. Vaughan.

Could you comment upon that, that PhRMA, this whole idea that

PhRMA has that you kind of grade yourself? You pick the stuff

that you want to make to public.

Mr. VAUGHAN. Oh, we think it is an absolutely terrible problem,

in that most of the trials that do get published in the big journals

are favorable to the person who paid for the trial. It is a pretty rare

day that you get a trial published that isn’t favorable to the person

who is, again, paying the bill. And to get real honesty, we need to

know what was to be studied, what the end points were, and then

what the results were, because it can get written up in ways that

puts lipstick on a pig.

Mr. MARKEY. Well, let me ask you, Mr. Hubbard. Do you think

that they should be able to selectively pick the trials they release

or should they have to release them all?

Mr. HUBBARD. Certainly full disclosure would be the best thing.

Mr. MARKEY. Full disclosure would be the best thing. Mr. Thew?

Mr. THEW. I would have to say I am not really too sure on that,

sir.

Mr. MARKEY. You are not too sure on that? OK. Ms. Holcombe?

So good to see you, by the way.

Ms. HOLCOMBE. I am not going to give you a yes or no on this

globally, but I do want you to know that it is the policy of Genzyme

Corporation, a Massachusetts company, to register all of our clinical trials in accordance with the rules and to publish the results

of all of our studies, generally, in accordance with the principles

that were laid out in your previous legislation.

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Mr. MARKEY. OK, I thank you for that. So that then, Mr. Chairman, it puts us in a situation where, again, you have PhRMA down

here sitting isolated and I understand that position. It is a position,

however, that leads to serious risks that the public and, in fact,

physicians could be misled by the selective information which is

provided to them, that they don’t have access to all of the clinical

trials. And there is no penalty. The risk is run by the patients, by

the physicians, but there is no penalty for the companies. And I

think that Ms. Holcombe, in talking about Genzyme, is talking

about a company who has accepted that and knows that there is

a responsibility. And I don’t think, honestly, that we shouldn’t finish this process without ensuring that the public gets the information they need. If PhRMA opposes this legislation based upon that,

then there is something fundamentally wrong with PhRMA. This

voluntary system just can’t continue because of the danger to patients. And we go back through Paxil, but we can’t go back through

so many other instances where information was withheld that

would have been of very critical importance to families. It just can’t

be selective. You have to know it all, because the decisions which

people make have to be informed decisions. And I look forward to

working with my colleagues to return the FDA to its role as a

watchdog for the health of our country, and I hope, through this

process, we are able to accomplish that goal and to put those safeguards in place. And I thank each of you for testifying and I yield

back the balance of my time. Thank you.

Mr. PALLONE. Thank you very much, Mr. Markey. I am going to

look around again and make sure we have no additional people

coming. But that concludes our questions and thank you all for

being here. I thought it was very useful to hear your testimony and

the back and forth. I just wanted to remind members that they

may submit additional questions, for the record, to be answer by

the witnesses and the questions should be submitted to the committee clerk within the next 10 days, so you may get additional

questions to answer. And without objection, this meeting of the

subcommittee is adjourned.

[Whereupon, at 2:05 p.m., the subcommittee was adjourned.]

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