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ASSESSING THE SAFETY OF

OUR NATION’S DRUG

SUPPLY

HEARING

BEFORE THE

SUBCOMMITTEE ON HEALTH

OF THE

COMMITTEE ON ENERGY AND

COMMERCE

HOUSE OF REPRESENTATIVES

ONE HUNDRED TENTH CONGRESS

FIRST SESSION

MAY 9, 2007

Serial No. 110–43

(

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 ............................................................................. 3

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

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

Hon. Diana DeGette, a Representative in Congress from the State of Colorado, opening statement ...................................................................................... 6

Hon. Joe Barton, a Representative in Congress from the State of Texas,

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

Hon. John D. Dingell, a Representative in Congress from the State of Michigan, opening statement ....................................................................................... 8

Hon. Michael C. Burgess, a Representative in Congress from the State of

Texas, opening statement .................................................................................... 10

Hon. Hilda L. Solis, a Representative in Congress from the State of California, opening statement ........................................................................................ 11

Hon. Mike Rogers, a Representative in Congress from the State of Michigan,

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

Hon. Edolphus Towns, a Representative in Congress from the State of New

York, opening statement ...................................................................................... 13

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

of Pennsylvania, opening statement ................................................................... 13

Hon. Jan Schakowsky, a Representative in Congress from the State of Illinois, opening statement ....................................................................................... 14

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

Tennessee, opening statement ............................................................................ 15

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

opening statement ................................................................................................ 16

Hon. Anna G. Eshoo, a Representative in Congress from the State of California, opening statement ........................................................................................ 17

Hon. Tom Allen, a Representative in Congress from the State of Maine,

prepared statement .............................................................................................. 18

Hon. Barbara Cubin, a Representative in Congress from the State of Wyoming, prepared statement ................................................................................... 18

WITNESSES

Steven K. Galson, M.D., Director, Center for Drug Evaluation and Research,

Food and Drug Administration ........................................................................... 19

Prepared statement .......................................................................................... 22

Answers to submitted questions ...................................................................... 161

Marcia Crosse, Director, Health Care Issues, U.S. Government Accountability

Office ..................................................................................................................... 36

Prepared statement .......................................................................................... 38

Lisa Van Syckel, Flemington, NJ ........................................................................... 78

Prepared statement .......................................................................................... 78

Ellen Sigal, chairperson and founder, Friends of Cancer Research .................... 81

Prepared statement .......................................................................................... 83

Susan Ellenberg, University of Pennsylvania School of Medicine, on behalf

of the Coalition for a Stronger FDA ................................................................... 87

Prepared statement .......................................................................................... 88

Caroline Loew, senior vice-president, scientific and regulatory affairs, Pharmaceutical Research and Manufacturers of America ........................................ 90

Page

VI

Caroline Loew, senior vice-president, scientific and regulatory affairs, Pharmaceutical Research and Manufacturers of America—Continued

Prepared statement .......................................................................................... 92

Diane Thompson, vice-president, public policy and communications, Elizabeth

Glaser Pediatric AIDS Foundation, on behalf of the Alliance for Drug Safety

and Access ............................................................................................................. 122

Prepared statement .......................................................................................... 123

John Theriault, chief security officer and vice president, global security,

Pfizer ..................................................................................................................... 125

Prepared statement .......................................................................................... 127

Sharon Levine, M.D., associate executive director, Permanente Medical

Group, on behalf of the Kaiser Permanente Medical Care Program ............... 129

Prepared statement .......................................................................................... 132

John Powers, M.D. assistant professor of medicine, the George Washington

University School of Medicine, and University of Maryland School of Medicine ........................................................................................................................ 143

Prepared statement .......................................................................................... 144

SUBMITTED MATERIAL

Drug Safety & Drug Efficacy Two Sides of the Same Coin .................................. 172

(1)

ASSESSING THE SAFETY OF OUR NATION’S

DRUG SUPPLY

WEDNESDAY, MAY 9, 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 Waxman, Towns, Eshoo,

Green, DeGette, Capps, Schakowsky, Solis, Matheson, Dingell,

Markey, Deal, Buyer, Pitts, Ferguson, Rogers, Murphy, Burgess,

Blackburn, and Barton.

Staff present: Ryan Long, Chad Grant, John Ford, Virgil Miller,

Bobby Clark, Jack Maniko, Melissa Sidman, Lauren Bloomberg,

and Nandan Kenkeremath.

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

Mr. PALLONE. Today the subcommittee is holding a hearing to assess the safety of our Nation’s drug supply, and I feel very strongly

that today’s hearing is long overdue. For far too long, the subcommittee has not paid enough attention, I think, to the issue of

drug safety, despite the growing concerns that the health and wellbeing of millions of Americans may be at risk due to a broken and

inadequate drug safety system.

In recent years, there have been a number of revelations about

drug safety that have shaken public confidence in the FDA’s ability

to ensure that consumers have access to safe and effective medications. From Vioxx to Paxil, tens of thousands of patients have been

placed in harm’s way due to the failings of our current drug safety

system. And as a result, the American people have steadily begun

to lose faith in the FDA. That should change.

We must restore public confidence in FDA’s ability to protect people from harmful products and to safeguard the public health. But

first, the FDA itself must change. There are a number of issues we

must consider as we move forward. First and foremost, FDA is

woefully underfunded. This was highlighted, as you know, in the

hearing that we had a couple weeks ago on the reauthorization of

PDUFA. More money is necessary for FDA to carry out its responsibility to protect consumers from harmful drugs.

2

However, it is an issue of where that money is going to come

from. And obviously there is a lot of debate. There is growing concern regarding the increasing amount of user fees that FDA relies

on to fund its budget. And as I have said before, if given the option,

I think everyone would agree that FDA should be funded more, if

not entirely, by annual appropriations. But realistically speaking,

we are not in a place where we can’t rely on user fees to help support the functions of the FDA.

That is not to say that we should give the drug industry carte

blanche on how these fees should be applied. FDA should have

more flexibility about what functions these monies can be used for,

such as postmarket and surveillance.

For far too many years, the focus of FDA has been to approve

the amount of time it takes to improve new drugs. And this is, of

course, a direct result of previous PDUFA agreements in which industry provides a new revenue stream to FDA and in exchange establishes benchmarks for a more timely drug approval process.

Unfortunately, however, this has caused an imbalance between

the pre-approval process and the post-market monitoring of drugs.

We have to fix this imbalance and focus more of our attention on

what happens with drugs once they reach the marketplace. Assessing the risk of the drug once it is on the market is just as important, if not more, than before it is approved.

Now, how are we going to achieve a more robust post-market

drug safety system? Fortunately, we seem to already have many of

the answers. First, we need to give the FDA greater authority and

flexibility to manage the risks associated with a new drug once it

has been approved. Currently FDA has little authority to control

how a drug is marketed and how the risks and benefits are communicated to consumers.

FDA should have more options to mitigate the risks consumers

face from a particular drug other than pulling it off the market entirely. Let us give the FDA the ability to require label changes,

should it deem them necessary. Similarly, FDA should have the authority to require, as a condition of approval, that manufacturers

follow through on their commitments to conduct and publish phasefour trials.

Even more important is ensuring that information about the clinical trials, including the results, is made public. It makes no sense

that we would allow such information to remain locked away at the

discretion of the industry. If my Republican friends are keen on

transparency in the health care market, as they say, then let us

start with full transparency of clinical trials. Let the consumers

and their doctors decide what they think is safe or not based on

complete information. The results of these clinical trials contain

valuable information for patients and their physicians, and we

should demand that they be made available.

Finally, I want to voice my concern about direct-to-consumer advertising. I realize that this is a very contentious issue, and I appreciate the industry and FDA’s willingness to work out a compromise, which was included in this year’s PDUFA proposal. However, as I said a couple of weeks ago, I am not certain that the new

program outlined in the PDUFA proposal will suffice.

3

The fact that the program relies on voluntary participation from

the industry strikes me as a program with no teeth. I am skeptical

of these advertisers and the alleged value they bring to consumers.

We will have to look at this program further and ensure that consumer’s best interests are being served well.

There are many other issues that need to be discussed as we talk

about drug safety. That is why today’s hearing is an important one.

And like I said at the beginning of my statement, it is long overdue

that we have these hearings. I am looking forward to hearing from

today’s witnesses, and I thank you all for being with us and now

recognize my friend from Georgia, Mr. Deal, for an opening.

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

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

hearing today on an issue that certainly will be a component of our

discussions on other FDA-related legislation that comes before our

committee this year. Recent incidences, such as the recall of Vioxx

that highlighted the importance of FDA’s role in evaluating the

safety of products both pre- and post-market, these events undermine consumers’ confidence in the safety of medications they are

taking and remind us that, while drugs provide useful life-saving

treatment, there are risks associated with any medication.

In February 2005, the FDA announced the creation of a new

independent drug safety oversight board to oversee the management of drug safety issues and provide information to help providers and patients about the risks and benefits of medicines.

I hope that our witnesses will be able to tell us about some of

the work this board has been doing to monitor drug safety in addition to the FDA’s other drug safety efforts. I also look forward to

hearing about the role of databases in studying drug safety. I believe one of these studies was instrumental in highlighting that

Vioxx increased the risk of heart disease. Studies like these show

promise and demonstrate some of the possibilities for the FDA

make use of existing drug data.

I want to thank our witnesses for their time and attendance

today, and I look forward to your testimony as we evaluate the best

means for ensuring patients have access to safe medications.

Thank you, and I yield back.

Mr. PALLONE. Thank you, Mr. Deal. Mr. Waxman.

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

Mr. WAXMAN. Thank you, Mr. Chairman. I want to applaud you

for holding this hearing today, for taking up the issue of drug safety at an opportune time. The Prescription Drug User Fee Act, or

PDUFA, must be reauthorized this year, and everyone knows that

in the end, it will pass. There is no realistic argument that it won’t.

So we have a vehicle that will move, and as recognized in the administration’s own PDUFA proposal, this vehicle could serve as a

means to strengthen FDA’s oversight of drug safety. We need to ensure that FDA not only has the ability to collect fees that help to

4

finance its oversight in our drug supply, but it also has the authority it needs to do this job well.

There is recent and mounting evidence that FDA’s ability to

oversee drug safety is a pale shadow of its ability to review drugs

before they are approved. We are familiar with the series of postmarket safety problems in the past year with drugs like Vioxx and

Ketek. They demonstrate beyond a shadow of a doubt that FDA’s

post-market drug safety oversight is in serious need of repair.

The Institute of Medicine, the GAO, have examined this situation. Both concluded that FDA cannot protect Americans from unsafe drugs unless Congress provides more resources and more legal

authorities. For example, right now, FDA cannot require post-market safety studies, even when FDA believes they are necessary to

fully understand the drug’s risk. FDA’s only choice is to ask a company to perform these studies and hope they will agree. And in the

case where the companies do commit to doing the studies in advance, if they don’t do it, the only option is to take the drug off the

market completely, which is a very serious one called a nuclear option, in fact. It is too tough for FDA to actually pursue.

According to the FDA’s own figures in 2006, manufacturers submitted only 11 percent of the 1,200 open study commitments. 71

percent of these studies hadn’t even started. The FDA also can’t

compel companies to make labeling changes after approval, as the

case of Vioxx illustrates. FDA must haggle with companies, often

for many months on end about the wording that should be used to

notify the public about what are often very serious risks associated

with taking their drugs. And throughout this process, the American

public continues to take these drugs without any knowledge of

these risks.

I have my own ideas for drug safety. Congressman Markey and

I have introduced a bill, which incorporates the recommendations

of the IOM and GAO. It is a counterpart to the drug safety legislation being debated on the floor of the Senate this week as part of

its consideration of PDUFA. H.R. 1561 represents the blueprint for

what we should be working on to fix the FDA’s ailing drug safety

system. I hope the committee will have an opportunity to consider

it.

Thank you, Mr. Chairman.

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

Mr. BUYER. I will waive my time.

Mr. PALLONE. 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, Mr. Chairman, and thank you for having

this hearing, as others have said. I thank our witnesses for being

here. I know the issue of drug safety has to be front and center as

we discuss ways to go forward with PDUFA reauthorization. It is

vitally important for the millions of people who depend upon pharmaceuticals and reasonably assume that they will do no harm.

FDA is charged with the responsibility to ensure that there are

safe and effective drugs, and that is the purpose of our hearing

today, to discuss ways to ensure that this responsibility is fulfilled.

Drug safety must be addressed before clinical trials and continue

5

not only through the approval process but extend to post-market

activity as well.

In the pre-approval period, we have to make sure that clinical

trials are conducted with the highest scientific and ethical standards, ensure also that the members of the advisory committees,

who make such important decisions about drug approvals, are free

of ties to the industry.

The FDA has taken a supposed first step in this direction. I understand they have proposed a regulation which prohibits voting

advisory committee members from holding more than $50,000 in

stock in a drug before being considered or any of its competitors.

But do we really believe that goes far enough? Certainly we

know that it hasn’t yet been implemented. We must have confidence that drug approval decisions are based on scientific data,

not on financial interests. As my colleague has mentioned, the high

profile cases of Ketek and Vioxx and many others were fateful reminders about the importance of post-marketing studies and data

collection.

I also hope we can discuss direct-to-consumer advertisements. It

is a great concern to me that so many consumers who are patients

rely on these ads and that proper oversight of their content does

not exist. Perhaps most importantly, I believe we must equip the

Food and Drug Administration with adequate resources. User fees

have been instrumental in reducing drug approval time, but we

must make sure that fees do not make up such a large proportion

of FDA funding that it becomes a conflict of interest.

So I thank you, Mr. Chairman, again for holding this hearing. I

look forward to ways in which we can work together to improve

drug safety. I yield back the balance of my time.

Mr. PALLONE. Thank you. Mr. Ferguson.

Mr. FERGUSON. Thank you, Mr. Chairman. I am going to waive

my opening statement for additional time in questioning, but I do

just want to welcome constituent and friend Lisa Van Syckel. She

will beon the second panel today. I am delighted that she is here

today. I know she has several folks with her, including Ellen

Liversage and Vera Sheral and Kim Witsack also here with her

today. And because of the many, many meetings that she and I

have had talking about drug safety over the course of the last several years, I have become very involved in the medication guide

issue. We have been doing an investigation in our office and working with FDA and others. So I am looking forward to getting into

that today, and I will look forward to using my extra time during

questioning. I yield back.

Mr. PALLONE. Thank you. Ms. DeGette. I didn’t count that. I

guess I should have. Yes, we are going to have to watch——

Mr. FERGUSON. I think I am owed a little latitude by a chairman

from my home State.

Mr. PALLONE. I will do better in the monitoring this in the future. Ms. DeGette.

6

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

Ms. DEGETTE. Thank you, Mr. Chairman. I think it is important

that as we prepare to mark up legislation affecting regulation of

pharmaceuticals and biologics that we put the safety of patients as

paramount. And so I know these drugs will save countless lives,

but we have to do what we can to mitigate unintended harm.

I really have three concerns today. The first one has been mentioned by several of my colleagues, and that is how we can make

systemic changes to the FDA to make sure that they are really approving drugs that are safe. And our own investigations of Vioxx

and Ketek as well as a number of other drugs over a period of

years have shown that we really can’t have that confidence that

the safety is paramount.

The second issue that I have is that the FDA just really doesn’t

have the resources to adequately address drug safety concerns. And

the most PDUFA agreement provides a significant increase in resources for post-market surveillance, but the fact remains that

Congress still has to provide additional funds.

Also because of the drug safety problems, the American public

has lost faith in the FDA and its ability to protect them from adverse effect. And this problem has been exacerbated by the ambiguous nature of the drug safety process. The general lack of transparency to the American public means that they don’t see how decisions are made, and therefore they don’t see why the drug companies are accountable to the FDA.

And finally, the full Senate is currently considering legislation to

reauthorize PDUFA as well as a seemingly endless array of other

drugs included in it. Though watered down, the Senate bill includes drug reimportation. Those of you who read the New York

Times this last weekend saw the front page article that should

make us all think twice about that policy. According to that article,

counterfeit drugs made in China were exported to Panama for sale,

and they included a deadly toxin. Last year, 365 families reported

deaths as the result of the tainted cough syrup and fever medication. And they think that that number is vastly underreported.

Mr. Chairman, the dangers from counterfeit and contaminated

drugs are frighteningly real, even under the current construct. Permitting reimportation would significantly increase the risk of counterfeit, misbranded and adulterated drugs that would end up in my

constituents home. I hope we keep this in mind as we mark up-

[Applause.]

Ms. DEGETTE. I might have to take that back given the response

from the other side. But seriously, I hope we keep this in mind as

we mark up legislation on prescription drugs. If we have a problem

with drug prices being too high in this country, we need to confront

that problem head on and not allow reimportation policies that

may affect the efficacy and safety of our drug supply in this country.

Mr. PALLONE. OK, now we have applause. Our ranking member

of the full committee, Mr. Barton.

7

OPENING STATEMENT OF HON. JOE BARTON, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BARTON. Thank you, Mr. Chairman. It is good to have this

hearing. I just got back from the trilateral committee hearing in

Ways and Means where we had Ways and Means, Financial Services, and Energy and Commerce. Their opening statements will go

on until about 5:00 this afternoon, I guess. So it is good to be here

with one committee and one subcommittee and focus on one subject.

We do appreciate this hearing today. When I was full committee

chairman of this august committee, I took the issue of drug safety

very seriously. I am glad to see that Mr. Dingell and Mr. Pallone

are continuing this. I requested a Government Accountability Office review of how the FDA approaches issues related to drug safety. I am looking forward to hearing from that agency today about

what steps it has taken to improve the safety of our drug supply.

Where action is needed to improve drug safety, I think that Congress should be prepared to act. I do hope that we do it right instead of just in a hurry. I can testify personally that the development of new prescription drugs have revolutionized medicine and

is saving lives.

Forty years ago, a person who had a heart attack like I had a

year and a half ago would have been given nitroglycerin, a pat on

the back, and sent home. Now, modern pharmaceuticals can help

prevent attacks from occurring or even reoccurring. I know because

each morning when I get up, I take six prescription drugs before

I begin my day.

We must take steps to ensure that the drugs that we are taking

are safe when they are approved and remain safe as they are put

into commercial use. No drug can be 100 percent safe for every person who might take it. Even aspirin, the ubiquitous miracle drug

that does everything from curing headaches to stopping heart attacks, has to be avoided by some people.

No responsible authority insists on absolute 100 percent safety

because that standard would have the reverse effect of increasing

the likelihood that many people would suffer or even die because

they didn’t have access to that particular drug.

As a drug used in the general population, less common side effects may be evident. Congress could impose Draconian new regulations that provide marginal benefits so that we appear to address

the problem. What we would actually be doing in that case, in my

opinion, is severely limiting access to life-saving drugs for tens of

thousands or hundreds of thousands of people, lives that might be

lost without that particular drug.

The history of drug regulation in this country reflects a conscious

weighing of the drug’s risks versus the drug’s benefit. If more

needs to be done to bring this balance into equilibrium, this Congress and this committee should and must explore those options,

but we should never lose sight that millions of Americans depend

on these medications to preserve and improve their lives.

Twenty-first century medicines must come with 21st century surveillance. Our health care system produces large quantities that

can and should be used to monitor drug safety issues. We should

have systems in place that can link up clinical data with prescripVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00013 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
8

tion drug use. Pre-market clinical trials are useful to determine the

safety and efficacy profile of a drug, but if rare side effects occur,

they must not become known until after the drug has been taken

by a larger population.

It is my understanding that the FDA has begun to use clinical

databases as a methodology to monitor safety concerns. I believe

we should enhance that ability to tap into the existing health information. I am pleased that the agreement on Reauthorization of

Prescription Drug User Fee Act will provide the FDA the ability to

obtain access to additional drug safety information, including population-based epidemiological data and other types of observational

data resources. I look forward to hearing from the FDA on their efforts in this area.

I also am looking forward to hearing from the testimony of Mr.

John Theriault who will discuss the issue of prescription drug

counterfeiting. It is shocking and unacceptable that the maximum

penalty for counterfeiting a prescription drug in this country is 3

years in prison. Three years in prison. Phony drugs are the ultimate bad medicine. Impurities in the counterfeit drugs pose dangerous consequences for patients, and intentionally giving a serious

ill person a drug that does not contain the active ingredients that

they think it does could actually be considered to be murder.

Addressing counterfeit drugs requires public and private entities

working together. Unfortunately, our anti-counterfeiting drug problems are not nearly as smart as the counterfeiters are. A first step

to address the problem would be for the House to pass Congressman Rogers’ legislation to substantially increase the criminal penalties for drug counterfeiters.

Second, we should look at new technologies that will allow us to

better track these drugs in our supply system. I look forward to

hearing from the company Pfizer about what steps that they are

taking in this area.

Again, Mr. Chairman, thank you for holding this hearing. I look

forward to participating.

Mr. PALLONE. Thank you, and I will recognize the chairman of

our full committee, Mr. Dingell.

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

Mr. DINGELL. Mr. Chairman, thank you for holding this important hearing. The committee is here today to discuss the safety of

our Nation’s drug supply. And included in that is the competence

and ability of FDA to carry out its very important mission.

The question here is what does it mean to say that a drug is

FDA approved. Good government would say that the Food and

Drug Administration approval should be the gold standard

throughout the world, that the drugs approved provide needed

therapies for consumers without causing further medical complications or worse, death.

Unfortunately, Food and Drug approval of pharmaceuticals as

the gold standards has been called into question. Incidents highlighted by the recall of the arthritis drug Vioxx have created a crisis of confidence in the Food and Drug Administration.

9

It should be observed, however, that problems with Food and

Drug go more broadly than this. It is an agency which has inadequate resources, inadequate numbers of personnel, inadequate financial support, and inadequate ability to carry out its responsibility, over both drugs manufactured and food manufactured in this

country, and over imports, something which has shaken my confidence in a very real way in the agency.

I publicly express my dissatisfaction with the way in which Food

and Drug has handled the important issue of drug safety. FDA’s

lack of transparency and recent recalls have greatly contributed to

the loss of public confidence. The agency must aggressively monitor

and assess safety and efficacy throughout the entire life cycle of a

product. Simply stated, FDA must ensure that just as much time,

resources and energies are invested in the aggressive post-market

observation as is spent in pre-market trials, consultation, and

meetings with the industry.

Unfortunately, it appears that there is a singular lack of resources at Food and Drug to carry out these responsibilities as it

is to carry out other important responsibilities of that agency. A recent Institute of Medicine report concluded FDA and the pharmaceutical industry do not consistently communicate safety concerns

in a timely and efficient and effective manner.

In addition to insisting on structural and resource changes within the agency, the country must also see to it that FDA continues

to push for significant improvements in cultural changes at that

agency. Public health policy is ultimately a human enterprise, and

all facets of FDA’s drug programs must work in a coordinated fashion for a common purpose, thereby ensuring consumers that the

drugs they take are safe and effective. Again this will require a cultural change, but more importantly, it is going to require adequate

funding and support for the agency which it currently lacks.

FDA has taken steps to boost consumer confidence. In 2004, they

introduced a new drug safety initiative that promised to promote

a cultural of openness and enhanced oversight within the agency.

And it has included additional drug safety provisions in its recent

PDUFA proposal.

The agency also asked the Institute of Medicine to evaluate its

current system of drug safety and make recommendations for improvement. The Government Accountability Office, GAO, has also

weighed in, and in 2006, released a report on FDA’s ability to ensure a safe drug supply. The report included a number of recommendations. I am pleased that a representative from GAO is

here to discuss this report. We will also want to discuss it with representatives of FDA and of higher officials in the Department of

Health and Human Services.

It is, I think, appropriate that we should appreciate these efforts,

but it is not clear to me that they, when coupled with the budget

shortages of the agency, are sufficient. We are here today to see

what additional steps that Congress may need to take so that

American citizens are protected and the confidence in the agency

is restored.

I appreciate this hearing, and I look forward, Mr. Chairman, to

the testimony of our witnesses and the input of our members as we

discuss the safety of the U.S. drug supply and the reasons why it

10

is not as safe as it should be and what steps we will take to improve it. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you, Chairman Dingell. The gentleman

from Texas, Mr. Burgess.

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BURGESS. Thank you, Mr. Chairman, and frankly about the

referenced aspirin, I guess I can’t help but wonder if we were to

send aspirin now through the Food and Drug Administration process if it would survive the approval studies or whether it would

survive the post-market surveillance.

But this is a good hearing. This is an important panel of witnesses. I believe that we must strive to seek a balance between the

safety measures that we put in place, at the same time allowing

and facilitating new drugs coming to market. I believe that the

FDA has done a good job with the resources available to it, but we

can make it better. And Chairman Dingell may be correct about

the allocation of resources.

Senator Mike Enzi from Wyoming has made a reasonable start

to this discussion over in the other body by introducing his bill. His

legislation would bring the risk/benefit analysis in at the beginning

of the drug approval process. It would facilitate a lifetime approach

to drug evaluation through the establishment of a drug safety oversight board.

Senator Enzi’s bill also addresses two topics that are of particular interest to me, the critical path initiative and the establishment

of databases. The critical path initiative strikes me as having great

potential to fundamentally improve the way that we approve new

drugs by utilizing the science that the research has yielded. If we

could make our approval process more personalized, more efficient,

safer, and faster, than I certainly support this.

In reading the materials supplied by the general accountability

office, they raise a question what safety action that the FDA

lacks—or rather they raised the point that the FDA lacks the information about what safety actions to take and when to take them.

I believe that additional databases and data mining can help utilize information that is already available but needs to be collected

properly. This can be helpful whatever we are examining, whether

we are looking at the results from clinical trials or searching for

adverse drug events through, for example, the Permanente patient

population.

Data mining and rapid learning techniques are tools that are

available but not being used to their full potential. Mr. Chairman,

there is lots of information out there. It is a time of rapid change

in the medical field. Going on clinicaltrials.gov Web site this morning, you can see that they have had 143 new hits during last week

alone. And that is the pace at which information is coming into the

FDA. This deals with illnesses as varied as asthma and appendicitis, pulmonary hypertension, and magnetic therapy for depressed

adolescents. Innovative therapies must reach the clinical applicability stage with greater speed, but there also has to be the collection

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ies. Data collections should be available to arrive with greater

speed and clarity for the clinician.

Finally, I do have to agree with my colleague from Colorado

about reimportation. If the debate is over cost, then let us be honest and have that debate. Don’t reimport drug price controls from

countries who refuse to participate in paying for the research and

development of those products in the first place.

Thank you, Mr. Chairman. I will yield back my time.

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

Solis.

OPENING STATEMENT OF HON. HILDA L. SOLIS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA

Ms. SOLIS. Thank you, Mr. Chairman, and good morning. I am

very pleased that you are having this hearing today and have an

opportunity to talk about this important issue. Hundreds of millions of Americans rely on FDA’s judgment regarding the safety of

prescription drugs.

In 2005, the number of prescriptions purchased was about 3.6

billion, on an average, about 12.3 prescriptions per person. And

FDA regulates daily 25 percent of gross domestic product and is

sometimes called the largest consumer protection agency. It is critical that our consumers are actually being protected.

Each decision made by FDA is crucial and has life or death consequences for many of our constituents. In the past, drug safety

may have been taken for granted. Patients have great trust and

faith in FDA. However, the publicity surrounding many several

drug recalls in the Institute of Medicine’s report ‘‘The Future of

Drug Safety: Promoting and Protecting the Health of the Public’’

shows that much work is needed to improve the safety of our medicines. The Institute of Medicine identified serious problems in monitoring drug safety and created numerous recommendations.

FDA has a difficult balancing act indeed. So I am pleased that

FDA has taken the initiative to strengthen and improve the drug

safety efforts. We know that FDA has to deal with external constraints, including significant funding gaps at the Center for Drug

Evaluation and Research. However, FDA has a responsibility to

evaluate and address the safety of prescription drugs after they

have reached the market.

We must enable providers and patients to make the best possible

decision about using medicines to improve their health. I have serious concerns regarding the transparency of the drug approval process, specifically adverse event reporting and the fact that FDA

lacks authority to require that a manufacturer conduct a rigorous

clinical trial to investigate post-market safety. Even if FDA requests a trial to be conducted, it has no way of enforcing the completion of that study. The fact that the completion rate of the postmarket studies was less than 25 percent between 1991 and 2003

is disturbing.

The Adverse Event Reporting System is not an adequate drug

surveillance system and does not capture all the adverse drug

events. We need greater transparency and better communication in

order to protect American consumers.

12

I thank the witnesses for coming today, and I look forward to

hearing their recommendations, and I yield back the balance of my

time.

Mr. PALLONE. Thank you. Mr. Rogers.

OPENING STATEMENT OF HON. MIKE ROGERS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

Mr. ROGERS. Thank you, Mr. Chairman. I have a long statement,

and I would like to waive it at the end so that I can get more time

in questions. Just kidding. If you are from New Jersey, you think

that is funny, Mr. Chairman.

I want to bring your attention to an article published in The New

York Times on May 6, 2007. It highlighted an investigation into

the global and often deadly epidemic of counterfeit drugs. The investigation by the Times examined how counterfeit glycerin, a

product often used in cough syrup, fever medication, and injectable

drugs made its way via a poison pipeline stretching halfway around

the world.

The counterfeit product was diethylene glycol, an industrial solvent and prime ingredient in antifreeze. Through shipping records

and interviews, the counterfeit product from Panama was traced

back through trading companies in Barcelona, Spain, a permitted

country, I might add, under the legislation currently being considered—and back through Beijing, China.

Seventy years ago, when medicines laced with diethylene glycol

killed more than 100 people in the United States. It led to the passage of the toughest drug regulations of that era and creation of

the modern Food and Drug Administration. This creates an interesting contrast to the current debate over the potential drug safety

and reimportation legislation. This has to be a component of that

discussion, Mr. Chairman.

Last year, in Panama, 365 deaths were attributed to this poisoning with diethylene glycol in cough syrup. The World Health Organization estimates that global sales of counterfeit drugs were $32

billion in 2003. That is the last best year we have information. 10

percent of all those medicines sold worldwide, the value seized for

counterfeit and diverted drugs in the United States alone was almost $200 million in 2003. And that was a sevenfold increase from

the previous year.

Authorities have encountered significant difficulty in tying

deaths to the actual consumptions of fake drugs mainly for the reporting system that is in place today. In Canada, it is currently investigating the death of a British Columbia woman, who died apparently after taking counterfeit pills she ordered online from what

she believed was a Canadian Internet pharmacy. Officials have

linked the death to pills purchased from this alleged Canadian

Internet pharmacy about a month before she died. Her toxicology

tests revealed that the counterfeit pills contained dangerous high

levels of heavy metals strontium, uranium, and lead.

The World Health Organization estimates that 50 percent of the

medicines purchased over the Internet from sites that conceal their

address are counterfeit. This is a serious and growing problem, Mr.

Chairman. The five top countries ranked for counterfeit incidents

to the FDA are: one, China; two, Columbia; three, Russia; four,

13

India; and five, the United States. So I have introduced H.R. 780,

a counterfeit drug protection act to strengthen the criminal penalties against those who participate in the production, distribution,

and sale of counterfeit drugs, understanding the prevalence and

dangers of counterfeit drugs is absolutely necessary, Mr. Chairman,

in determining the safety of prescription medications in our Nation.

And would yield back the remainder of my time.

Mr. PALLONE. Thank you. Mr. Towns.

OPENING STATEMENT OF HON. EDOLPHUS TOWNS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW

YORK

Mr. TOWNS. Thank you very much, Mr. Chairman, for having

this very important hearing today. Making sure that drugs are safe

means making sure that they are safe for the diverse segments of

our population as well. That simply is not the case. Minority participation in clinical trials has been cut in half over the last decade

from 12 percent to 6 percent. And African-Americans represent less

than 8 percent of those enrolled in cancer clinical trials, while Hispanics make up just 3 percent.

While pharmaceuticals are largely an effective means for addressing a wide range of health care needs, I am concerned that

minority patients have not been adequately represented in many

clinical trials. This means that as we seek to reauthorize the FDA,

that we take into account the needs of diverse populations. To do

this, we must increase the number of racial and ethnic minorities

in clinical trials, particularly for diseases and conditions where

there are health disparities.

This will increase public confidence in the FDA’s ability to ensure drug safety. We must also make sure that the FDA itself is

diverse. In addition, data from diverse populations must also be included in both pre- and post-marketing reports on safety and effectiveness to ensure that these studies look like America. Mr. Chairman, if we are to serve a diverse America, we cannot continue a

one-size-fits-all approach to the development of new drugs and ensuring patient safety. Thank you, Mr. Chairman, for bringing this

critical subject before us today, and I look forward to the testimony

coming from the witnesses.

Mr. PALLONE. Thank you. Mr. Murphy.

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

Mr. MURPHY. Thank you, Mr. Chairman. The recent case, the

tragedy at Virginia Tech, and actually the less publicized but

equally problematic problems throughout our universities with

mental health issues remind us that we have a large mental health

problem nationwide that is not being adequately addressed. And

when it comes to FDA and drug safety, and given my career as a

psychologist, I want to emphasize some of the problems with this

that I hope the FDA will address.

Today we are scheduled to hear some rather tragic testimony

from a mother about her daughter, about some of the problems she

had with antidepressant medication. And I want to emphasize this

14

for the FDA. That dealing with safe drugs is not just a matter of

running clinical trials and posting more news in the PDA. It is also

making sure that careful trials on adults and children and any of

the population that will be using the medication is done, that research is ongoing, and that information is readily available and

sent to all those who are prescribing the medications.

In the example of psychiatric medications, I find it disturbing to

note that 75 percent of psychiatric medications are prescribed by

non-psychiatrists. Even though we also know that a combination of

medications with regular psychotherapy provided by trained licensed professionals is the most helpful, very often what happens

with patients, they are given some medication and have little or no

additional follow-up.

I believe it is critically important, whenever the FDA looks at approving drugs, they also make it absolutely clear under what context medication should be used, not only providing information on

the use and side effects and regular and rapid updates to positions,

but also making sure that information on the full context of treatment under which that medication is used is part of the prescribed

regimen and not just the idea of handing off a pill.

It is also essential that messages continue to go out to the prescribers that clear communication must be ongoing with the parents when dealing with the pediatric population. Unfortunately we

have set up so many barriers where parents are not aware of what

is happening with their children’s medication and with treatment,

we are actually contributing to the problems of these children, and

that is wrong.

Good health care has never been just a matter of taking a pill.

Our culture, our whole health care system, has too often supported

this past approach of take a pill and call me in the morning. We

have to make sure that the FDA, in approving any medication,

makes it absolutely clear the context that medication is prescribed

and make sure that all involved are part of that communication

system. And parents of the pediatric population, psychologists, psychiatrists, and others who are involved. Failure to do so will mean

that more families will be harmed, and I hope that is one of the

outcomes of what the FDA will be working on. Thank you.

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

Schakowsky.

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

Ms. SCHAKOWSKY. Thank you, Mr. Chairman. I first want to associate myself with the remarks of Mr. Towns, the clinical trials

are to look like America. I know that women weren’t included in

cardiovascular trials until women were present in the Congress.

And so now that we are a grand number of 72, I was surprised to

hear at one of our last hearings that still the clinical trials, only

25 percent are women that are being tested. And yet we know already that there are great differences, as we know with AfricanAmericans as well when it comes to cardiovascular disease and others.

I also wanted to talk about the approval process. The fact that

it has been trimmed down from over 29 months in 1987 to cut in

15

half since then is a good thing for many people who are facing serious illness or chronic disease. But as we move forward with this

conversation, it is very important to consider the other end of this

approval process, the proposed approval process, which is essential

to the health and safety of our constituents. If we accelerate preapproval procedures, then tracking a drug in its post-approval lifespan becomes ever more important.

Relying on the current Adverse Events Reporting System, the

AER System, is not sufficient. Not all adverse reactions are obvious

to those who experience them. In cases like Vioxx, they only become apparent after months of use. Additionally a person won’t always make the correct connection between a prescription drug and

the side effect they are experiencing. Or they will fail to make any

connection at all.

Furthermore, one has to consider how often a person or doctor

will take the time to actually report a serious side effect. How

many adverse effects are we missing with this process? We need

to make sure that the right mechanisms are in place at the FDA

to deal with these adverse events information in an efficient, objective, scientifically sound way and that the reported data is accessible to those who can use it to help avoid further incidents down

the road.

One other concern I want to mention, we are relying on patients,

many of whom are frail, elderly to understand complicated medical

advisories, unclear directions issued by pharmaceutical manufacturers. Who is making sure that this information makes sense to

them? Can they understand the relevant safety information on the

drug inserts that come with their prescription medications? Is this

information in the appropriate language? Are seniors and other relying on advertisements in the paper or able to read warnings that

may be in four-point font? I am concerned with the dependency on

adverse reporting to recognize post-market problems, troubled by

the lack of oversight and authority on FDA’s part to monitor the

information on prescription drugs that is received or we think is received by those who need them. So I look forward to hearing from

our witnesses, and I thank each of you for being here. 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. Thank you for the

hearing, and I did want to say welcome to our witnesses. We do

look forward to hearing from you, and we look forward to the information you are going to give us.

According to the GAO, the FDA lacks a clear and effective process for decision making about and providing oversight of post-market drug safety issues. I have often thought it would be interesting

if the FDA were a patient to see what kind of diagnosis we would

provide the agency.

The situation is exactly what my constituents complain about

when they reference those bureaucrats in Washington, DC. We

have two FDA offices functioning without clear guidelines and duVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00021 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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plicating each other’s work. And it is unfortunate that the Federal

Government both allows and tolerates this kind of bureaucracy.

And it is amazing that it comes at the risk of public safety.

I would hope that there are some best practices that someone is

looking at implementing. Any private sector company would be out

of business if they ran their business like the FDA runs the

public’s business. However, our drug review system is not totally

broken, as many would believe, and sometimes it is as if we are

trying to scare people to death by chipping away at the public’s

trust in this drug review process that we have. The U.S. has the

best pharmaceuticals in the world and will continue to ensure that

all drugs are properly vetted using the highest safety and review

standards. And I hope that the FDA has the institutional will to

reform their process and work toward restoring this trust.

While I understand the need for oversight and increased transparency in the FDA’s drug review process, Congress should work

toward a system with appropriate checks and balances. We must

refrain from tactics, such as imposing a litany of needless regulation on the drug review system, which will prevent access to lifesaving drugs. Expediency, transparency, efficiency should be a big

part of the discussion.

As we continue to learn about drug safety issues, we must not

forget that it is our duty to protect the public from unsafe drug approval and post-market review tactics.

I am looking forward to hearing from our witnesses. Mr. Chairman, I thank you, and I yield back.

Mr. PALLONE. Thank you. I 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 this hearing

on the safety of our drug supply. This hearing will complement this

subcommittee’s work on the Reauthorization of Prescription Drug

User Fee Act as well as the Oversight and Investigation Subcommittee work on drug safety lapses at the FDA.

And the O&I subcommittee has uncovered serious problems with

the FDA’s handling of Ketek, antidepressants, and, of course,

Vioxx. These cases have shed light on the structure and cultural

and administrative problems at the FDA with regard to drug safety. They also have contributed to a decline in the American people’s

confidence in the FDA’s ability to ensure the safety of our drug

supply.

According to a Harris poll, 58 percent of Americans gave the

FDA a negative rating when it came to public confidence, a number

that has increased from 39 percent 2 years ago. To improve the

public’s confidence in the safety of our drug supply, there needs to

be some big changes in the FDA. Some of the drug safety concerns

can be addressed administratively at the FDA. I know that Dr. von

Eshenbach has made significant effort to implement many of the

Institute of Medicine’s recommendations.

To correct other problems, however, the agency needs expanded

authority from Congress. And it is our job to give the FDA the resources it needs to improve drug safety. We need to take a serious

look at the Adverse Events Recording System and its ability to

17

identify adverse drug reactions following the drug’s approval. The

system is plagued with underreporting, and the FDA currently has

a very high threshold for action. When taken together, these two

factors unfortunately result in too many Americans being subject

to harmful drugs for too long before the FDA steps in.

While the high profile cases make the nightly news, we know

that problems continue beyond Vioxx, Ketek, and antidepressants.

According to the GAO, 51 percent of all approved drugs have had

at least one serious adverse drug reaction that wasn’t caught during the approval process. There is no question we should be catching more of these adverse drug reactions before approval, but we

should also have a robust post-market system that is nimble

enough to recognize problems and act quickly to correct it.

Unfortunately, the scope that the FDA has authority to react is

currently severely limited, and I hope that we change that in the

PFUDA. If we are going to expand the FDA to ensure safety of our

drug supply, they need to have the authority to require changes to

drug labels when their scientists determine that black box warnings are necessary or that products should be restricted.

The FDA also needs the authority to enforce post-market study

commitments made by drug manufacturers. With 71 percent of

post-market study commitments not even begun by drug manufacturers, it is clear that the FDA lacks an enforcement mechanism

with any teeth. Otherwise, the drug sponsor wouldn’t show such

blatant disregard for their post-market commitments to the FDA.

I would like to commend my colleagues, both Mr. Waxman and

Mr. Markey for addressing many of these issues in their current

legislation, a good portion of which is currently being considered on

the Senate floor. I look forward to hearing from our witnesses on

these issues and many others surrounding drug safety, and we appreciate their being here today. And I yield back my time, Mr.

Chairman.

Mr. PALLONE. Thank you. 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. I think that the issues that we are dealing with in

this hearing are amongst the most important for the American people because there isn’t a person in the country that, on their own,

on their very own, can guarantee in any way, shape, or form that

what they are taking, what they are ingesting is absolutely safe.

They know that they have to depend on really the government and

its blue chip agency, the Food and Drug Administration for it.

Now, we know that we have a problem, and it lies, I think, more

in the post-marketing phase of drugs. The FDA actually does not

have an active drug surveillance system. So I think now is the

time. We are reauthorizing PDUFA, and we need to build in a process by which and an authorization, a direction for the FDA to actually have an active drug surveillance system.

The drugs that have caused problems or high profile Vioxx and

Ketek, first of all, the agency has to have the funding to do this.

I think that we have gotten to a point now where there is an overVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00023 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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reliance on user fees. And the Congress has to step up to the plate

to make sure that the agency has the resources it needs to carry

out what, I believe, we need to do, and that is to set up a postmarketing drug surveillance system.

So I look forward to what the witnesses are going to inform us.

I would like to thank publicly the IOM for the work that they have

done on this. I think it has been useful and instructive to us. And

I look forward to a reauthorization of PDUFA that is going to very

clearly define the responsibilities for the FDA in this very particular area, as well as our recommendation relative to the resources

for it. I think if we do one without the other, that it simply won’t

happen, and this is just too critical.

So thank you, Mr. Chairman. This is important, and we have

had, since you have taken over as the chairman of this subcommittee, I think the hearings that we are having are the hearings that

really matter on the most important things that are challenging us

in the health arena. Thank you.

Mr. PALLONE. Thank you very much. I believe we are done with

the opening statements, and any other statements for the record

will be accepted at this time.

[The prepared statements of Mr. Allen and Mrs. Cubin follow:]

PREPARED STATEMENT OF HON. TOM ALLEN, A REPRESENTATIVE IN CONGRESS FROM

THE STATE OF MAINE

Mr. Chairman, thank you for calling for this important hearing to examine efforts

to improve the current drug safety system.

I want to commend Representatives Waxman and Markey for their work on this

issue and for the introduction of H.R. 1561, the Enhancing Drug Safety and Innovation Act, which will make the critical changes necessary to improve our current

process for ensuring the safety and effectiveness of prescription drugs.

A pillar of U.S. policy on prescription drugs is the protection of the individuals

who use them. Public confidence in our Nation’s drug supply has been shaken in

recent years by recalls of heavily marketed and widely prescribed drugs such as

Vioxx. A new poll by Consumer Reports indicated that the vast majority of Americans want stronger drug safety laws and believe that more authority should be

given to the FDA to protect consumers.

The Institute of Medicine report issued last fall offered 25 recommendations to

improve the FDA’s pre-approval processes. One of the most important recommendations, in my opinion, is the need for continuous safety monitoring throughout the

life of the drug, including post-marketing surveillance.

The study found that ‘‘the FDA lacks the clear, unambiguous authority needed to

enforce compliance with regulatory requirements and instead relies on the prospect

of productive negations with industry.’’

This is troubling, and a clear indication that the system is broken.

I look forward to working with my colleagues to address this and other important

issues; including improving public access to clinical trial results and ensuring that

the FDA has adequate staff and funding to fulfill their mission to protect the public

health.

I look forward to hearing the views of our distinguished panelists on ways to improve the current system to protect consumers from unsafe prescription drugs and

restore their confidence in the FDA.

PREPARED STATEMENT OF HON. BARBARA CUBIN, A REPRESENTATIVE IN CONGRESS

FROM THE STATE OF WYOMING

The Food and Drug Administration’s safety activities are directly relevant to the

everyday lives of every U.S. citizen. The 10,000 person agency is charged with monitoring roughly 124,000 firms that manufacture or process FDA-regulated products,

which compose roughly one-fifth of our Nation’s gross domestic product.

With this in mind, the notion that the public may be losing faith in the FDA’s

drug safety activities is unsettling at best. Over the last few years, the heavily pubVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00024 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
19

licized removal of drugs from the marketplace has cast a shadow of public doubt

over the FDA’s ability to protect the American people from harmful products. 64,000

seniors in Wyoming now have access to affordable Medicare prescription drug coverage, but this means little if our drug supply is not safe.

In response to public and congressional concern, the FDA asked the Institute of

Medicine to assess and make recommendations for our Nation’s drug safety system,

in addition to their own ongoing drug safety assessment. I am hopeful that today’s

testimony will help our committee understand both the extent of the safety reforms

the FDA and industry have embarked upon, as well as steps that may need to be

taken by Congress.

I would urge my colleagues to keep in mind that the FDA is charged not only with

assessing drug safety, but also drug efficacy. These two prongs of the FDA’s mission

are not mutually exclusive, and should not be separated as we consider legislative

changes to the agency’s structure and authorities.

The agency does not just conduct risk management. It must also conduct risk-benefit analysis. Risk-benefit analysis can and should vary based on the severity of an

illness and the availability of alternative therapies. We must consider the cancers

and neuro-degenerative disorders for which patients have few, or even no, existing

treatment options.

The acceptable risk for a drug treating mild arthritis will not be the same as for

a drug treating Alzheimer’s or Lou Gehrig’s disease. There are seriously ill patients

whose access to innovative treatments would be jeopardized by regulatory overreach, now matter how good intentioned. Their voices deserve to heard in this debate.

While I believe there is no one-size-fits-all regulatory solution for drug safety,

there is no question that drug safety assessment should be based, to the greatest

extent possible, on sound science.

Perhaps the greatest room for improvement in drug safety lies with post approval

monitoring. Rare and serious side effects may not emerge until after a drug has

been approved based on clinical trial data, in particular, drugs that treat smaller

populations.

I hope today’s panels will have suggestions for the tools and resources the FDA

needs to conduct science-based, risk/benefit analysis throughout the market life of

a drug. The dire need for innovative medicines among the seriously ill does not start

and stop with the FDA’s approval time-line, nor should serious efforts to ensure the

health and safety of the American people.

Thank you Mr. Chairman. I yield back.

Mr. PALLONE. I will turn to our witnesses and ask the two for

the first panel would come forward if you would. Now, let me introduce the two of you.

First, we have Dr. Steven Galson, who is Director of the Center

for Drug Evaluation and Research at the Food and Drug Administration. And next is Dr. Marcia Crosse, Director of Health Care

Issues at the U.S. Government Accountability Office. You have 5

minutes each. Your statements will be made part of the record, and

you may, at the discretion of the committee, submit additional brief

and pertinent statements in writing for inclusion in the record.

And I will now recognize first Dr. Galson.

STATEMENT OF STEVEN GALSON, M.D., DIRECTOR, CENTER

FOR DRUG EVALUATION AND RESEARCH, FOOD AND DRUG

ADMINISTRATION

Dr. GALSON. Thank you very, very much, Mr. Chairman and

members of the committee. I am Rear Admiral Steven Galson,

FDA’s director for the Center for Drug Evaluation and Research.

I am very pleased to be here to talk about FDA’s drug safety program and to reemphasize our continued commitment to drug safety.

As a physician, I have dedicated my career to serving public

health. As a career medical officer in the U.S. public health service

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since 1986, I have worked in the Nation’s public health agencies to

assess scientific data and make health recommendations and regulatory decisions that protect and promote the health of the American people. In my current position as director of CDER, I am deeply committed to leading an organization that inspires the trust and

confidence of the people we serve.

My detailed testimony submitted for the record talks about the

many initiatives CDER has on the way to strengthen drug safety.

Modernizing the science of drug regulation, improving our internal

operations, and enhancing our communications. I will focus my

brief remarks today on describing my vision for the center and our

vital role in protecting and promoting the public health with an increasingly complex health care system.

As you know, no drug is risk-free, and FDA plays a key role in

assuring that a drug’s benefits outweigh its risks, beginning with

our determination whether a drug can be approved for marketing.

And if so, ensuring that is it truthfully and adequately labeled.

Scientific progress is key to improving drug safety. CDER is

meeting this challenge in many ways, including partnerships with

outside groups who can assist us in developing new tools to improve safety. One example is an ongoing FDA scientific collaboration intended to yield better tests for toxicity than our current

screening techniques. Such new tests would detect toxicity problems earlier in drug development than our current approaches.

Our responsibility continues, as you know, post-marketing when

our programs identify adverse events not previously brought forward. To meet this challenge, CDER has taken a number of steps

to strengthen the science that underpins these regulatory decisions.

These scientific activities include developing and incorporating new

tools to assess benefit and risk, upgrading our adverse event reporting system, and expanding our database resources. One example of the work we are doing to support the science of post-marketing drug safety assessment is exploring opportunities for linking

private sector and public sector post-marketing safety monitoring

systems to create a nationwide medical product safety network.

Such a system could enable better safety information about medical

products to get to health care professionals and patients at the

point at which they are providing and receiving their care.

Communicating about marketed drugs is one of our key responsibilities, and health communications technology is rapidly evolving

in this century. We too must change as this technology changes

and improves. In this area, we have recently issued final guidance

that describes our approach to communicating drug safety information, including emerging drug safety information to the public

quickly, even if, in some cases, we are still evaluating this data.

Another part of improving our approach to drug safety is to listen to people outside FDA for ideas. Next month, on June 25 and

26, we will hold a public workshop to seek input from outside experts to discuss how risk management plans are working to enhance patient safety. In addition, we plan to establish a new advisory committee to obtain input on how to improve our external

communications.

Lastly, I would like to address the steps we are taking to affect

a culture change within CDER to become the kind of effective, effiVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00026 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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cient and integrated center I am committed to leading. We are addressing tensions between our pre-approval and post-approval staff.

We have enlisted the help of external experts to help to identify opportunities for improvement and assist us with implementation of

these steps. We are examining ways to improve our handling and

resolution of scientific disagreements.

CDER has employed process improvement teams to recommend

changes to our drug safety program. A number of their recommendations have already been implemented, including the establishment of new safety-related positions in each of our drug review divisions and conducting regular safety meetings between

groups.

We are also developing pilot projects to evaluate models of integrating our surveillance staff more into our drug review process, including having the staff participate in new drug reviews. We are

firmly committed to ensuring that our surveillance staff have a

strong voice pre- and post-marketing in safety decisions.

In conclusion, CDER’s mission is to ensure that Americans have

access to safe and effective drugs. Toward that end, our regulatory

decisions must be based on sound science, applied with consistency

and integrity. My personal commitment is to ensure that these decisions are informed by diverse points of view and vigorous academic debate.

We are committed to creating a comprehensive, systematic approach to improving the drug safety system, as quickly and efficiently as available resources allow. As always, we value input

from Congress, the public, and the medical community as we develop and refine these drug safety initiatives.

Thank you for the opportunity to testify in front of the committee

today, and I am happy to respond to questions after the next person. Thank you.

[The prepared statement of Dr. Galson follows:]

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Mr. PALLONE. Thank you, Doctor. Am I supposed to refer to you

as Admiral or Doctor?

Dr. GALSON. Either.

Mr. PALLONE. Well, I guess we will stick with Doctor, I guess.

And, Dr. Crosse, If you would give us your statement, thank you.

STATEMENT OF MARCIA CROSSE, DIRECTOR, HEALTH CARE

ISSUES, U.S. GOVERNMENT ACCOUNTABILITY OFFICE

Ms. CROSSE. Mr. Chairman and members of the subcommittee,

I am pleased to be here today as you examine the safety of the

drug supply. My remarks today are based on GAO’s March 2006

report on FDA’s process for decision making regarding post-market

drug safety and on steps FDA has taken that respond to the recommendations we made in that report.

Our work focused on two FDA offices that are involved in postmarket drug safety: the Office of New Drugs, OND, and the Office

of Drug Safety, ODS, which has since been renamed the Office of

Surveillance and Epidemiology. Consistent with our report, I am

referring to this office as ODS.

As we reported in March 2006, we found that FDA lacked a clear

and effective process for making decisions about post-market drug

safety issues. We found a lack of clarity about how decisions were

made and about organizational roles. There was insufficient oversight by management. There were significant data constraints, and

the agency lacked sufficient resources and authority to effectively

ensure the safety of marketed drugs.

The decision-making process for post-market drug safety is complex, involving input from a variety of FDA staff, drug sponsors,

the public, and many other information sources. Central to the

process is the iterative interaction between OND and ODS, and

many of the problems we identified derived from the ways these

two offices managed their drug safety responsibilities. In particular, there was a lack of criteria for determining what safety actions

to take and when to take them, which contributed to disagreements

over decisions about post-market safety.

We found that insufficient communication between ODS and

OND was an ongoing concern and hindered the decision-making

process. For example, ODS did not always know how or whether

OND had responded to safety analyses and recommendations for

safety actions. ODS management did not systematically track information about the recommendations its staff made and OND’s response. This limited the ability of ODS management to ensure that

safety concerns were resolved in a timely manner.

Moreover, FDA faced data constraints that contributed to the difficulty in making post-market safety decisions. FDA’s access to

post-market clinical trial and observational data is limited. FDA

does not have authority to require that a drug sponsor conduct a

study for the purpose of investigating a specific post-market safety

concern.

In the absence of such authority, FDA has relied on drug sponsors voluntarily agreeing to conduct these studies. However, as we

heard, these studies have not consistently been completed. FDA

was also limited in the resources it had available to obtain data

from outside sources. Annual funding for this program was less

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than $1 million a year for 2002 through 2005 and was $1.6 million

in 2006, which allowed for four data contracts.

Today, just over a year after our report was issued, FDA has

begun to take steps that could address the goals of three of our four

recommendations to the agency. First, we recommended that FDA

systematically track post-market drug safety issues, and the agency is in the process of implementing a tracking system.

Second, we recommended that FDA revise and implement its

draft policy on the decision-making process for major post-market

safety actions. And FDA has made revisions to, but not finalized,

its draft policy.

Third, we recommended that FDA clarify ODS’s role in scientific

advisory committees, and the agency is developing, but has not finalized, guidance to clarify their role.

And fourth, we recommended that FDA improve its process to resolve internal disagreements, but FDA has not taken action in response to this recommendation.

In addition, we suggested in our 2006 report that Congress consider expanding FDA’s authority to require drug sponsors to conduct post-market studies as needed to collect additional data on

drug safety concerns.

In conclusion, while FDA has taken positive steps, its actions are

not yet fully implemented, so it is too soon to evaluate their effectiveness in addressing these problems. Most importantly, the agency needs additional resources and authority to be able to fully address the range of post-market drug safety concerns.

Mr. Chairman, this concludes my prepared remarks. I would be

happy to respond to questions that you or other members of the

subcommittee may have.

[The prepared statement of Ms. Crosse follows:]

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Mr. PALLONE. Thank you, Dr. Crosse, and we will start with the

questions. I will recognize myself for 5 minutes, and I wanted to

ask these questions of Dr. Galson.

In your testimony, you talked about all the things that FDA is

doing in response to the IOM report. For example, you cite steps

you have taken to improve communications and information flows

as well as improve operations and management, especially between

the Office of Surveillance and Epidemiology and the Office of New

Drug. And I think these are positive steps that FDA has taken to

reform itself administratively.

But as you know, there are some recommendations made by the

IOM report that FDA can’t do administratively. And I would like

to know where the administration might stand on some of these

recommendations. It is important for us to know where the administration stands as we move forward with reforming our drug safety system and whatever legislation we are going to put forward.

So I have three questions. Let me begin with the clinical trials.

Does the administration agree with the IOM report that Congress

should require industry sponsors to register in a timely manner at

clinicaltrials.gov, at a minimum, all phase two through phase four

clinical trials wherever they may have been conducted if data from

the trials are intended to be submitted to the FDA as part a MBA,

SMBA or to fulfill a post-market commitment? This goes on. Why

or why not? And if Congress were to include this in our drug safety

reform package, do you know whether or not the administration

would object? That is my first question.

Dr. GALSON. Yes, as you know, provisions changing the way that

we register and require registration of clinical trials has been part

of the debate and the discussions going on in the Senate. And we

are very actively participating in providing technical assistance to

those provisions, and it has changed as time has gone by. We have

supported some and not supported others, so we look forward to

continuing the work——

Mr. PALLONE. I haven’t necessarily followed the Senate. Sometimes we take pride in not following the Senate. Do you just want

to comment, as best you can, on what you have been saying over

there in this regard?

Dr. GALSON. We are very much in favor with providing as much

transparency as possible, concerning clinical trials that are underway. There has been a huge amount of progress made over time

in getting more of these trials registered, and I am sure you are

going to hear more about this from the pharmaceutical representatives that are up here. But if you look on that Internet site now,

there is a lot more information on there than it used to be, and we

are in favor of that.

Mr. PALLONE. Well, what about the mandate though, the mandatory aspect?

Dr. GALSON. With regard to the specific provisions, we will continue to discuss that with staff, and the administration hasn’t

taken a firm position on exactly where we stand on each one of

those provisions.

Mr. PALLONE. OK. Well, let me go to No. 2. The IOM recommended that Congress ensure that the FDA has the ability to

require such post-marketing risk assessment and risk management

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programs as needed to monitor and ensure safe use of drug products. They go on to recommend that FDA should have the ability

to impose these conditions before and after approval of a new drug,

as well as having increased authority and better enforcement tools,

such as fines, injunctions, and withdrawal of approval to ensure

compliance by drug sponsors. Are these recommendations something that the administration would support, and again why or

why not with regard to the risk management assessment?

Dr. GALSON. Thank you. As you know, I am sure, there are risk

management plans that are currently part of approval of a number

of drugs that are on the market, and we thought them through

very carefully. And after the drugs are on the market, we evaluate

those plans to see whether they are working. This is another area

we have been very active providing technical assistance to the Senate and other Members of Congress that are interested in talking

about this. And we think when there are drugs that have special

risks, they do require special attention and special risk management plans for the drugs to be approved and for us to carefully follow up afterwards.

Mr. PALLONE. But again in those cases, you have mentioned special cases, would you think the FDA should have the ability to require the risk assessment and the risk management in those cases?

Dr. GALSON. We don’t feel comfortable approving drugs that have

special risks, unless there is a way to manage that risk. And it is

very much on a case-by-case basis that we make that assessment.

We are concerned about a one-size-fits-all approach in the discussions that we have had with the Senate on this provision because

the work is very time consuming for our staff. And we want the

ability to focus our attention on the most pressing public health

problems. So, in general, we haven’t favored a one-size-fits-all approach but our ability to make a case-by-case assessment. And that

could include, in some cases, being able to make sure that some

studies get done.

Mr. PALLONE. OK, I have to ask one more question only because

I didn’t get a chance last time. This is about the new DTC user fee

program that was included in PDUFA Four Proposal. That was negotiated between the FDA and industry. I wanted to ask this at the

PDUFA hearing, but I ran out of time, and again I am running out

of time. What assurances do we have that drug companies would

actually participate in this new program, given that it remains voluntary? And would the administration support a program that requires all advertisements for new drugs be reviewed by the FDA?

Dr. GALSON. Again, this is a complex regulatory and legal area,

and as you may be aware, there are a large number of television

ads and, of course, even much larger number of printed materials

that are produced by the pharmaceutical industry. And we have a

fairly modest staff that is able to review those as it is. So again

we are concerned that if we are asked to review more materials

that we have adequate ability to do that, and that has been a challenge between the resources and the number of products that have

come in.

What this new program does is give us additional staff so that

we can do a lot more comprehensive job of looking at this particular subset as they come in. And we are very, very interested in

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making sure that they are truthful and they are not misleading.

And I suspect that the industry is interested in that as well.

Mr. PALLONE. So it is a question of money as always. All right,

thank you very much. I yield to the gentleman from Georgia, Mr.

Deal.

Mr. DEAL. Thank you. One of the issues that has come up before

this subcommittee on other hearings as it relates to approval of

products has been the question of where intellectual property

rights become an impediment to making information more available.

With regard to clinical trials, both pre-approval and post-approval, one of the discussions has been to make more information

about those clinical trials available to the public. Are intellectual

property rights one of the constraints that you encounter in those

environments? And if so, would you elaborate on that?

Dr. GALSON. Absolutely. One of the challenges in all the work

that we do is having our scientists able to look at all the vast information that is available concerning products. We digest this. We

evaluate it. We sometimes debate it, and in the end, we come out

with assessments and communication that helps both practitioners

and patients make the right decisions about risk and benefit.

Putting every single piece of information that may be in that

drug company application down to the patient level does raise intellectual property issues. And we are obligated by our laws to protect the intellectual property, and I am not sure that it would really benefit patients as well because they don’t want the undigested

data. They want to know what is FDA’s assessment of this data.

An additional point on that is that we do think very carefully

about patients who need new products, patients who have cancer

and other chronic conditions. And we don’t want to do anything

that is going to stand in the way of getting those products through

the development process and evaluated by us in making those appropriate products available.

Mr. DEAL. One of the tools for post-market determinations and

safety, of course, is in mining data that may be available. To what

extent has the FDA utilized whatever resources, if any, might exist

in mining data collected by CMS, since they have a huge bank of

data? Has there been any correlation between the two agencies in

that regard?

Dr. GALSON. Yes, there has. As you know and you have heard,

some of the statements that you all have made have indicated the

very, very exciting frontier really in drug safety—our ability to look

at large data sets as they are being developed specifically, electronic medical records, more records from these larger payer databases, such as CMS. And as you all are very, very aware, the new

provisions in Medicare drug benefit are going to make a lot more

data available in the Medicare system that will allow us to link

eventually medical outcomes with the drugs that are prescribed.

And to prepare for that very optimistic future of being able to

use more of this data, we have been engaged in an interaction with

the Medicare program, looking at the existing data to try to see

how can we work with that and learn lessons with that interaction.

We have been working with our sister agency, AHRQ as well, and

I just got a briefing on this earlier in the week. And we are making

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some good progress and hopefully will learn some lessons that will

allow us to move forward as we get more funds from Congress to

be able to use this data and hire our staff so we are prepared to

mine any available data sets that are valuable for patients.

Mr. DEAL. Dr. Crosse, have you had the opportunity to look at

what other countries are doing on post-market surveillance of

drugs, and how does that compare with what we are doing in the

United States?

Ms. CROSSE. Sir, I am afraid we have not done any recent work

at all looking at drug safety systems in other countries. As you

know, there are a number of differences in the review and approval

process in those countries and also in the kinds of data that may

be available to them because of the national health systems they

have. But we have not done any recent reviews that would help

you on that.

Mr. DEAL. Dr. Galson, with regard to imported drugs, does the

law, as it is currently written, in your opinion, give FDA sufficient

authority to deal with drugs that are actually manufactured in

other countries? What are the limitations that you incur in dealing

with those imported drugs?

Dr. GALSON. Right. I assume you mean the legally imported

drugs that are part of our current system, and there is a significant

portion of the drug supply that is currently manufactured by some

of the same companies that are household names, but they happen

to be manufactured overseas.

All of our requirements for drug approval generally apply for

drugs that are imported, as they do here. So we go overseas, and

we inspect foreign manufacturing facilities when those companies

are importing their product to the United States. When clinical

trials are done overseas and those clinical trials are used in our application process, we go overseas and inspect them. So we have

good authorities to do that.

Mr. PALLONE. Thank you. Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman. Dr. Galson, if you look

at the drugs where there have been problems or drugs that have

been withdrawn from the market, it looks like a pattern where the

risks appeared before approval, and the agency got caught off

guard. To fully address this trend, I think it is clear you need some

help from Congress. You need more resources. You need more authorities. But within the confines of FDA’s current authorities and

resources, what are you going to do to fix this problem?

Dr. GALSON. That is a very challenging issue, and I think the

first thing is we have to be very wary about looking backwards and

trying to figure out what we may have done wrong in the past

when the situation was very different back when you were looking

at data initially, but your point is well taken. And I think the real

future of improvements in drug safety lie in scientific areas, and

we are very invested in that and our critical path initiative and

talking to many of you working on projects with not just the industry but also with academic groups and non-profit organizations to

try to make sure that the information that we are getting before

approval gives us the best possible data so that we do a better job

of being able to predict which drugs are going to work and which

drugs are going to cause adverse events in other people. And so

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that 10 years down the road, we will be able to stand on our laurels and say that these sort of surprises after approval have been

avoided. Now, we do sometimes get signals before a drug is approved, as you said, that there may be a safety issue. And each

time we see that, based on clinical trial data, we look carefully into

that, and we try to make an assessment about whether that signal

is going to result in a problem post-approval. The way to do a better job of that and to avoid what you are pointing out is better

techniques, techniques like pharmacogenomics that will allow us to

understand better individual differences between patients.

Mr. WAXMAN. In the meantime, there are problems that are discovered after the drug has already been approved. FDA asks the

manufacturer if they would be willing to do a drug surveillance

after approval. And especially if you have those signals, you want

the manufacturer to do that because you think there may be a

problem down the road. When FDA identifies, after a post-market

survey, a need to change the drug’s label, including adding a black

box warning, can you describe the process FDA uses to compel a

drug company to make a change? Can you compel a drug company

to make that change?

Dr. GALSON. We feel pretty strongly that when we need a black

box, or we feel like a drug has to be labeled better, either with a

black box or another kind of warning for the drug to stay on the

market—we have a very good process of sitting down with the company and saying look, there is this new information that has come

out. We are really not comfortable——

Mr. WAXMAN. When you negotiate in this process with the company, that can take a long time, can’t it?

Dr. GALSON. We are committed to reducing that time, and it has

been reduced. And the other thing that we are doing related to that

is that if there is not agreement there, we will go ahead—and we

have done this in numerous cases over the last couple years. We

will go ahead and put that information out without discussing it

with the company. We will put out patient or physician information

sheets. We will issue a public health advisory.

Mr. WAXMAN. But how about that label, even a black box label,

if the company refuses as you are negotiating, and it takes months

to negotiate. Meanwhile the public is unaware of these problems.

If the company refuses to make the labeling change that FDA believes is necessary, what are your options? Isn’t it just simply to

take the drug off the market?

Dr. GALSON. We could take the drug off the market, but we push

the companies, and in general, they respond. It doesn’t take

months, and once we say we are going to go out and put this information in the public realm, whether or not you move quickly

enough, they usually move.

Mr. WAXMAN. Dr. Crosse, from what Dr. Galson has told us, it

seems like he feels comfortable with the situation. Yet you made

a recommendation that Congress provide FDA with the authority

to require post-market studies and to be able to put these labels

on and to insist that these studies be done.

Ms. CROSSE. Yes, sir. The information that we have reviewed

over a number of years has found that it can be a lengthy process.

I think it is a very positive step that FDA is now taking to more

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publicly notify physicians and individual patients of concerns that

have arisen. In the past, that was not their general practice. And

so I do think that that is a positive step that the agency is taking

to put the information out publicly if the company is not moving

expeditiously to make these changes.

But our understanding is that the FDA’s options are limited if

the company is not cooperating. And while I agree that pressure

can be brought to bear, and making this information public helps

to bring that pressure, still the options available are quite limited

if FDA feels that there is a positive benefit of this drug and that

there are patients who need to continue to be able to receive it, and

they don’t therefore want to enforce the withdrawal from the market.

Mr. WAXMAN. Just a last comment. I know my time is up, but

I am in a situation now where I am chairman of the Oversight

Committee, try to get information to conduct investigations. But

knowing that I have the authority to issue a subpoena doesn’t

mean I have to issue subpoenas. But it does mean that those who

have to deal with me are more forthcoming. I would rather have

FDA be able to deal from a position of strength rather than pleading for information, which they need and ought to have in order to

protect the public health and to make sure the public is aware of

the problems once they are discovered.

Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. Mr. Barton.

Mr. BARTON. Thank you, Mr. Chairman. Back in August 2007,

Mr. Whitfield and I wrote a letter to the Department of Justice,

asking for them to review current law in terms of FDA authority

with respect to imports of drugs both legally and illegally into this

country. And their response back to us was this past December.

And in that letter, the Assistant Attorney General, a Mr. Klinger,

said that they, the Department of Justice, would support a change

in the Food, Drug, and Cosmetic Act that would make sure that

that Act gave the FDA explicit jurisdiction over conduct that occurs

outside the United States for drug products that are subject to the

Food, Drug, and Cosmetic Act when they are imported into the

United States. I would assume that the FDA supports that. Is that

correct?

Dr. GALSON. Yes, we do, as well as stiffer fines in those circumstances.

Mr. BARTON. And if we did give this authority, this explicit authority, how would the FDA and would that give the FDA the authority to inspect facilities overseas on a random, surprise basis

like you have here in the United States? My understanding is

when you inspect a pharmaceutical factory in China, you have to

get permission before the fact and they actually announce sometimes 2 to 3 months in advance so that the day you show up, everything is sparkling clean and smiley-faced.

Dr. GALSON. I am not an expert at international comparative regulatory law; however, it is very important that we are able to go

into foreign factories. The current situation is we do work with foreign countries, governments, when we make these visits. Even to

get into many countries, they have to be aware that FDA officials

are coming in.

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On the other hand, we do do a lot of these inspections, and we

send teams over, and they successfully inspect and identify problems. And those problems are addressed or we move forward to

take the next step.

Mr. BARTON. In the United States, you can just show up and

flash the badge, so to speak, and do the inspection. Isn’t that correct?

Dr. GALSON. That is correct.

Mr. BARTON. But overseas, you can’t do that. Is there any country that you can inspect as you do here in the United States? Or

do you have to pre-clear it?

Dr. GALSON. I am happy to look into that to see whether there

are any countries where we have the capacity to do that and get

back to you.

Mr. BARTON. And on counterfeit drugs, what is the current status of trying to prevent the counterfeit drugs in terms of number

of inspectors and things like that?

Dr. GALSON. We do focus some resources on counterfeit drugs,

and we are very concerned about this. We work with pharmacies,

with States, to move forward when we identify problems and to

make sure that we have an open policy wherein people hear about

counterfeit drugs. They are reported to us. We investigate it. We

are concerned about counterfeits that are available on the Internet.

And of course, if there are more drug imports coming in, that

would be something we have to focus on more.

Mr. BARTON. Dr. Crosse, would you like to comment on any suggestions for combating counterfeit drugs?

Ms. CROSSE. Well, we had undertaken a review about 21⁄2 years

ago of Internet pharmacies, and we placed a number of orders from

pharmacies over the Internet, both in the United States and in

Canada and other foreign countries. We found a number of problems including counterfeit drugs. Some of the samples that we received were counterfeit medications, and a very small sample of

drugs we purchased, out of about 63 purchases, we have four counterfeit drugs. And we had other drugs that were provided without

any instructions for use, without appropriate labels or warning information or directions on how many tablets to take and at what

interval. There are a number of difficulties that we identified in

that review in the use of foreign pharmacies.

Mr. BARTON. But four of the 63 purchases were counterfeit?

Ms. CROSSE. Yes, sir.

Mr. BARTON. That is pretty amazing. Well, Mr. Chairman, my

time has expired, but I hope that is something that, as we move

forward, this whole issue of counterfeiting is, I think, a very great

concern and based on what Dr. Crosse just said, I was assuming

it was maybe 1 percent, 1 out of 100. But 4 out of 60 is—what is

that—about 8 percent, something like that. So that is non-trivial.

Thank you, Mr. Chairman.

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

DeGette.

Ms. DEGETTE. Thank you, Mr. Chairman. Following up a little

bit on Mr. Barton’s question. Dr. Crosse, I think the time is now

to start looking at these counterfeit drugs because we had some

hearings in the Oversight Investigation subcommittee in the last

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Congress where customs is just seizing all kinds of these drugs

coming in, and as Dr. Crosse described, they have no description

what they are and when they are tested. Some of the drugs from

South America were actually yellow paint, dyed paint. And there

is no indication if the proper climate controls or other kinds of controls have been established.

And so I guess my question to you is what mechanisms do we

currently have in the U.S. to expose counterfeit drugs before they

reach a U.S. consumer? Do we have enough laws to do that, and

maybe more importantly do we have enough resources to do that?

Dr. GALSON. Let me talk about a couple of the things that we

have been doing. We have been focusing on this for quite a few

years, but there is no doubt that this is something that probably

needs more attention into the future. And you only have to open

up the newspaper to see some of the problems that have occurred.

One of the things that we did is we were hearing that it was

cumbersome for people to figure out how to report when they found

a counterfeit or when they heard about a counterfeit. So we modified our standard adverse event reporting form that comes in to

make it easier for people to explicitly say when they find a counterfeit.

Ms. DEGETTE. When did you modify that report?

Dr. GALSON. I believe it was 2005.

Ms. DEGETTE. And have you noticed an increased number of reports coming in?

Dr. GALSON. We haven’t, but that probably reflects the fact that

the adverse reporting system is not that sensitive.

Ms. DEGETTE. It has probably been the least effective way, waiting until the drug actually gets to the consumer. And then they

have to make a report.

Dr. GALSON. Absolutely.

Ms. DEGETTE. So what else are you doing?

Dr. GALSON. Well, one of the things that does concern us, and we

are going out with education efforts about this, is the increase of

number of drugs that have been purchased over the Internet and

the proliferation of Internet pharmacies and people thinking that

this is an answer to getting their drugs. And clearly that makes it

easier for people to get. Even if the drug is advertised that it is

‘‘from Canada’’ it may come from somewhere else.

Ms. DEGETTE. I know that, so what are those efforts?

Dr. GALSON. Those efforts are trying to communicate with people

and with pharmacists and.

Ms. DEGETTE. And have those born fruit in finding additional

counterfeit drugs?

Dr. GALSON. I don’t think our detection of counterfeits is robust

enough to really know whether——

Ms. DEGETTE. And so what do we need to do?

Dr. GALSON. Yes. Well, I think one thing is resources, and we do

expect to be getting more resources under PDUFA that we will be

able to put out in the field to detect more of these. As you know,

there is just a sea of drugs coming in through the mail and through

the borders. And it is a challenge for us to open up every single

package. But there is more that we could do, and we will be focusing——

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Ms. DEGETTE. Dr. Crosse, do you have any opinions what we

could do to beef up our detection of counterfeit drugs coming in?

Ms. CROSSE. I think it is a very difficult issue for FDA alone to

face because a lot of the drugs that are coming from the Internet

pharmacies from overseas are coming directly to consumers.

Ms. DEGETTE. Right.

Ms. CROSSE. They are not passing through the normal drug supply chain in this country. And so, there really is very little, short

of intercepting packages at the border, that FDA, I think, can do

beyond these kinds of steps to monitor the pharmacies that are on

the Internet. We found Web sites popping up and closing in a matter of days when we were undertaking our work. It is very difficult

to track all of the Web sites that may be available to sell some of

these drugs.

Ms. DEGETTE. So really consumer education will be important?

Ms. CROSSE. That is one of the steps, and certainly, I think there

are some technological solutions that are being proposed to try to

put in some sorts of tracers and other kind of tracking information

that would allow the drug supply system to more adequately monitor when the drugs that are coming in are authentic.

Ms. DEGETTE. Now, do you think that this problem we have got

right now would be exacerbated if more reimportation was allowed

by Congress?

Ms. CROSSE. I am not aware of what the specifics are for proposals that are under consideration for the limits that we placed on

that importation. In the small review that we did, we did not find

problems with the drugs we purchased from Canadian pharmacies.

But, as Dr. Galson has indicated, one cannot always determine just

from looking at a Web site whether a site that identifies itself as

being Canadian actually is.

Ms. DEGETTE. Dr. Galson.

Dr. GALSON. Yes. A couple points. The first is just following up

on the technological solution. We do think that there are some

technological steps, and these radio frequency identification tags,

RFID, is one of the technologies that has been identified that can

mark packages so they can be tracked and traced more efficiently.

We have issued guidance on the use of this technology, and we are

going to be putting more effort towards that. So that is a technological solution. On your question about importation, I don’t think

there is any question that if there are more drugs coming into the

country from other places, it is going to be more difficult. And I

think about my challenge in being responsible for all the currently

legally imported drugs. If the number of manufacturing facilities

and companies doubles or triples with drugs coming in from a lot

more countries or from countries that are difficult for us to inspect,

there is no question that it is going to be more of a challenge to

detect these counterfeits and go out and inspect the sources.

Ms. DEGETTE. Thank you.

Mr. PALLONE. Thank you. The gentleman from Indiana, Mr.

Buyer.

Mr. BUYER. I want to thank Ms. DeGette. I welcome her to this

issue. This is a pretty strong concern of members on this committee. We reauthorized PDUFA, and we are now examining the postmarket review. I don’t understand how a manufacturer out there

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can do the very best they can, they are responsive to these reports

of adverse effects that are being sent on, yet their ability to police

the counterfeit—it is almost as if we have a system—so what do

we have in America? We have got this system, and we have a leak.

And the strength of the policing of that leak is going to come from

who? Those whom have the most at stake. So it is going to come

from, first would be the manufacturers themselves. They are going

to protect because they have liability on the line. Second it is you,

us, the Federal Government because we have given this assurance

to the American people that we are going to have a closed system

with regard to our drug supply, and that it is that FDA stamp of

approval. It has got to mean something. So I think it is pretty

clear. An unapproved FDA drug lacks your assurances of safety, effectiveness, quality, and purity. Now, if the FDA cannot assure the

safety and efficacy of a drug product line because you can’t gain access to the manufacturing process, we have serious problems.

So if that drug is manufactured in a foreign country and you

gain access to that manufacturing process, there is not a problem

there, and you do that all the time. In the mid 1990’s, we had this

political escalation and the attacks of our pharmaceutical manufacturers and as if well, just run off to Canada and get your drugs.

And this reimportation issue began to erupt.

And then we see this increase in the volume of adverse event reports. So my question is do you know of any correlation between

this increase in adverse reports and the amount of FDA unapproved drugs that are finding access into our country. Is there a

correlation between this? Do you know?

Dr. GALSON. We are not aware of a correlation between those

two. There are a number of hypothesized explanations for why that

number is increased. One is there are more drugs out there. More

people are taking more prescription products. If you look over time

at the number of prescription drugs taken per person in the United

States, it has gone up. And similarly there is absolutely more

awareness of drug adverse events. I am not at all trying to say that

there is no correlation, but I wouldn’t want to blame that increase

entirely on this issue.

Mr. BUYER. All right, let us bubbacize this. So last night, I

picked up the phone and I called an internist, Dr. Lauren McClure

in Muncie, Indiana, OK. Now, she is dealing with a problem because the mayor of Muncie, he is going to reduce the drug costs to

the city of Muncie, Indiana. So what does he do? He instructs the

city employees and the workers and the retirees to do what? Get

their drugs from Canada. Now, as a practicing internist, she has

a challenge. She will do her diagnosis, and in her prognosis, she

will prescribe particular drugs. And she doesn’t know what is working and what is not working and why.

So here we have someone that we as a country have invested

greatly into this medical expertise, and it is a scratch of the head.

She doesn’t know whether the drugs the person is taking are FDAapproved drugs, or are these the counterfeit drugs? And so she has

been challenged as she continues on. Now, this happens to be a

doctor that actually knows that a patient is gaining access through

Canadian pharmacies. How about if the docs all across the country,

you prescribe a drug, and they don’t even realize that their paVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00067 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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tients are out there. Ma’am, when you said I don’t have a problem

with Canadian pharmacies, what about these Canadian Internet

sites? People think that they are approved, and many of them are

unapproved, and they are the flow, the pathways of these illegal

substances.

Now, our challenge is the person may not get better and die if

it doesn’t get reported. Those who say well, let us go to reimportation. People aren’t dying from reimportation. You never know. So

now if we want to make sure that we really understand about a

drug that is out there, what do we in Congress need to do here?

Do we have to mandate that doctors ask their patients that—I gave

you that prescription. When you come back and you are not better,

we ask them where did you buy your drugs? I hate to do something

like that. Are we going to have to do that? And No. 2, when you

talk about tools and modernization in the aftermarket, are you

going to take into account the knowledge that we have about this

escalation of the counterfeit drugs that are coming into the market? Those are my two questions.

Dr. GALSON. Yes. Well, we have identified one of our major goals

in drug safety is to improve how we communicate to the public

about drug risks, through the Internet, through other types of

media, through medical organizations, other professional organizations, such as the pharmacists. There are other players in this, as

you may know. The pharmacy world is regulated by and large by

the State pharmacy boards, so talking to State people. And there

is no question that we need to do more communication. We have

a lot of activities underway in the agency focused on this, particularly warning people about Internet pharmacies and to get their

drugs through a traditional source. But there is no question we

could do more.

Mr. BUYER. Here is how you stop the mandate. How about you

contact the AMA and through the continuing medical education,

advising counsel with regard about asking that question. Where

are you getting your drugs?

Dr. GALSON. Yes, we do work with the AMA.

Mr. BUYER. In medical schools?

Dr. GALSON. Yes.

Mr. BUYER. In the training? You work with the medical schools?

Dr. GALSON. We do some work with medical schools. That is an

excellent idea.

Mr. BUYER. Let us do more with our medical schools and teaching so that they know it is part of their prognosis is what I would

recommend, and the continuing medical education piece. And you

can take that with you.

Dr. GALSON. Thank you.

Mr. BUYER. The last is on the increase in surveillance. I like the

fact that you are checking our ports of entry and working properly

with customs. So in PDUFA, if we want a purity with regard to

that close market review sample, what in resources do we need to

put in this bill? Tell me what you want and need to get the assurances of clients.

Dr. GALSON. Right, the FDA staff who are out in the field who

are at the ports working with customs are not part of the drug center. It is a different part of the agency. I would be happy to go back

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and ask them exactly to let you know what they think is needed

to move forward here. We do provide technical and other kinds of

compliances systems and work together with that group. And we

are looking very much forward to additional resources coming in

through the PDUFA program so that we can do more of this kind

of assistance and participation in our compliance efforts.

Mr. BUYER. What agency is it?

Dr. GALSON. It is part of FDA. It is called the Office of Regulatory Affairs.

Mr. BUYER. All right, thank you. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. Recognize the gentlewoman from Illinois, Ms. Schakowsky.

Ms. SCHAKOWSKY. Thank you, Mr. Chairman. I wanted to ask

Dr. Galson, you may have said this already. Maybe I missed it. The

GAO suggested that Congress expand or consider expanding FDA’s

ability to require drug sponsors to conduct post-market studies,

and so what is your view on that?

Dr. GALSON. Well, we have been working, as you know, with providing technical assistance to the committees in Congress and both

sides that are working on issues of authority, so we will continue

to do that. We do feel like we are able to get a lot of information

post-marketing, and we are very committed to what we have talked

about, improved surveillance by getting data sets and groups of

data about drugs and how they are prescribed and the adverse

events that may result through them that had nothing to do with

even requiring drug companies to do studies. This is kinds of surveillance data that other groups, such as the health care payers—

you are going to hear a little bit from them in the afternoon—that

I think is the future of drug safety, looking at the databases that

are out there.

Ms. SCHAKOWSKY. I understand you are talking about outside

groups, but if we maintain a voluntary infrastructure on this in

general, why would we as members of Congress or the public have

confidence when we have seen so many problems with failure to report things and poor reporting of clinical trials and all kinds of

things that the pharmaceutical companies have done? I mean I am

trying to understand the source of your confidence when you emphasize this relationship with the private sector and pharmaceutical companies.

Dr. GALSON. Yes, a couple points. First is that what many people

don’t realize in the debate is that we can require some studies to

be done in several different categories. The first of those are under

the legislation that has promoted the development of more information about drugs for children, and we are able to require companies

to do studies.

Ms. SCHAKOWSKY. How is it that many of them have been started

but incomplete?

Dr. GALSON. In the pediatric area, I will get to that in a second.

The other second area is the program that we have under our regulations called accelerated approval. When there is something that

is really needed to fulfill a medical need, such as a cancer drug

where there isn’t another drug out there, we can approve the drug

and then require a company to do a study after approval. And

those studies do get done. And the third area is in the counter-terVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00069 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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rorism area where there is a drug that we think needs to be made

available in case of a terrorist attack, but it wouldn’t be ethical to

do that study in humans. We can approve the drug using animals

and then require a later study or a later collection of data.

But with regard to your main question, we are happy to continue

to discuss it with this committee and with others your ideas for requiring more study to be done and give you our views on the specifics.

Ms. SCHAKOWSKY. Dr. Crosse, I wondered if you wanted to comment on that.

Ms. CROSSE. Yes, we do believe that FDA would benefit from

having additional tools at hand to be able to take steps when they

believe they were necessary and they were not getting voluntary

cooperation. With regard to the pediatric studies, that certainly has

promoted a number of drugs being studied for pediatric uses; however, almost 20 percent of those drugs that FDA asked to be studied, the sponsors declined to study for a variety of reasons.

But nevertheless, there still are a number of drugs out on the

market that FDA had indicated were important for review. And it

was at the option of the manufacturer whether to pursue those.

The alternative path that the pediatric—and specifically Best Pharmaceuticals for Children Act—have provided for the Foundation for

the National Institutes of Health to pursue the studies has not

been effective. None of the drugs that have been referred for study

by that organization have yet been studied.

Ms. SCHAKOWSKY. We have a problem here. I was intrigued by—

both Dr. Crosse mentioned that there were some problems with the

pre- and post-marketing divisions of the FDA. You called it tensions, Dr. Galson. Do we have to really deal with tensions here? I

mean can you resolve those problems?

Dr. GALSON. Well, there is tension inherent in drug regulation,

and I don’t think we will ever get away with a totally stress-free

easy job. And that is really not what I am looking for. And the fact

is that two people looking at the same scientific data may come to

different conclusions, and so it is not just between offices but even

within the staff. And again this is normal, and the other regulatory

and scientific agencies that I have worked in, you have had this

same tension.

I am not meaning to diminish it or anything by calling it tension.

It is part of the regular scientific debate when we make sciencebased decisions in public health agencies, and we have to do our

best. And we are working to improve how we handle those disagreements to make sure that both sides are able to articulate

their views and that we document our position in relation to those

views and move forward and make our decisions.

Ms. SCHAKOWSKY. I am out of time. Thank you.

Mr. PALLONE. Thank you. Mr. Ferguson.

Mr. FERGUSON. Thank you, Mr. Chairman. Thank you both for

being here, and thank you for your testimony. Dr. Galson, I have

a lot I want to try and get through, and I am just going to try and

get through it as quickly as I can. I appreciate your cooperation as

well.

As you are aware, I have been interested in this issue of regulation and distribution of medication guides, med guides, for a while

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now. I want to focus my time today on this alarming situation in

which young patients and their parents may not be receiving the

information that they need to make fully informed decisions about

the treatment of certain medications, particularly including

antidepressant medications.

Specifically, it has been brought to my attention by constituents

in New Jersey that the FDA-required med guides are in many instances not distributed when antidepressant medications are dispensed, even though such a distribution is required under the regulations introduced by the FDA, by your agency. In examining this

issue, I contacted the FDA representative from the National Association of Chain Drug Stores, the National Community Pharmacists Association, the New Jersey Pharmacists Association, the

New Jersey State Board of Pharmacy, and four different drug manufacturers of these products, of antidepressant medications.

In fact, I have two letters that I sent to Dr. von Eshenbach and

the two responses that I received from the FDA. Mr. Chairman, I

would ask unanimous consent to submit them for the record in this

hearing. It has appeared to me throughout this investigation that

a significant breakdown is occurring between the FDA and the

State regulatory authorities, a breakdown that is depriving parents

of children for whom antidepressant medications are prescribed,

that their ability to make these fully informed decisions, to have

all the information they really need. And med guides are so important because it gives us information in English that normal people

can understand.

For example, it is impossible to determine with certainty that the

med guides are in fact being distributed with the prescribed

antidepressant medications because regulatory authorities at the

Federal and State levels are not enforcing the FDA’s Stated protocol on medication guides. I am going to just read the portion of the

statute that is relevant here, and I quote,

Each authorized dispenser of a prescription drug product for which a medication

guide is required under this part shall, when the product is dispensed to a patient

or to a patient’s agent, provide a medication guide directly to each patient or to the

patient’s agent unless an exemption applies under 208.26.

Did the FDA issue this regulation?

Dr. GALSON. Yes.

Mr. FERGUSON. Yes. Thank you. Can you or anybody tell me with

certainty that medication guides are being distributed to patients

and parents when they ought to be?

Dr. GALSON. Right. I know you are in a hurry. I will be quick.

We have invested a huge amount of time in determining what

should be in these medication guides. Every word is looked at very,

very carefully because we want these messages to get to patients.

So let me make it easier for you and tell you that we share your

concern and we are not denying this. We know that in many cases,

these medications are not being given out. The challenge, like so

many things at FDA, is what is the best thing to do about it. They

are required to be given out. On the other hand, we don’t regulate

the practice——

Mr. FERGUSON. Right, and we are going to get to that right now.

Dr. GALSON. Yes.

Mr. FERGUSON. I appreciate your——

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Dr. GALSON. So it is really our interaction with the States and

the pharmacy organization.

Mr. FERGUSON. That is exactly right. In my investigation, I also

contacted the New Jersey State Board of Pharmacy, and I got this

response from Joann Boyer, who is the board’s executive director

in New Jersey, and I quote,

The board does have the authority to enforce the Federal regulation regarding the

distribution of these guides. An overview of this Federal regulation will be included

in the Board of Pharmacy newsletter with a statement addressing the need to be

compliant and the fact that our inspectors will be including this item in their normal inspection routines. I will provide the inspectors with all necessary information

regarding medication guidelines and instruct them to ensure compliance when they

perform their inspections in our retail pharmacies. Those pharmacies identified as

being noncompliant will be brought to the board’s attention for review and action,

which may include financial penalties.

Before my inquiries, States like New Jersey were not using their

authority to monitor pharmacists and their distribution of medication guides. Does the FDA have the authority to contact and instruct State board of pharmacy to follow New Jersey’s example?

Dr. GALSON. We certainly don’t need any special authority to contact the board of pharmacy and encourage them to action. What we

have heard from some of the people that we have contacted is that

they consider the regulations that we have onerous, that there is

a lot of paper, that they don’t have the capacity to store all the

paper that is required to be given out, and that there are some real

logistic issues.

Mr. FERGUSON. Right.

Dr. GALSON. And it is because of this that we have organized and

announced a public meeting coming up this spring so we can get

the views of all the constituents involved with pharmacies and

States, hopefully the patients.

Mr. FERGUSON. That is where I am going next.

Dr. GALSON. They will come with suggestions——

Mr. FERGUSON. We didn’t even coordinate this, but that is where

I am going next.

Dr. GALSON. Absolutely, yes. We agree this is a problem.

Mr. FERGUSON. I would urge you to use the authority that you

say you don’t even need, I would urge you to take those actions to

contact State boards of pharmacy because there are actions that

they could be taking to make sure that parents and patients get

these very important information.

Moving on, I have heard from pharmacists in our district and

elsewhere that they encounter problems getting the med guides, as

you were just saying, from manufacturers and storing the adequate

numbers of the med guides in their stores. Shelf space can become

an issue. Under the FDA’s rule, medication guides must be generated by manufacturers, then sent to the pharmacists, in most instances via a wholesaler and then given to the patient when the

drug is dispensed.

Is the FDA monitoring whether manufacturers are actively providing these med guides to pharmacists so they can dispense them

to patients? Is that something FDA does?

Dr. GALSON. We certainly could do that. I would have to get back

to you. I don’t know for sure whether there have been any compliance or inspectional kind of activities specifically focused on that.

67

Mr. FERGUSON. If it not going on, I would urge the FDA to take

that step. That is another potential breakdown, and in some cases

I am sure has been a breakdown in the system. Does the agency

also monitor whether manufacturers of generic versions of brand

name drugs are distributing these as well?

Dr. GALSON. They are required to give out the same forms as the

brand names.

Mr. FERGUSON. OK, so they would be included in this oversight

as well? In our investigation, the National Association of Chain

Drugstores told me that they delivered a proposal to the FDA 2

years ago, asking if they could distribute med guides electronically,

thereby greatly simplifying the lengthy and unreliable distribution

chain. Can you tell me if the agency will allow pharmacists to print

these electronically, just sort of print them off the computer rather

than having to store reams and reams of paper in their pharmacy?

Dr. GALSON. Yes, this is one of the issues that we are going to

take comment on and talk about at this public meeting. I am not

certain whether the electronic provision of an identical medication

guide to the one that we require companies to put out, I suspect

there is no problem with that. The problem is that the format

sometimes changes. It is different, and we have to look at those

issues.

Mr. FERGUSON. My time is almost up. I understand in my letter

from the FDA that you will be holding a public meeting soon to discuss the distribution of medication guides. I am delighted. That is

a very important part of the process. I am pleased the FDA has

taken that important step.

My last question. In the last week, the FDA has drafted many

changes to the med guide for antidepressants, and I have copies of

each of the two. Most strikingly, the title of these med guides was

changed. The previous one said ‘‘Medication Guide about Using

Antidepressants in Children and Teenagers.’’ That title has

changed, and I would like to submit both of these for the record

under unanimous consent, Mr. Chairman. It was changed to ‘‘Medication Guide: Antidepressant Medicines, Depression, and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.’’ Just

seems to me that the old version of the medication guide was more

thorough and sort of concentrated exclusively on the potential adverse reactions that could occur when taking antidepressants. The

new version seems to sort of delve into a whole discussion on depression. Can you tell me why? Do you have any idea why these

changes were made in that way?

Dr. GALSON. Yes, I have a very good idea, and it is not easy to

explain. If you could give me just a few minutes to do it. This has

been one of the most contentious and difficult areas of drug regulation over the past few years in FDA but not atypical in that new

information has been developed about potential risks related to

these products since they have been on the market, and those are

the risks that are discussed in the med guide with suicidality.

Now, we have taken steps going back a number of years to add

information to the labels and to the med guides, making sure that

patients and physicians are aware of this new information and

what it may mean to patients. And what we have heard is some

people think that this is great. Other people think it is bad.

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The psychiatric community, the American Psychiatric Association

has been very, very angry at the FDA because they think that telling people about these risks is dissuading people who really need

these drugs for depression from taking them and therefore contributing to the number of people that are expressing suicidal activity.

And this is, of course, something that worries us a lot.

What we try to achieve in our communications products is to balance benefit and risk, which is what is absolutely critical in explaining the risks and the benefits of drugs so that people can

make the decisions. So what we have attempted to do with these

latest changes in the med guide is not to excessively focus on the

risk but also talk about the balance of what these drugs are for,

the risks obviously of feeling suicidal, and to make sure that people

understand.

And I know that it is a more complex task, but this isn’t an easy

goal to communicate. We are working. We continue to work with

experts on how to communicate with patients and with physicians,

and we hope to continue to improve the messages that we are getting across, the points we want to.

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

Mr. GREEN. Dr. Galson, thank you for being here and listening

to all our opening statements before we could actually ask questions.

It is correct that the FDA currently does not have the authority

to grant conditional approval for a new drug application. Is that

correct?

Dr. GALSON. Yes.

Mr. GREEN. Can you comment on how the extension of your authority to implement a conditional approval process would offer the

FDA additional tools to ensure that drug’s safety.

Dr. GALSON. Well, that is something that would have to come

from you all from Congress to do that. We are implementing a new

pilot program, in the center to look back at drugs a year or 18

months after they are approved to see whether new information

that has been developed about them changes the way that we balance benefit and risk and may require us to communicate about

changes.

Mr. GREEN. So would this stand in the place of a post-market

study, or would it just be implemented a second way——

Dr. GALSON. What this pilot project does is it takes the information that is available from the reports that have been submitted by

companies from adverse event reports from any information that

has been developed in literature, and it has us do an additional

benefit/risk assessment to see whether there has been any change

and to see whether there are changes that are required and how

we communicate. If there is a post-marketing study that has to

happen, it wouldn’t influence that one way or another.

Mr. GREEN. OK, in your testimony, you indicated that the responsibility for correcting many of the organizational problems has

fallen on you and your position. Can you expand on your efforts to

focus on the drug safety within the center, particularly what protections as the FDA put in place to ensure that any analysis of

post-market data by the Office of Drug Safety is accepted and acted

upon in a timely manner? Is there a process going on now?

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Dr. GALSON. Yes, there is a process going on now, but as you

have heard before, there is a challenge to making sure that the decisions that we come out with at the end of the day reflect the best

possible input that we receive from people across the center. And

what I have heard is that some people in the process sometimes

feel undervalued. And my goal is to make sure that that doesn’t

happen, that we improve that situation, and that the people from

all the different perspectives in the center have those perspectives

considered. If there is a disagreement, it comes to light so that we

can make sure that the more senior people are the people that

have to make those decisions, can weigh the evidence on each side

and come out with the right decision.

Mr. GREEN. I think from our hearings in the Oversight and Investigations Subcommittee, that is what we are hearing, that there

has been a discrepancy, and some of the FDA employees feel like

that their statements or status wasn’t considered. So I appreciate

that.

Let me ask you a specific issue. I am concerned about the safety

of signing both the approval process and the post-market surveillance. On the approval side, there is an issue that has come up

about safety issues and particularly surrounding RHLF, recombine

human lacto-ferin, which has been widely studied for treatment of

serious illnesses, including cancer. On the drug safety side, I think

that is on the drug side, but I also understand there is a potential

for using that as a food additive. And I have some concerns because

the food additives are not as rigidly controlled as a pharmaceutical.

Can you speak to that issue?

Dr. GALSON. Well, in general—and I don’t want to refer to a specific product that is under review—but in general, of course, we

don’t want drugs to be put in food. And that would concern me a

lot. This particular product is a natural product and, as you may

recall a number of weeks ago, that the deputy commissioner, Dr.

Woodcock, came and testified to you about follow on protein products.

We have to make sure that if there are products entering the

marketplace, they get the appropriate types of medical and other

testing that are necessary to make sure that we understand well

what the impacts are going to be. This sounds like it is a very complex regulatory matter between the food side and the drug side,

and we will have to have our legal experts look into that and follow

through on it.

Mr. GREEN. But the concern is that using it as a food additive,

the regulation and the oversight is much less as making that an

actually prescription drug.

Dr. GALSON. Yes. Well, we have to follow our procedures, but just

in general, as I said, the idea of a drug being in the food supply

doesn’t strike me as a great idea.

Mr. GREEN. I agree, and that is my concern. Thank you, Mr.

Chairman. I yield back my 6 seconds.

Mr. PALLONE. Thank you, and we have the other gentleman from

Texas, Mr. Burgess.

Mr. BURGESS. Great, I will take the extra 6 seconds. Dr. Galson,

Dr. Crosse, thank you both for being here with us. Dr. Galson, let

me ask you, you mentioned in your testimony the importance about

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communicating and drug safety and the emerging data on drug

safety. Do you get an annual report from a manufacturer every

year on the anniversary date of introducing a new product?

Dr. GALSON. Yes, we do.

Mr. BURGESS. So we consider that post-marketing information?

Dr. GALSON. We get a huge amount of post-marketing information.

Mr. BURGESS. But that report on the anniversary date, would

that be fair to call that post-marketing information?

Dr. GALSON. Of course.

Mr. BURGESS. So how do you utilize that?

Dr. GALSON. Well, we look at those reports. There is a specific

requirement that companies let us know about any serious and unexpected adverse events. And those are the ones that we spend the

most time looking at very carefully to make sure that what we

aren’t seeing is a new emerging kind of risk with the product that

we wouldn’t see before.

So we look at those. We combine it with almost half a million adverse events reports that we get that come into our spontaneous reporting system, separately from that. And we have safety evaluators look at those data and then meet with other staff if there

is a concern that is developing.

Mr. BURGESS. So you would regard this information as helpful?

Dr. GALSON. Yes.

Mr. BURGESS. And you have developed the computer algorithms

and protocols to help you sift through all that voluminous information?

Dr. GALSON. We need to do a lot more in that regard, and we

are moving forward but it is—yes.

Mr. BURGESS. Let us come back to that thought if we have time,

but there is also a lot of information that is just out there in the—

we might call open source information that is not necessarily the

purview of the FDA or even necessarily the—well, we could reference the CMS database, and I am sure NIH has their own databases and their private databases. Do you peruse those sources for

information about products, particularly when something has come

to your attention?

Dr. GALSON. We look at any available data. I do want to emphasize though that the number of staff that we have been able to devote to this activity traditionally has been limited by our resources,

and that is why we have been working through the user fee program with Members of Congress to beef up in particular that part

of our operations so——

Mr. BURGESS. Since you brought that up, so how many FTEs do

you devote to that? Can you tell us?

Dr. GALSON. Well, it is difficult to say but——

Mr. BURGESS. Perhaps you can provide it after the fact—the

number of people who are actively working on that and in an ideal

perfect world what that number would be so this committee could

perhaps deal with that——

Dr. GALSON. We will get it to you.

Mr. BURGESS. The stuff that is it the open source, do you ever

go out and purchase information from private sources?

Dr. GALSON. Yes, we do.

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Mr. BURGESS. And is that important?

Dr. GALSON. Extremely important and will be more important in

the future.

Mr. BURGESS. And does funding play a role there? Is price important? Is price a benefit for purchase of that private source information?

Dr. GALSON. Price has been important, so that is another way

that I am looking forward to more progress.

Mr. BURGESS. Could you possibly again provide us with some actual data on the specifics of what we are talking about so we perhaps could make informed decisions?

Dr. GALSON. Yes.

Mr. BURGESS. And I know in the past, you brought up the question of tension. The folks that do the pre-market and the post-market testing and the tension that exists between them. Is any of

this—and I worked in offices. I am well aware of the front office/

back office tension that is going to occur. But is any of the tension

related to any perceived financial impetus that is placed on either

hastening the approval or strengthening the post-market surveillance? Does that enter into the equation at all? Is that something

this committee needs to be concerned about?

Dr. GALSON. Well, I haven’t seen any evidence——

Mr. BURGESS. Well, let me change the context a little bit because

it keeps coming up, and I think that it is a good idea. And I think

it is something that we should continue to do, but this concept

keeps coming up. It is fair to ask the question is this a problem?

Is this entering into the tension equation that you referenced? And

if so, could you help us quantify it? And could you help us by providing areas where—if that is an issue, and I don’t know that it

is—but if it is, how can it be mitigated? How can it be qualified?

Dr. GALSON. Yes, I may have misunderstood you. You mean the

disparity in funding issue, but that is a factor if that is what you

mean. I am not sure what you mean by financial.

Mr. BURGESS. The theme keeps recurring that there is a problem

with how the FDA does its work because of undue influences that

are placed on it by outside industry because of the funding mechanism, and I don’t know. Is that the situation or not?

Dr. GALSON. I wanted to make sure I understood what you were

saying.

Mr. BURGESS. Is that a source of the tension that you alluded to?

Dr. GALSON. I don’t think so. There are 2,300 people in the drug

center, and no matter which office they are in, they are very, very

dedicated to doing the right thing for public health regardless of

where their source of funding is. Individual drug reviewers don’t

know if their salary is coming from user fees or from appropriations. I haven’t seen any evidence that that is a factor.

Mr. BURGESS. Thank you. That is a very direct answer, and I appreciate that. Mr. Chairman, I will yield back.

Mr. PALLONE. Thank you. Ms. Eshoo.

Ms. ESHOO. Thank you, Mr. Chairman, and thank you, Drs.

Galson and Crosse for your testimony and the answers that you

have given to the questions that have been posed by my colleagues.

I want to make a couple of comments before I ask my questions.

Number 1, the whole issue of advertising, of drugs. I can’t help but

72

think it is kind of in the middle of this. I mean the heavier something is marketed, the more pressure there is to buy, and obviously, this pipeline to examine and for efficacy and then the pressure that I think justifiably is brought on the Congress and the

agency for post-market surveillance.

For the life of me, I really don’t know what good advertising has

done except for, I mean for corporate reasons to market. And I

can’t help but think that we should revisit this. We should take a

look at this and not only examine, in my view, the genesis but all

the issues that surround it. To see someone skipping through a

meadow, and the tagline being buy such and such a product. I remember my mother used to say, ‘‘what is it that they are advertising here?’’ So I think that we should take a look at that.

It is curious to me of the whole issue of reimportation being

raised by Members here. I have always thought that it was a very

important issue, and there is the bastardization of drugs by others

and the attempt to bring them into the country. But I also think

it is a political curiosity about what the Congress did in the name

of trying to save money to bring other drugs into the country. I

never thought that was a good policy. I didn’t support it. I don’t

support it now, and I think that we have our hands full because

there is more and more coming into the country. And we have to

take a look at what to do with it.

Now, my questions. In your testimony, Dr. Crosse, you found

that FDA’s access to post-market clinical trial and observational

data is limited by both resources and by authority. This is a softball issue, but do you think that the FDA should have such an authority?

Ms. CROSSE. Yes, we do. We have recommended to Congress to

do that.

Ms. ESHOO. Right. Now, would the administration’s PDUFA for

a proposal include this authority, and specifically what types of

post-market observational and clinical studies will FDA be permitted to exercise under the administration’s plan?

Dr. GALSON. Right, in our PDUFA proposal and in the legislation

that is on the Hill, we will get important new sources of resources——

Ms. ESHOO. Does the Waxman-Markey legislation match what

the administration has proposed?

Dr. GALSON. I don’t believe it does.

Ms. ESHOO. It doesn’t?

Dr. GALSON. Yes, I am not an expert.

Ms. ESHOO. OK. One, I think, is stronger than the other?

Dr. GALSON. I believe so, yes.

Ms. ESHOO. OK, so it is Waxman-Markey that is the stronger of

the two. I think we should know that. I mean in my view it is. Do

you agree?

Dr. GALSON. It depends which provision specifically you are talking about here.

Ms. ESHOO. Well, overall, is it weaker or is it stronger?

Dr. GALSON. I don’t like that characterization.

Ms. ESHOO. OK, I think we know what the answer is here. All

right. Now, thank you. I want to go to something that I feel strongly about, and that is health information technology. Your testiVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00078 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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mony, Dr. Galson, indicates that an additional $4 million is adequate to upgrade FDA’s current drug review system. Is it really?

I mean what is an additional $4 million going to buy?

And how long will it take to go to full implementation? This is

about, my colleagues, I think this is about expeditious review. I

mean I don’t know. Someone is sitting in a back room and going

through this sheet by sheet. Or is it all part of a technology system? First of all, what is the $4 million going to buy? Is it really

enough, and how soon does that get the agency to full implementation?

Dr. GALSON. We are in the middle of a very rapid transformation

from a paper environment to—there are some areas, depending on

what you are talking about, where the technology is there.

Ms. ESHOO. Help us. We want to help you accomplish this.

So what is the $4 million going to buy?

Dr. GALSON. The $4 million is helping us move from a paper system to an electronic system.

Ms. ESHOO. How much of the system is still paper, using percentages?

Dr. GALSON. A lot of it is still paper.

Ms. ESHOO. But give me—come on.

Dr. GALSON. I think we are getting about half of all our applications in by paper, but again that is from the pharmaceutical industry. We need to get there faster.

Ms. ESHOO. I think we need to revisit this, and I think that you

are tremendously low balling the amount of money that needs to

be invested in this. We should really take a look at it. You tell us

what you need to move to full implementation and over what period of time. $4 million, my sense is, represents snail’s pace.

Dr. GALSON. We will be happy to get you there.

Ms. ESHOO. OK, good. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. Mr. Murphy.

Mr. MURPHY. Thank you, Mr. Chairman. Doctor and Doctor, I

don’t know if you heard some of my opening comments about my

concerns about the breadth of the kind of warnings and comments

made when FDA approves a product. That currently it is one that

focuses, I think, a lot of the other reactions and things, but part

of my concern as a psychologist, at least when it comes to psychiatric medications, particularly pediatric ones, that I am concerned that 75 percent of drugs are prescribed by non-psychiatrists

and that oftentimes there may not be coordination with other people providing consultation with the family and therapy, et cetera.

What kind of actions does and can the FDA do to make sure that

the proper use of the medications and not just prescribing them is

part of the plan?

Dr. GALSON. Right. We, as you know, we don’t regulate the practice of medicine. So what goes on in the prescribing room and all

sorts of other questions having to do with the way physicians work

is not under our purview. But what we do do and what we are

very, very committed in is making sure that physicians have the

best possible information as quickly as possible when we develop

new recommendations or new views about safety and efficacy, the

benefit and risk of products.

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And we see our role here in making sure that the information accompanying products, the information that is available to the public, is as accurate as possible. We also work with professional organizations, the people who provide different, some specialty organizations. When there are issues, we bring them in. We talk to them,

so that is the way that we work with the medical community, but

we don’t actually have regulatory authority over that operation.

Mr. MURPHY. Dr. Crosse, do you have some comments on that?

Ms. CROSSE. No, we are well aware that this is an issue for the

FDA and that many of the problems that have arisen with drugs

and some of the post-marketing safety concerns that have arisen

have been in instances where medications have been prescribed

that are not in accordance with the label indications or for populations for whom they are not indicated. And FDA, in a number of

instances, has taken additional steps to try to add warnings to the

labels of those drugs to try to put out information to the public and

to try to put on some other kinds of controls on who can prescribe

these medications. But it remains a problem of great concern.

Mr. MURPHY. Certainly, Dr. Crosse, you are involved with some

of the labels and some of the information that goes to physicians

on things even though you can’t regulate them and tell them who

has to do it. When it comes to some of these psychotropic medications, however, what kind of commentary goes into the warnings,

et cetera, with regard to, I guess, the pool of knowledge someone

should have or that medications should be used in conjunction with

other types of treatment.

Dr. GALSON. Well, we have a team of people who are experts and

psychiatrists who look specifically at the labeling and the information that we provide to the public about that kind of medication,

as we do oncologists for cancer drugs. And we get together, and for

a new drug, we look at the information that is available from the

clinical trials.

And we determine the best way to communicate about that, having to do with the dose, having to do with contraindications, other

types of warnings or precautions, concomitant diseases that may

affect the use of the drug. And we endeavor to make sure that all

that information is put together in the drug label, and if there are

special ways that that has to be communicated, we will get together and discuss that as well.

Mr. MURPHY. But is it done, again the psychotropic medications,

where it is described that the medication—the volumes of research

indicate it should be done, provided, in the context of a sort of

structurally trained psychotherapy and monitoring these cases, No.

1. The second issue is that in many cases, I don’t know if these

drugs are really evaluated on a pediatric population.

What is done to communicate those issues of the full spectrum

of treatment under which these medications seem to work best?

Dr. GALSON. Our authority doesn’t, in most cases, extend to some

of the things that you are mentioning. When we do think that

there is a drug that has such severe risks that we think that only

a physician with a certain kind of training should give it. Or there

is a drug, for example, that has risks that we think it should only

be administered in a hospital, we can require that.

75

Mr. MURPHY. Well, I am not saying just in terms of who prescribed it, but also other components of therapy that go with that.

Many medications may have other side effects. Take insulin for

diabetics. It is not enough just to say here is the insulin, but it

should be used in accordance with a strict dietary and exercise information.

Dr. GALSON. We can put that information in our labels, and we

do all the time.

Mr. MURPHY. I am not sure that is done adequately when it

comes to psychiatric medications, especially when it comes to recognizing a lot of these medications have not really run through

proper trials on a pediatric population.

Dr. GALSON. Right. We have under our authorities to require and

to urge that studies be done in pediatric populations. We have succeeded in having more of the studies looked at for younger age

groups, but there is no question this is a challenge.

Mr. MURPHY. I would hope, Mr. Chairman, as we pursue this because our culture is becoming so much giving kids drugs, and it is

amazing how many youth are given drugs for psychiatric reasons

to quiet them down, to stabilize them. And the almost explosion of

diagnosing these things. I really hope this is an area that you continue to investigate. Thank you very much.

Mr. PALLONE. I appreciate your comments. I agree with you. I

recognize the gentleman from Massachusetts, Mr. Markey.

Mr. MARKEY. Thank you, Mr. Chairman, and again I appreciate

your giving me this opportunity. Mr. Galson, Mr. Waxman and I

have introduced the House counterpart to the Kennedy-Enzi drug

safety legislation, which includes many of the recommendations of

the Institute of Medicine and GAO. And we are hopeful that it will

be included as part of PDUFA reauthorization on the House side.

So Dr. Galson, if I may, my wife is a doctor. So I apologize for calling you mister.

Dr. GALSON. I am a doctor.

Mr. MARKEY. Doctor, yes, I apologize. Let me begin with you. In

response to Chairman Pallone’s questions about clinical trials, you

stated that there has been tremendous improvement in registration

of clinical trials. However, companies aren’t in 100 percent compliance with registration of required trials. Is that correct?

Dr. GALSON. I am not sure that is exactly what—you are quoting

my response from just a few minutes ago?

Mr. MARKEY. Yes, they are not in 100 percent compliance.

Dr. GALSON. I would have to look specifically at the rules. What

I believe I was trying to convey is that not all the detailed information that some people think should be put on public databases,

going down to patient-level data, is on there. I am not aware of

compliance issues.

Mr. MARKEY. OK, would you agree that if registration is not

mandatory and the FDA does not have any enforcement mechanisms to require registration, that we will never get 100 percent

compliance?

Dr. GALSON. I don’t know really and wouldn’t want to speculate.

Mr. MARKEY. And I appreciate that.

Dr. GALSON. Yes.

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Mr. MARKEY. If we are trying to ensure that we know about all

of the trials that have been conducted on a product after phase one

and eliminate the problem of selective disclosure of trial results,

which can give the public a distorted view of the risk of benefits

of the drug getting most of the trials doesn’t really fix the problem

because the trials the companies are registering may be the most

important for the public to know about. By only selecting the answers that you want to give, the public might be denied information that could be useful, or the physicians could be denied the information. Do you agree with that?

Dr. GALSON. I agree that it is very, very important when there

is a marketed product, if there is a clinical trial that is done that

is relevant to patient care and drug safety, that it is important that

the information that could have an impact on whether patients and

physicians want to use a drug, that that be available.

Mr. MARKEY. OK. And, Dr. Galson, some people have raised the

concern that emphasizing post-market safety could slow down the

approval process. However, it would seem to me that if FDA is confident in its ability to detect and manage problems after approval,

then the FDA should actually be able to approve the drugs faster

even if there are some lingering questions about the safety

preapproval because there will be a strong system to monitor and

invest those issues, if necessary, after the drug is on the market.

Do you agree that having a stronger post-market safety system,

a safety net if you will, is important to giving the FDA the confidence that they don’t have to catch everything pre-approval because the approval is not the last chance to address the safety

issues.

Dr. GALSON. That is a complex, multi-part question. Let me just

say starting that it is not possible to catch everything with the current state of knowledge. If we want new products for patients who

need them, we are going to sometimes find out things after approval that we didn’t know when the drugs were approved.

Mr. MARKEY. So the point I am making is don’t you think a

stronger post-market safety system would give people more confidence?

Dr. GALSON. Yes, I am a very strong supporter of a stronger postmarket safety system.

Mr. MARKEY. OK, Dr. Crosse, in your testimony, you described

some major gaps that currently exists in the FDA’s post-market

safety net system. In his statement, Dr. Galson testified that the

FDA’s PDUFA proposals will transform the drug safety system at

FDA. Do you believe that additional resources for post-market safety without additional authority to require post-market studies and

changes is enough to transform the post-market drug safety program in FDA?

Ms. CROSSE. We believe that additional authority is warranted

for FDA to give them all the tools that they need to be able to effectively oversee this process.

Mr. MARKEY. How does FDA’s current lack of authority to require post-market studies affect the FDA’s ability to assess safety

problems after a drug is on the market?

Ms. CROSSE. I think it complicates and slows the availability of

information that is needed to be able to fully understand certain

77

types of problems. Absent certain types of information, the agency

often cannot make a determination quickly or possibly even at all

about what kind of action ought to be taken.

Mr. MARKEY. I thank you. I think of it as a trainer for tightrope

walkers. Before the walker steps off the platform, the FDA is in a

strong position to make sure the walker will succeed by requiring

a harness, if necessary. But once the drug is approved and the

walker leaves the platform, the FDA can do little to require protections if companies don’t want to accept them.

Knowing this, the FDA is unlikely to let products go if felt a little wobbly. However, if the FDA had a strong safety net in place

to catch problems and prevent a major crash, the FDA is more likely to feel comfortable in getting products to patients who need

them. That is what the Waxman-Markey safety bill would do. It

would create a strong but flexible drug safety net, and it is something that, I believe, at the end of the day is actually essential to

having a good drug approval system. I thank the chairman for allowing me that little extra time.

Mr. PALLONE. Thank you, Mr. Markey. That concludes our questions, and thank you both for being here today. I thought it was

a very good questions-and-answers series. Let me just say though

that we are going to take a break before the second panel goes in.

We have 11 minutes left on one vote, and then there will be three

5-minute votes after that. So figure about half an hour we will be

back and start with the second panel. But we are now in recess.

Thank you.

[Recess.]

Mr. PALLONE. The subcommittee hearing will reconvene, and I

will ask the panelists to come forward and sit down. Welcome to

all of you. Let me introduce each of you actually. We have a pretty

large panel here today.

We will start on my left with someone from New Jersey, Lisa

Van Syckel, who is from Flemington, New Jersey. We are going to

have a video that she has brought us. And then we have Dr. Ellen

Sigal, who is chairperson and founder of the Friends of Cancer Research. And Dr. Susan Ellenberg from the University of Pennsylvania School of Medicine. She is speaking at the request for the Coalition for a Stronger FDA. Dr. Caroline Loew, who is senior vicepresident for scientific and regulatory affairs of the Pharmaceutical

Research and Manufacturers of America. Diane Thompson, who is

vice-president for Public Policy and Communications at the Elizabeth Glaser Pediatric AIDS Foundation. She is speaking on behalf

of the Alliance for Drug Safety and Access. John Theriault, chief

security officer and vice president, global security at Pfizer. Dr.

Sharon Levine, associate executive director for the Permanente

Medical Group, speaking on behalf of the Kaiser Permanente Medical Care Program. And Dr. John Powers, who is assistant professor

of medicine at George Washington University School of Medicine,

and I guess also at the University of Maryland School of Medicine.

So thank you all for being here today. We are going to start with

Ms. Van Syckel, and does the video go first, or how does that work?

We will do the video first? Now, we were going to try to put it on

the big screen, but it didn’t work. So we are using the TV. Thank

you.

78

[Video shown.]

Mr. PALLONE. First of all, let me thank you for being here and

for bringing us the video and relating your own story of your

daughter. I know it has got to be tough, but we really appreciate

your being here.

STATEMENT OF LISA VAN SYCKEL, FLEMINGTON, NJ

Ms. VAN SYCKEL. Yes, it is very tough, and I just want to make

sure that no family ever has to endure what our family endured.

The FDA and pharmaceutical industry continues to downplay the

risks of antidepressants in children. They have gone from causal

low to increased risk and to most recently the Johns study, saying

that the benefits of antidepressants outweigh the risks.

When we hear about increased suicide within the media, they

think that it is something that is very quiet. And that is why I

thought it was important to come and play the tape so Congress

can actually see it for themselves, hear about it, because it is a violent suicide. It is not something quiet, and I think it is very disturbing for this FDA to allow the pharmaceutical industry to negotiate the labels that are placed on antidepressant medications.

They should never be allowed to negotiate the lives of our children, and I think that is what the very important issue here is.

And, Mr. Chairman, we have another serious concern, especially in

the State of New Jersey where infants are being given

antidepressant medications, not only antidepressants but

antipsychotics to medicate children as young as infants, 12 months.

And we need to ask why.

So with the FDA and their failure to provide the medication

guides, which is an issue I have been speaking with Mr. Ferguson,

it is quite clear that the FDA is incapable of doing their job and

notifying the public of severe side effects. And I am begging you,

as parents from the State of New Jersey, from district 6 and district 7, because I represent all of New Jersey, we need an independent office of drug safety.

We need better control of direct consumer marketing, and we

need a better med watch program. I want to give you an example.

My brother had a severe condition and was critical, and a nurse

had stated to me—I said ‘‘well, what about the side effects.’’ And

it was the particular drug Zocor. And she says you can actually get

the side effects from the television, from the commercial. And I said

to the nurse you are telling me, as a caregiver, that I should look

to the television, to a commercial for side effects. That was ridiculous, and I said I think you are saying that to the wrong person.

So I am really concerned as to the direct consumer marketing.

I realize they have a right to free speech, but medical professionals

should not be telling patients to watch it on TV.

[The prepared statement of Ms. Van Syckel follows:]

STATEMENT OF LISA VAN SYCKEL

Mr. Chairman, members of the committee, thank you very much for inviting me

to testify at today’s important hearing.

I would like you to hear how corporate greed, our woefully inadequate mental

health system and over-reliance on pharma-psychiatry, and the little pink pill,

Paxil, have forever altered the life of my most precious gift from God, my daughter

Michelle.

79

Michelle was raised in a loving, stable home in the small town of Dunellen where

she participated in many community events and was proud to be a girl scout.

In 1995 American Standard transferred my husband to their European Division

in Brussels, Belgium.

Michelle, who had always been an honor roll student, attended St. John’s International School in Waterloo. Michelle traveled and explored many European countries. She became fluent in the French language.

Our family returned to the United States in the summer of 1999. Our life, as we

once knew it, would change dramatically. Michelle began complaining of ill health

and missed her friends in Belgium. She was also upset over the declining health

of her grandmother.

In April 2000 Michelle continued to complain of ill health, she was losing weight

and had stopped eating. She was admitted to Somerset (New Jersey) Medical Center’s eating disorder unit, where she was diagnosed with depression and anorexia

nervosa and was prescribed the antidepressant Zoloft. Within hours of digesting

Zoloft, she reported to hospital staff that she had the urge to hurt and cut herself

and two days later, again reported she was uncomfortable taking the medication.

Her complaints were dismissed. Several weeks later, Zoloft was discontinued due to

dramatic orthostatic changes and bradycardia. (very slow heart beat). Michelle became very hyperactive and was diagnosed with a personality disorder. No one apprised me of what was happening to her. She was fourteen; I should have been informed.

In June 2000 Michelle was placed on Paxil. Within a few weeks she began to selfmutilate with knives, razors and broken plastic CD cases. She became verbally abusive and was displaying extreme oppositional behavior, along with severe insomnia,

diarrhea, chest pain, weak muscles, and on a few occasions vomited blood and had

rectal bleeding.

In August 2000 the Paxil was increased to 40 mg along with a diagnosis of major

depressive disorder with psychotic features.

In September Michelle’s self mutilating behavior was increasing. During one episode, she had inflicted over 23 wounds and cut the word ‘‘die’’ onto her abdomen.

She became violent and suicidal and was hospitalized because she was deemed to

be a danger to herself and others. Her Paxil was reduced from 40 to 20 mg and

Depakote was prescribed.

On October 6, 2000 my daughter Michelle attempted suicide and became extremely violent. She assaulted her brother as he was desperately trying to keep her

from killing herself. He was just 4 days shy of his 12th birthday. She then viciously

attacked three police officers and managed to escape from her handcuffs twice. She

was kicking, spitting and screaming obscenities. She even attempted to kick out the

rear window of the patrol car. When they arrived at the hospital, it took five men

to place her in leather humane restraints. The next day Michelle awoke dystonic

and unaware of her surroundings. Again, she became violent and had to be restrained.

Michelle was transferred to UMDNJ Behavioral Health. Paxil was discontinued,

but she was then prescribed Celexa and Risperdal (what I didn’t know then, but

have since learned, was that Michelle was placed in a clinical trial of these drugs

without my knowledge or consent). Within 36 hours, Michelle again became violent

and self mutilated. She was injected with Thorazine for her out-of-control behavior.

Approximately two weeks later, she was released from UMDNJ with a 3-day supply of medication (what I know now and didn’t know then, was that this was a very

dangerous thing to do). In an abrupt withdrawal, Michelle again became violent and

threatened to kill me. She thought I was the devil and told me I was evil.

In April 2001 Michelle was removed from all psychotropic medication. Recovery

was a long, tedious process. Everything Michelle endured while on the drugs was

suffered through the withdrawal process.

Michelle’s Paxil-induced psychosis, self-mutilation, violent, and suicidal behavior

are gone now. What remains upsetting is that the physical scars of her self mutilation will be with her forever.

Michelle’s beautiful smile and sweet disposition were returned. Michelle never

had violent and suicidal behavior prior to taking antidepressants, nor displayed this

behavior after recovering from withdrawal.

I believe, without question, drug companies and their apologists are putting a

great deal of pressure on the FDA. Despite all of the controversy and exposed failures surrounding the FDA in the last few years, it appears that the FDA simply

cannot muster the guts to act without industry influence. Absent this influence,

there would be no reason why the FDA wouldn’t insist on label warnings for all ages

on anti-depressants. No doubt drug companies are a formidable force, but the FDA

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must remember whose interests it is supposed to protect. If it does not, the representatives of the people, Congress, will have to step in and do it for them.

I would like to show you about a minute and half of a video of Michelle and other

families’ children who have suffered because the FDA failed to better warn the public about dangerous side effects.

LEGISLATIVE SUGGESTIONS

So that other families are saved from the tragedy and heartbreak that my family

and other families in this hearing room have endured, I urge you to approve—as

part of the must-pass user fee legislation—the strongest possible FDA drug safety

reform legislation.

PDUFA: Break the ties that are distorting the FDA’s mission. First, on the extension of the Prescription Drug User Fee Act (PDUFA IV), I know that the FDA needs

the resources, and more, that the user fees bring. The user fees need to be continued, and expanded to provide more resources for safety.

But under the current law, the industry’s user fee money comes with a huge cost.

It comes with detailed requirements to serve the drug industry—and that is a cancer that is eating at the culture and integrity, both real and perceived, of the FDA.

If anyone doubts that the user fees are having a corrupting influence on the culture

of the FDA, I urge them to read last summer’s poll by the Union of Concerned Scientists, to which about 1000 of the FDA’s medical scientists responded. Many

poured out their frustration at being pressured to approve drugs on which they had

serious safety concerns, and a number cited PDUFA as an inherent conflict of interest. A recent study by a group of Harvard researchers has found that drugs approved just in time to meet the PDUFA time goals have many more post-market

safety problems than drugs which receive more review time. An earlier study by

Harvard Professor Daniel Carpenter pointed out that the FDA’s time-to-approve

drugs was declining in the years before PDUFA’s first passage in 1992; the study

found that the FDA staff was being increased through regular appropriations, and

that every 100 person increase in staff was resulting in a 3.3 month decline in approval times. I think this study shows that while the FDA does need more resources, it does not need the rigid framework of PDUFA.

This committee is famous for its tough oversight. I am sure that you can make

sure that the user fee money is well spent and that the FDA continues to give priority, timely attention to truly life-saving drugs. Therefore, I urge you to break the

entangling webs of obligations that come with the user fees and just let the FDA

use the fee money to do its job. Congressman Hinchey has previously introduced legislation that would achieve this reform.

Kennedy-Enzi (S. 1082), and Waxman-Markey (H.R. 1561)

The bill the Senate is passing makes important improvements for safety. And in

many ways, the bill by Representatives Waxman and Markey is even better, because it

• requires a warning signal for the first 2 years a drug is on the market (an important fact for consumers, since the real test of a drug’s safety comes once it is

mass marketed and used by the general population);

• requires a review of a drug’s safety history after 7 years (important because only

about half of a drug’s side effects and labeling changes are detected in the first 7

years it is on the market);

• provides much more meaningful civil monetary penalties than the Senate bill;

• protects the public from overuse of particularly dangerous drugs by limiting direct-to-consumer ads for up to three years; the First Amendment does not give the

drug companies the right to kill Americans, and moderation of ads on a new drug

with serious warning signs of danger should be one of the FDA’s tools;

• ensures that the results of all clinical trials (other than phase 1 trials) will be

made publicly available in a timely manner.

To save other families from future drug safety disasters, I urge you to take this

best opportunity in the next five years to pass this kind of legislation, and I urge

that it be made even stronger.

We need a better Adverse Event/MedWatch Reporting system. The Senate bill includes a major new monitoring of huge medical databases to detect quickly problems

with drugs. It is said that the problems with Vioxx might have been detected in

about 3 months under such a system.

But I believe we also need to educate and involve the American consumer more

in reporting adverse events. Today, the average citizen has no idea how or where

to report a problem with a drug. I urge you to require all drug ads to prominently

display a 1–800 number where problems can be reported. The FDA should also start

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using the tools of the Internet and e-mail to, with patients’ permission, periodically

query people who are taking a new drug whether they notice any adverse reactions.

Instead of passively waiting for reports of trouble, a modern FDA should be seeking

out the areas of danger.

We need someone responsible and accountable for safety at the FDA. I support

a separate Office of Drug Safety in the FDA, one that will be free of the control

and overwhelming presence of the Office of New Drugs.

The FDA Commissioner and many others have said that a separate office would

be duplicative, expensive, and hold up approvals. If that is a problem, the same goal

of accountability for safety could be achieved by giving the head of the Office of

Drug Safety the power to call for a safety action (a REMS adjustment in HR 1561).

If the head of the Office of New Drugs disagreed, the Commissioner would decide

between them, all within a week or so (so that there can be no charge that we are

delaying the approval of vital new drugs). There needs to be a locus of safety accountability in the FDA. This proposal, or a wholly separate office, would achieve

that goal.

No Conflicts of Interest (COI) in FDA Advisory Committees. The FDA recently announced guidance that makes major improvements in the Advisory Committee (AC)

process: no participation in an AC if one has over $50,000 in conflicts, and participation in the AC, but no vote if one has any conflict. I hope you will codify the FDA’s

action, but go beyond it by requiring the active recruitment of COI-free experts, and

prohibiting those with conflicts from sitting with the AC (they can testify, but they

should not be part of the camaraderie-building AC process where they can influence

outcomes even though they can not vote).

Thank you for your consideration of these legislative ideas. If enacted, you could

give the American people the FDA they need and deserve.

Mr. PALLONE. Thank you. And we are going to ask you some

questions later, but thank you for being here today. I appreciate it.

Dr. Sigal.

STATEMENT OF ELLEN SIGAL, CHAIRPERSON AND FOUNDER,

FRIENDS OF CANCER RESEARCH

Ms. SIGAL. Thank you, Mr. Chairman, members of the committee. Thank you for the opportunity to testify today about drug safety. It is an extremely important issue.

My name is Ellen Sigal. I am chair of Friends for Cancer Research. Friends is a coalition of all of the major groups in cancer

research. Our mission is the importance of cancer research. We

represent patients, scientists, clinicians, cancer center directors,

and we care deeply about research.

The issue of drug safety is very personal to me. My own sister

died 21 years ago of toxicity of a drug for breast cancer. So I know

personally what this means. She left a 4-year-old child. So this is

a very important issue to me and to all of us.

My testimony will cover four major points today that are extremely important to the patient community and the science community. Patients needs for life-improving therapies and a crucial

pipeline and access to drugs, providing additional resources for

FDA—you have heard that before, and you have heard it here

again—establishing a systematic routine and easily accessible safety monitoring system, and finally integrating science into the regulatory process, the critical path initiative and the proposed FDA

foundation. I also do want to point out that the president of

Friends, Molly Mallick, is here today, and I thank her for coming

here and supporting us.

Millions of other people have shared my experience and care

deeply about this issue of drug safety, just as Ms. Van Syckel and

others that you will hear today. So this is a concern that the paVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00087 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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tient community cares about deeply. I am going to read a quote

from Meryl Wineberg, who is the chair of the National Health

Counsel. ‘‘Speaking on behalf of 100 million Americans with chronic conditions and disabilities, it is equally important that patients

whose quality of life or indeed life itself are not deprived of the

medications they need.’’ I did have other testimony for the record

from the American Cancer Society and other patient groups.

When the issue of drug safety was surfacing and it was clear

there were going to be hearings and legislation about it—we are

very research oriented at Friends of Cancer Research, and we convened a group of experts in cancer and outside of cancer, clinicians,

scientists, epidemiologists, patients, to look at the issue because we

wanted to have an informed position on this. And we wanted to

make sure that we looked at the position from a scientific point of

view. We are science oriented, and we thought it was important to

have clinicians, people that actually treat patients, weighing in on

this issue.

Our major recommendations—the White Paper is drug safety

and drug efficacy. I would like it to be submitted to the record.

Thank you. The paper highlights three major areas: active surveillance, systems of the life cycle of a drug. We don’t have all the information up front in preclincal environment. We really find most

of it in post-surveillance. Resources for the FDA and training,

training for FDA personnel. That is absolutely critical. The integration of science through critical path, and the public/private partnerships. We can’t, as much as we need to fund FDA, and we support

substantial increased funding, partnerships through this critical

path initiative and this hopefully relief from foundation will be critical to it.

We also think that we have to use existing networks, such as the

VA, Kaiser, Blue Cross and others. The database and the information they have are critical. I want to read a quote from the recent

IOM report. The recent IOM report on drug safety states ‘‘to expect

a pre-market studies or FDA review of these studies can reveal all

the information about the risks and benefits of new drugs that is

needed to make optimal treatment decisions with occasion and reasonable delay in approval.’’

Authority is fine for the FDA. We support additional authorities.

We do not support those authorities without the resources crucial

to make these informed decisions. FDA is a chronically underfunded agency that is continually assigned more responsibilities

without matching resources. It is unreasonable to starve an agency

of the resources it needs yet hold it solely accountable for protecting the health of Americans.

One thousand five hundred people a day die of cancer. Four thousand will be diagnosed today. They cannot afford to wait. They

need new treatments. Other patients with chronic diseases need

treatments too. They deserve better treatments and more informed

treatments. They should be safe, and they should be effective.

The pipeline for these new patients is critical. They must be informed and must have choices, and allow them to participate in the

process. Patients are crucial to the process. Patient needs are not

monolithic, nor do all patients respond the same to a particular

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treatment. Only science and evaluation of patients will really make

us understand that and why that happens.

In conclusion, we remain extremely supportive of the goal to improve our drug safety system, and we believe that we can best

achieve this goal through a science-based approach, taking into full

account the voice and perspective of patients. We applaud the committee for holding these hearings, and we welcome further thoughtful policy discussions. Thank you.

[The prepare statement of Ms. Sigal follows:]

STATEMENT OF ELLEN V. SIGAL

Mr. Chairman and distinguished members of the committee, I thank you for the

opportunity to discuss the important topics of drug safety and efficacy as the committee begins to take important steps to strengthen FDA as part of the upcoming

reauthorization of the Prescription Drug User Fee Act.

My name is Ellen Sigal, and I am the Chair and founder of Friends of Cancer

Research. Friends is a non-profit organization that over the past 10 years has pioneered innovative public-private partnerships, organized critical policy forums, educated the public, and brought together key communities to develop collaborative

strategies in the field of cancer research. We are a coalition of major cancer groups

representing patients, researchers, physicians, and survivors. It is our belief that a

science-guided approach will best enable us to improve drug safety and efficacy in

this country.

We urge this committee and Congress to pursue a legislative course that provides

FDA with the resources it needs to conduct systematic risk assessment across a

drug’s lifespan while protecting patients’ access to needed treatments. Specifically,

we believe that any legislative approach to strengthening FDA must give priority

consideration to:

• Patient need for life-improving therapies

• Providing additional resources for FDA

• Establishing a systematic, routine and easily accessible safety monitoring system

• Integrating science into the regulatory process through the Critical Path Initiative and the proposed FDA Foundation

We all want the safest possible drugs. But we recognize that no drug is 100 percent safe or 100 percent effective. We also realize that each patient responds differently to medication. Like the patients I speak on behalf of, and many of you in

this room today, I have encountered this reality in a very personal way.

Twenty years ago, my own sister died of toxicity associated with a bone marrow

transplant to treat metastastic breast cancer. She was 40 years old and left behind

a 4-year-old daughter. This was a tragic event that clearly changed my life. While

I hope that no one would have to go through such an event themselves or with their

loved ones, this was a risk that we knowingly accepted based upon what was best

for my sister at the time.

As emotional as my experience was, I recognize that emotions cannot be the guiding force behind decisions about what treatments should and should not be available

to patients. We believe that a science-driven approach to drug development and approval will help to ensure that each person receives the treatment that is most likely to be effective and safe for them.

In examining treatment options, all patients must weigh the benefits and risks

when determining their own course of treatment. Legislation aimed at strengthening drug safety must take care to preserve patients’ access to a wide array of treatment options while not impinging on the development of new treatment options or

removing existing options for patients in need—bearing in mind that for many diseases, including many cancers—patients still have few or no treatment options

available to them at all.

We are confident that increased funding for FDA and policy that is grounded in

science can achieve an optimal balance between protecting patients and expanding

treatment options. A benefit-risk approach conducted across a product life cycle—

guided by sound and systematic data collection and careful, regular assessment of

a drug’s safety and efficacy across subpopulations, dosage levels, and other factors—

is the cornerstone of drug development and should be the foundation of drug regulation.

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1 Roberts, Lauren. Multiple Sclerosis Patients v. FDA Over-Caution. Washington Legal Foundation. May 19, 2006

In any treatment decision, consideration must be given to the condition the drug

is meant to treat as well as to the extent of the patient’s disease, its duration and

its impact on the patient’s functional status and quality of life. Depending on the

particular illness, drugs can potentially be designed for and used at a specific point

in the continuum of disease from prevention to terminal illness. Patients’ needs are

not monolithic, nor do all patients respond the same to a particular treatment.

Legislation should acknowledge the great variability across diseases, patient preferences, and individual circumstances and facilitate continued access to a wide

array of treatment options accordingly. Indeed, across the board, one need stands

paramount for patients—it is the need for more and better options to fight disease

and improve disability. We believe that any legislative initiative that limits patient

choice and access to treatments in the name of safety would be counterproductive

and not achieve the goal of improving patient outcomes.

As this committee considers ways to enhance the FDA’s ability to monitor drug

safety to help patients make the most informed decisions about their treatment options, it is of the utmost importance that patient needs and voices be at the forefront of discussions and that all decisions pertaining to drug safety be driven by

sound scientific data.

Dr. Jerry Yates, National Vice President of Research for the American Cancer Society, describes a scientific foundation for FDA:

‘‘Based on the course of cancer—from prevention to terminal illness—improving

the science of safety will help identify the proper balance between risk and benefit

for each stage of the disease and assure optimal investments in both cancer research

and the care of patients.’’

This issue, of course, impacts not only the cancer community, but the entire patient community as well. For example, Myrl Weinberg, president of the National

Health Council, expresses her community’s needs:

‘‘Of course, prescription drug safety is of paramount importance, and—appropriate

measures should be taken to ensure the public is not unnecessarily exposed to—potential harm. However, speaking on behalf of 100 million Americans with chronic

conditions and disabilities, it is equally important that patients—whose quality of

life,—or indeed life itself—are not deprived of the medications they need.’’

Lauren Roberts, a multiple sclerosis (MS) patient who was directly affected by the

temporary removal of Tysabri from the market, described her experience by saying:

‘‘MS progresses on its own timetable, not the FDA’s. In the course of 90 days,

there will be, on average, 2,160 more people who hear the words, ‘‘You have multiple sclerosis.’’ My own MS continues to ravage my body—Tysabri was the first and

only therapy that helped me—the small risk from Tysabri pales in comparison to

the risks created by not having Tysabri available to us as a choice—As for me, I

am willing to take that risk, in exchange for having an improved quality of life, my

life, back.1

FDA must have the best tools to make these important assessments and effectively communicate with physicians and patients as they together make individual

treatment decisions. New policy to expand the authority of FDA alone will not sufficiently strengthen the agency. Simply put, FDA needs more dollars from Congress.

This is a chronically under funded agency that is continually assigned more responsibilities without matching resources. It is unreasonable to starve an agency of the

resources it needs, yet hold it solely accountable for protecting the health of Americans.

Now, in a time when public perception is declining, user fees are not the best answer. Due to the current budget climate, user fees are a reality, but a strong FDA

is an investment in patient and public health. Congress should find the money to

invest.

DRUG SAFETY & DRUG EFFICACY: TWO SIDES OF THE SAME COIN

Several months ago, we convened an independent committee of expert academic

scientists and clinicians, research advocates, and representatives of the patient community to examine and recommend ways to further strengthen the agency and its

product evaluation process.

It is extremely important that the patient voice be heard along with the perspective of expert clinicians experienced in clinical trial design and translational research. The members of this committee are distinguished experts in diseases such

as cancer, infectious disease, and diabetes. They are experts in drug development

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2 Institute of Medicine of the National Academies. ‘‘The Future of Drug Safety: Promoting and

Protecting the Health of the Public’’ Sept. 26, 2006.

but also have first hand knowledge in patient care and patient needs. This is a vital

perspective that cannot be excluded from the drug safety debate.

I would like to thank Dr. Robert Young, president of the Fox Chase Cancer Center

in Philadelphia and chairman of the board of Scientific Advisors of the National

Cancer Institute, for his leadership of the authoring committee. The resulting document, entitled, ‘‘Drug Safety & Drug Efficacy: Two Sides of the Same Coin’’ is a proposal for improving drug safety, ensuring new drug access, and strengthening the

FDA. I would like to ask that a copy of the full report be submitted to the record

as an addendum to my testimony, and I would like to briefly discuss some of the

recommendations.

A SYSTEMATIC APPROACH TO SAFETY SURVEILLANCE

It is most important for patients that FDA continuously evaluate both safety and

efficacy when determining public access to new products. At the level of medical

practice, safety and efficacy are always considered together by the treating

healthcare professional in the context of a patient’s specific circumstances and preferences. The regulatory process should reflect this essential balance that is fundamental to all medical decision-making.

Because it is impossible to know everything about a drug at the time of approval,

it is important to monitor the safety and effectiveness of drugs as they are used in

the general population. To strengthen the effectiveness of the current post-market

system, the agency needs to develop and implement a more systematic and automated approach to safety surveillance.

By utilizing drug safety and efficacy information from a variety of sources, such

as established healthcare networks like Kaiser or UnitedHealth Group, the FDA

could actively identify, evaluate and respond to signals more efficiently. New policy

should shift the emphasis of drug safety away from solely risk management, and

instead focus upon systematic benefit-risk assessment based on comprehensive and

valid information provided by the healthcare community.

Currently, a great deal of drug safety evaluation is based upon the limited data

available in the New Drug Application. A locked focus on safety at this early point

in a drug’s life cycle would increase the amount of pre-market data required, with

the likely result of stifling or unnecessarily slowing patients’ access to potentially

beneficial medicine. The recent IOM report on drug safety states, ‘‘to expect that

pre-market studies or FDA review of these studies can reveal all the information

about the risks and benefits of new drugs that is needed to make optimal treatment

decisions would occasion unreasonable delay in approval.’’ 2

It would be far better to utilize available data mining techniques and other potential new information sources to identify unanticipated adverse events sooner following product launch and adoption in medical practice.

New policy should focus on efficiently and accurately identifying unexpected serious adverse events in a scientifically rigorous manner. Once a serious signal has

been identified, FDA should have the tools to react in a proper manner that will

protect the public while ensuring responsible access for patients who may depend

on a particular drug. Such an approach would benefit all stakeholders.

ENHANCED TECHNOLOGY INFRASTRUCTURE

With the proper resources to improve the technology infrastructure, FDA could

routinely and systematically evaluate data from completed and ongoing clinical

trials and registry studies, perform useful epidemiological studies, and characterize

population subtypes and their response to treatments.

In addition, greater ability to compare and combine data across different sources

would result in greater flexibility and improved efficiency and the potential to generate novel insights about vulnerable populations. This includes the ability to share

information regularly with the Center for Medicare and Medicaid Services and with

sister agencies within the Public Health Service, including the National Institutes

of Health and the Centers for Disease Control and Prevention.

INCREASE TRAINING AND PERSONNEL

Just as FDA needs enhanced infrastructure and information systems, it also

needs adequate personnel training to meet emerging technology advances. Increasing the number of IT trained staff is essential for the overall advancement of the

bioinformatics systems. As the agency strives to monitor and evaluate the treatVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00091 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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ments of the future, it is imperative that FDA have the resources to effectively manage and interpret the wealth of information currently available.

FDA needs to attract and retain a greater number of professional staff with the

training required to perform accurate benefit-risk assessment, evaluate new therapies and implement scientific initiatives. As the FDA workload grows, so too must

the resources to recruit and increase staff with critical competencies. Increased

training of FDA personnel will also enhance agency effectiveness and standards.

FDA experts could play an integral role in the development of advanced clinical

trial designs that achieve greater efficiency and permit definitive conclusions to be

obtained more quickly. Such advancements to the current clinical trial system could

result in improved pre-market product evaluation, smaller trial sizes, more efficient

dosing determinations, and ultimately, safer products reaching patients faster.

INTEGRATING NEW SCIENCE THROUGH THE CRITICAL PATH INITIATIVE

As science progresses and new treatments emerge from laboratories and clinics

around the world, FDA must be equipped to perform accurate and efficient evaluation and continue its science-based tradition. It is imperative that resources be devoted to increase the support for the Critical Path Initiative to modernize FDA.

A central goal of the Critical Path Initiative is to provide tools to identify patients

who will most likely respond to particular treatments, thereby improving the risk

to benefit ratio. As this is accomplished, there will be new ways to diagnose, treat,

cure or prevent disease and allow life-saving therapies to reach patients faster while

reducing the overall cost of healthcare in the country.

Legislation introduced by Senators Kennedy and Enzi, and recently considered by

the Senate, would create the Regan—Udall Foundation for the Food and Drug Administration. This will establish a leading organization for the advancement of the

Critical Path Initiative and foster the advancement of the science of drug safety

through public-private partnership.

NIH initiatives and collaborative research partnerships should place high priority

upon the identification and use of biomarkers to (1) determine the role of genetic

polymorphisms in causing drug toxicities; (2) establish effective strategies for selecting patients for treatment with specific drugs and (3) identify early biomarkers of

drug benefit. The sub-populations most susceptible to an adverse event could be

identified by detecting the presence or absence of a biological indicator.

Further integrating science into the regulatory process will aid researchers who

design drugs, experts who evaluate their safety and efficacy, health care providers

who prescribe medicine, and most importantly patients who will benefit from continued medical discovery and more effective application of new treatments.

Conclusions

In conclusion, we remain extremely supportive of the goal to improve our drug

safety system and we believe that we can best achieve this goal through a sciencebased approach, taking into full account the voice and perspective of patients. Scientific advancements have led to better methods of disease treatment, early detection and prevention, and such technological advancements can translate to identifying safety signals more accurately and efficiently.

Increased funding for the FDA will help the agency access and utilize these tools

to assess the benefits and risks of medical therapies and, in turn, help patients

make the most informed decisions about the treatment options available to them.

A wide range of treatment options should and must remain available to patients.

While we, of course, want safer drugs, we caution against unintentional consequences that could remove or slow access to valuable therapies without actually

improving their safety. Of even greater detriment would be discouraging the future

innovation of potentially life-saving new products altogether.

We applaud the committee for holding this important hearing and we welcome

further, thoughtful policy discussions toward ensuring that FDA has the resources

and tools it needs to advance the science of drug safety while it continues its important work to evaluate and approve new therapies for patients in need.

We look forward to continuing to work with all of you to ensure that the lives

and hopes of patients continue to improve through sound, science-based, and patient-focused FDA policy. Thank you for the opportunity to speak to you today. I

look forward to answering any questions you may have.

Mr. PALLONE. Thank you. Dr. Ellenberg.

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STATEMENT OF SUSAN ELLENBERG, UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE, SPEAKING AT THE REQUEST FOR THE COALITION FOR A STRONGER FDA

Ms. ELLENBERG. Mr. Chairman and members of the committee,

I am Susan Ellenberg, professor of biostatistics and associate dean

for clinical research at the University of Pennsylvania School of

Medicine.

Prior to my current appointment, I directed the biostatistics and

post-market surveillance programs at the FDA’s Center for Biologics Evaluation Research from 1993 to 2004. I also recently

served on the Institute of Medicine committee on the assessment

of the U.S. drug safety system.

During my career with the FDA, I was deeply involved in one of

FDA’s most important functions, monitoring the safety of medical

therapies after they had been approved for marketing. As such, I

want to thank the committee for inviting me here today to testify

on the important issue of drug safety.

Although there are many aspects of drug safety that the committee is looking at, I am going to speak particularly from my own

knowledge and experience about one aspect of FDA’s drug safety

program that I feel most strongly about, and that is its resource

needs to carry out its congressionally-mandated responsibilities.

As you know and as others have said today, there is no such

thing as a totally safe drug. All drugs pose some risk to patients.

Drugs are deemed safe when it appears that their benefits outweigh their risks in a given population, safe enough.

The approval for marketing a new drug or vaccine is only the beginning of a drug’s lifecycle. It is critical drugs be monitored once

on the market. Drug manufacturers’, physicians and the FDA continuously watch for signals that a drug poses greater risks than

originally believed or it may be unsafe in certain patient populations, or require special restrictions to control hazards that would

otherwise cause FDA to remove it from the market.

For some years now, FDA scientists have recognized a growing

resource imbalance between the agency’s pre-market drug review

program and its post-marketing safety surveillance capabilities.

This imbalance has resulted from enactment of Congress of the

Prescription Drug User Fee Act, which has greatly enhanced and

enlarged FDA’s pre-market drug review program and a parallel

lack of increased funding for FDA’s post-market drug safety program.

The recent Institute of Medicine report, ‘‘The Future of Drug

Safety: Promoting and Protecting the Public Health,’’ which I am

sure many or all of you have seen, noted this resource imbalance

and concluded that our drug safety system was severely underfunded. The User Fee Act has required the drug review staff at

FDA to grow steadily larger to allow much more rapid review and

approval of drugs than ever before. That has been a great boon to

the citizens of this country, resulting in more new drugs to prevent

and treat illness. But the drug safety programs at FDA have received only very limited increases in staff and funding, and thus

these programs have continually lost ground in their ability to

monitor the rapidly increasing number of new drugs on the market.

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Further, the volume of adverse event reports submitted to the

FDA has increased steadily. As you can see on the monitor, the

numbers of reports of adverse events submitted to the FDA has

climbed so rapidly that they threaten the ability of drug safety

staff to review and process them effectively. And we discussed this

earlier, the various reasons. But in any case, the numbers have

gone up quite dramatically.

One of the initiatives of which I was most proud during my tenure at FDA was a thorough reevaluation of FDA safety monitoring

systems, an effort commissioned by then Commissioner Jane

Henney. That assessment, which was completed in 1999, resulted

in a series of recommendations for major changes in our post-marketing safety programs including, among other things, intense

monitoring of newly marketed products during the initial period on

the market, obtaining access to health care databases, such as

those of Medicare and the VA that we have talked about today, developing a new active surveillance capacity to complement existing

passive surveillance system, which also need to be improved, funding for research to improve FDA’s tools for monitoring the study of

medical product risks, more intense intervention such as stronger

warning labels or restricted distribution of higher-risk products,

and funding to conduct focus safety studies when needed.

Commissioner Henney’s request for a substantial boost in FDA

appropriations to fund these recommendations unfortunately were

not successful. But these recommendations made by FDA staff 8

years ago are very similar to the drug safety provisions of the current Senate and House bills that are currently being considered,

and are entirely consistent with the recommendations of the recent

IOM report. If the necessary funding had been provided at that

time, the proposed programs would be up and running today and

might have permitted much more rapid identification of many, if

not all, of the recent drug safety problems that we have been experiencing, meaning far fewer individuals would have been exposed

to excess risk.

And so, Mr. Chairman, I urge you to set as one of your highest

priorities this year provision of the necessary resources to FDA’s

drug safety programs. I thank you very much for inviting me to

present my views.

[The prepared statement of Ms. Ellenberg follows:]

STATEMENT OF SUSAN S. ELLENBERG

Mr. Chairman and members of the committee. I am Susan S. Ellenberg. Prior to

my current appointment as professor of biostatistics and associate dean for clinical

research at the University of Pennsylvania, I directed the biostatistics and

postmarket surveillance programs at the Food and Drug Administration’s Center for

Biologics Evaluation and Research from 1993 through 2004. That Center, as you

may know, is charged with assuring the safety of biological drugs, blood and blood

products, and vaccines, and works closely with FDA’s other programs for approving

and monitoring pharmaceuticals. I also served on the recent Institute of Medicine

Committee on the Assessment of the U.S. Drug Safety System, and am associate

editor of Clinical Trials (the official journal of the Society for Clinical Trials) and

of JNCI (Journal of the National Cancer Institute).

During my career at the FDA, I was deeply involved in one of FDA’s most important functions—monitoring the safety of medical therapies after they have been approved for marketing. As such, I wish to thank the Committee for inviting me here

today to testify on the important issue of drug safety, an issue that the Committee

will be considering this year as part of its effort to reauthorize the Prescription

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Drug User Fee Act. Although there are many aspects of drug safety that the Committee is examining, I have been requested by the Coalition for a Stronger FDA to

speak in particular, from my knowledge and experience, about one aspect of FDA’s

drug safety program—its resource needs to carry out its Congressionally-mandated

responsibilities.

BACKGROUND

As you know, there is no such thing as a totally ‘‘safe’’ drug—all drugs pose some

risk to patients. Drugs are deemed ‘‘safe’’ when it appears that their benefit outweighs their risks in a given population. The approval for marketing of a new drug

or vaccine is only the beginning of a drug’s ‘‘life cycle.’’ It is critical that drugs be

monitored once on the market—drug manufacturers, physicians and the FDA continuously watch for signals that a drug poses greater risk than originally believed,

may be unsafe in certain patient populations, or requires special restrictions that

must be imposed so as to control hazards that would otherwise cause FDA to remove it from the market.

A RESOURCE FOR IMBALANCE

For several years now, FDA scientists have recognized that there has been a

growing resource imbalance between the agency’s premarket review program for

drugs and its postmarket surveillance capabilities. This imbalance has been occasioned by two developments: the enactment by Congress of the Prescription Drug

User Fee Act, which has greatly enhanced and enlarged FDA’s pre-market drug review program, and a parallel lack of increased funding for FDA’s postmarket drug

safety program.

The recent Institute of Medicine Report, The Future of Drug Safety: Promoting

and Protecting the Health of the Public, of which I was a co-author, confirmed those

internal FDA concerns by concluding that our drug safety system was ‘‘severely underfunded.’’ As the IOM report noted, the user fee act has required the drug review

staff at FDA to grow steadily larger, which has allowed much more rapid review

and approval of new drugs than ever before. That has been a great boon to our citizens, resulting in more new therapies that can prevent or treat illness. But the drug

safety programs in FDA have received only very limited increases in staff or funding, and in fact have been largely held to their pre-PDUFA levels. Thus, FDA’s postmarketing safety programs have continually lost ground in their ability to monitor

the rapidly increasing number of new drugs on the market. Further, the volume of

adverse event reports submitted to the FDA has increased steadily. As you can see

from the attached FDA graphic, the number of required reports from drug sponsors

of adverse events they received from physicians has climbed so rapidly that they

threaten the ability of drug safety staff to review and process those reports effectively.

RESOURCE LIMITATIONS GREATLY AFFECT FDA’S CAPACITY

One of the efforts of which I was most proud during my tenure at the Food and

Drug Administration was a study commissioned by then-Commissioner Jane

Henney, in which she charged senior drug, device and biologics officials with a thorough re-evaluation of FDA’s safety monitoring systems. That assessment, completed

in 1999, resulted in a series of recommendations for major changes in our post-market safety programs, including:

• Closer monitoring of newly marketed products, particularly those for which safety ‘‘signals’’ suggest greater risk

• Obtaining access to health care databases, such as those of the Medicare program and the Veterans Administration

• Development of a new active surveillance capacity, to complement the existing

passive surveillance systems (which would also be improved)

• Funding for epidemiological and methodological research to improve FDA’s tools

for understanding medical product risks

• More intense intervention in higher risk products identified by postmarket surveillance as needing special attention, such as stronger warning labels or restricted

distribution, and

• Funding to conduct focused safety studies when needed

Commissioner Henney requested a substantial boost in FDA appropriations to

fund these recommendations, the implementation of which would clearly have required a substantial increase in FDA’s safety surveillance staff, but these requests

unfortunately did not yield any additional funding .

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Ironically, those recommendations are very similar to the drug safety provisions

of the current Senate and House bills that are being considered along with the Prescription Drug User Fee Act. I ask you to imagine, Mr. Chairman, the frustration

of the FDA drug safety staff who were denied the capacity to make those improvements, only to see the very same concepts emerge years later in Congressional legislation. One can also imagine that we as a nation would be in a far better place if

the necessary funding had been provided by Congress in those years past, as the

proposed programs could be up and running today, and might well have permitted

much more rapid identification of many, if not all, of the recent drug safety problems that we have experienced, meaning that far fewer individuals would have been

exposed to excess risk.

In conclusion, Mr. Chairman, while there are many, many issues that the Committee must grapple with in considering drug safety legislation this year, I urge you

to make resourcing the drug safety programs at FDA one of your highest priorities.

The agency’s scientists very much want to make the kinds of improvements you are

contemplating, and will do so with intensity and enthusiasm if you provide to them

the staff and resources to carry out your mandate.

Thank you for inviting me to present my views on this important matter.

Mr. PALLONE. Thank you. Dr. Loew.

STATEMENT OF CAROLINE LOEW, SENIOR VICE-PRESIDENT,

SCIENTIFIC AND REGULATORY AFFAIRS OF THE PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA

Ms. LOEW. Thank you. Mr. Chairman, Ranking Member Deal,

and members of the subcommittee, I want to thank you for the opportunity to testify today about the vitally important issue of maintaining the safety of Americans’ medicine supply. My name is Dr.

Caroline Loew, and I am the senior vice president of scientific and

regulatory affairs at the Pharmaceutical Research and Manufacturers of America, or PhRMA.

PhRMA shares the view of the importance of drug safety. It is

also a top priority for all our member companies. PhRMA is committed to working with the Food and Drug Administration and all

other stakeholders to continually improve our drug safety system

in a way that preserves innovation and patient access to medicine.

As we address this critical topic, however, it is important to remember that drug safety fundamentally involves a balance between benefit and risk. Neither can be considered in isolation.

Firstly and most importantly, we support the FDA’s proposal to reauthorize the Prescription Drug User Fee Act, also known as

PDUFA, because it most effectively addresses the issues that are

critical in improving drug safety in America today.

The PDUFA proposal will make a good system even better by addressing FDA’s most pressing drug safety needs: additional resources and access to the latest scientific tools and technologies.

The current drug safety is stronger but could be made even stronger by the passage of PDUFA. The agency already has robust and

effective systems in place for drug approval and monitoring of

medicines once they are on the market. Drug safety is an extensive

ongoing process that starts long before a medicine enters the market and continues long after it has been made available. It does not

begin with or end when the new medicine is approved.

Before patients can receive new medicines, they undergo rigorous

safety and effectiveness testing and evaluation. It often spans 10

to 15 years. Drug safety, or more precisely the benefit/risk balance,

is only determined after extensive testing in laboratories, animals,

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patients, and after FDA regulators have studied tens of thousands

of pages of scientific data for each drug.

In fact, fully one-half of FDA’s drug review project is devoted to

drug safety. Agency officials also have broad statutory authority to

monitor and ensure the safety of drugs after they are approved.

There are extensive adverse event reporting requirements, annual

reports filed by companies, and for the vast majority of approvals,

post marketing studies are conducted.

The impact of this systems is undeniable. Over the last two decades, only about 3 percent of the medicines approved for the American market have been withdrawn for safety reasons. That is an

enviable record by any estimation. It is also important to note that

drug safety assessments today are more effective than ever before,

thanks to new scientific tools and technologies.

What we need to do now to improve drug safety is to continue

developing and better utilizing these new modern techniques, and

we need more resources devoted to drug safety. The PDUFA proposal that FDA has put forward would help advance these crucial

goals. It would provide about $150 million over 5 years to hire 82

additional staffers for post-market drug safety activities, and it

would increase the use of large medical databases, which contain

a wealth of drug safety information.

The proposal put forward by the FDA also addresses all of the

Institute of Medicine’s most important recommendations for more

agency resources and improvements in the science of drug safety.

Any additional drug safety reforms considered by Congress should

strengthen FDA’s product oversight capabilities without harming

innovation or access to medicines.

PhRMA would support very targeted legislative revisions that

clarify FDA authority in the areas of clinical drug exposure, postmarket studies, labeling and distribution restrictions. For their

part, PhRMA and its member companies have contributed to the

drug safety improvement effort in recent years by initiating a number of major programs from clinical trial disclosure to biomarket research to research studies on new drug safety tools and methodologies to training programs for better adverse event detection and reporting.

In the end, we all want the same thing: the timely delivery of

safe and effective medicines to patients suffering from a wide range

of medical conditions and diseases. We have a system that is accomplishing that critical goal. FDA does need more resources to increase the use of today’s modern technology. And that is what the

FDA’s PDUFA proposal would provide, and we urge Congress to reauthorize the PDUFA proposal as quickly as possible.

Thank you for this opportunity to inform the subcommittee about

PhRMA’s perspectives in this critical public health arena. Thank

you.

[The prepared statement of Ms. Loew follows:]

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Mr. PALLONE. Thank you. Ms. Thompson.

STATEMENT OF DIANE THOMPSON, VICE-PRESIDENT, PUBLIC

POLICY AND COMMUNICATIONS, ELIZABETH GLASER PEDIATRIC AIDS FOUNDATION, SPEAKING ON BEHALF OF THE

ALLIANCE FOR DRUG SAFETY AND ACCESS

Ms. THOMPSON. Good afternoon, Mr. Chairman, Ranking Member

Deal, and members of the committee. Thank you for the opportunity to participate in today’s hearing. I am Diane Thompson, vice

president for public policy and communications at the Elizabeth

Glaser Pediatric AIDS Foundation. Today I am testifying on behalf

of the Alliance for Drug Safety and Access, a coalition of 11 patient

and provider organizations, whose members advocate on behalf of

over 30 million patients, suffering from hundreds of serious and

life-threatening and rare diseases. Alliance members also represent

over 100,000 providers of care to children and individuals with

mental illnesses.

The Elizabeth Glaser Pediatric AIDS Foundation has been focused on speeding patient access to safe medicine since its inception in 1988. The foundation’s creation was sparked by Elizabeth

Glaser’s outrage over the lack of safe and effective options for treating her two HIV-infected children. We know this committee shares

our goals of ensuring that patients continue to have timely access

to new therapies while strengthening and improving the drug safety system. Simply put, we do not accept that patients should have

to choose between safety and speedy access to new medications.

The history of our foundation, of the HIV/AIDS community and

that of many in our coalition is the story of the power of patients’

contributions to regulatory and scientific decision-making.

One mom’s determination to fight for her child’s survival helped

transform drug development for children. No one stands to benefit

or lose more than patients in drug safety decisions, and patients

must have a strong voice in decisions about safety and risk management.

In its September 2006 report on drug safety, the Institute of

Medicine proposed a fundamental paradigm shift in this country’s

approach to drug safety. We agree. Attention to safety must be integrated throughout the life cycle of every drug, and it must be recognized that continuous assessment of benefit and risk is every bit

as important once a product is on the market and in the hands of

patients as it is during the drug review phase.

FDA must be given the authority to require drug manufacturers

to continue to study the safety of products after approval, to force

changes to drug labels when safety issues are uncovered, and to require that the results of clinical trials be shared with patients who,

after all, are the people who make the clinical trials possible.

Giving the FDA adequate authorities and flexible tools to enforce

them, including civil money penalties, will benefit both patients

and the industry. By providing FDA the flexibility to impose fines

for noncompliance, we can avoid the worst possible outcome for everyone: having to pull a drug from the market that still holds some

benefit for some group of patients.

We also agree with the IOM’s recommendation that FDA safety

staff must have a greater formal role in drug review and in risk

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management decisions. Finally, safety-related performance goals

must be added to PDUFA. The IOM report notes that a recent

study found that 21 percent of prescriptions are written for offlabel uses. Any effort to reform the drug safety system that fails

to address one-fifth of the use of drugs in real world settings would

leave a significant safety gap, a safety gap that would particularly

affect children since still far too few drugs are ever tested in children before they are allowed on the market.

The FDA’s authority to require post-market safety studies must

clearly and unequivocally extend to both on-label and off-label uses.

We ask that the subcommittee make the public dissemination of

trial results a cornerstone of its drug safety efforts by establishing

a clinical trials results database. By linking the registration of new

trials with final outcomes, the database would provide patients and

providers with additional information with which to assess benefits

and risks and could help prevent selective reporting of positive results and the problems that have resulted from the withholding of

negative trial results. Given that clinical trials would not exist

without patients’ willingness to give of their time and health, such

a mechanism could help restore patients’ trust in the integrity of

the clinical trials process.

For FDA to succeed in implementing these reforms, it is essential

that new and expanded safety activities be explicitly paired with

increased resources, both in user fees targeted to drug safety activities and in appropriations. The need for new authorities and for the

increased funding are inextricably linked, and we strongly urge the

subcommittee to consider these issues along with legislation to improve the safety and access of pediatric drugs and devices as a part

of a single package.

Mr. Chairman, members of the committee, the committee has before it an historic opportunity to finally match our Nation’s success

in speeding new therapies to patients with a system that can better

ensure the safety of those products once they are on the market.

We appreciate your interest in the patients’ perspectives on these

critical issues and look forward to working with you to accomplish

these goals. Thank you again for the opportunity to share our

views.

[The prepared statement of Ms. Thompson follows:]

STATEMENT OF DIANE E. THOMPSON

Mr. Chairman, Mr. Deal, and members of the subcommittee, thank you for the

opportunity to participate in today’s hearing. I am Diane Thompson, vice president

for public policy and communications at the Elizabeth Glaser Pediatric AIDS Foundation. Today, I will be testifying on behalf of the Alliance for Drug Safety and Access (ADSA), a coalition of 11 patient and provider organizations. Collectively, members of ADSA advocate on behalf of over 30 million patients, including those suffering from HIV/AIDS, Parkinson’s disease, spinal cord injuries, paralysis, multiple

sclerosis, leukodystrophies, Tourette Syndrome, and over 6,000 known rare diseases.

In addition, our members represent over 100,000 providers of care to children and

individuals with mental illnesses.

As a representative of the Elizabeth Glaser Pediatric AIDS Foundation, I am also

proud to offer the perspective of an organization that has been focused on speeding

patient access to safe medicines since its inception in 1988. This issue is at the

heart of our mission—the Foundation’s creation was sparked by Elizabeth Glaser’s

outrage over the lack of safe and effective options for treating her two HIV-infected

children. Although Elizabeth’s efforts were too late to save her daughter, Ariel, who

died from AIDS at the age of 7, her legacy includes her son Jake, now 22 years old,

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and the thousands of HIV-infected children around the world who now have the

chance to grow up healthy and even start families of their own, thanks to the search

for lifesaving pediatric medicines that Elizabeth Glaser and the Foundation championed.

I would like to thank the chairman, the ranking member, Mr. Waxman, Mr. Markey, and other members of the subcommittee for your leadership on this issue, for

moving beyond the headlines to examine our nation’s current drug safety system

and discuss meaningful solutions to ensure that the Food and Drug Administration

(FDA) remains the world’s gold standard for public health protection. Your task is

not an easy one and we appreciate the historic nature of this undertaking.

We have the opportunity before us to both maintain timely access of patients to

new therapies, while strengthening oversight of drugs already on the market. We

believe that with sufficient resources both goals are achievable. Simply put, we do

not accept that patients should have to choose between safety and speedy access to

new medications.

Patients with serious illnesses understand that bringing drugs to market in a

timely way means that not every risk can be identified in advance. What they also

demand, however, is sufficient information for themselves and their providers to assess risks and benefits on an ongoing basis—which often means further testing of

the drug after approval. Yet, the FDA has virtually no authority to compel drug

manufacturers to continue to study the safety of products after they have been approved, force changes to drug labels if dangerous side effects are uncovered, or require that the results of clinical trials be shared with the patients who make them

possible.

Giving FDA these authorities and flexible tools to enforce them, including civil

money penalties, as legislation pending before the Committee would do, ultimately

benefits both patients and drug manufacturers. Allowing FDA to require additional

testing of drugs postmarket could actually allow the FDA to approve drugs more

quickly, knowing it will have the ability to act if there are new safety concerns once

the drug is in the hands of patients. Also, by giving FDA the flexibility to impose

fines for non-compliance, we can avoid the worst possible outcome for everyone: pulling a drug from the market that still holds some benefit for some group of patients.

We believe that the core of any effort to improve drug access and safety must be

a shift to a ‘‘life-cycle’’ paradigm, with an emphasis on the continuing pursuit of

knowledge about a drug’s risk-benefit profile and timely communication of that information to patients and providers. This approach, which is recommended by the

Institute of Medicine (IOM), has been included in drug safety legislation introduced

by Mr. Waxman and Mr. Markey. In our view, individualized risk evaluation and

mitigation strategies, rather than a one-size-fits-all approach to patient safety, will

be key to the appropriate balancing of drug risks and benefits that is so critical to

patients with life-threatening illnesses.

To further improve the depth and breadth of input into drug safety decision making, we ask the Committee also to adopt the IOM’s recommendation that the Office

of Surveillance and Epidemiology (OSE) be given a greater role in drug review and

the development of safety plans. The lack of communication and cooperation between that office and the Office of New Drugs, highlighted in both the IOM report

and a March 2006 report by the Government Accountability Office, is deeply troubling. At minimum, we recommend that the Committee formally assign OSE staff

a role in the review of new drugs applications and post approval regulatory actions,

as the IOM recommends.

We ask the subcommittee also to ensure that any drug safety legislation includes

mechanisms for greater public input and transparency. The history of our Foundation and of the broader HIV/AIDS community is the story of the power of patients’

contributions to scientific decision making. Although they began as three mothers

around a kitchen table with no formal training in science and medicine, Elizabeth

Glaser and the other founders of the Foundation ultimately changed the accepted

thinking of both the National Institutes of Health and FDA about the risks of not

studying AIDS drugs in children—a success story that is repeated throughout the

histories of patient organizations. Given that no one stands to benefit or lose more

than patients in drug safety decisions, we ask that you consider a significant role

for patients in the assessment and management of drug risks.

We also urge the committee to clarify that any new authority of FDA to require

studies of post-market safety concerns is not confined to on-label uses of the drug.

In our efforts to improve the drug safety system, we need to pay particular attention

to not only what happens inside the FDA, but also what goes on in the real world.

A recent study found that 21 percent of prescriptions written in 2001 were for offlabel uses. Any effort to reform the drug safety system that fails to address onefifth of the use of drugs in real-world settings leaves a significant safety gap.

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Children would be left at particular risk by the failure to clarify this authority,

since as much as three-quarters pediatric prescribing is off-label. Thanks to the efforts of many on this Subcommittee, there are mechanisms available to both encourage and require manufacturers to study their products for children. However, there

are gaps in those mechanisms. The existing pediatric study requirement does not

apply to off-label uses. While the existing incentives can be applied to off-label studies, they are voluntary—and we are seeing that manufacturers are increasingly opting not to conduct the studies FDA requests. Unambiguous authority to require

such studies when the off-label use is significant will help ensure that children too

can reap the benefits of an improved drug safety system.

In our view the subcommittee must make the public dissemination of trial results

a cornerstone of its drug safety efforts. The establishment of a results database

would be a significant step forward in giving patients and providers additional information with which to assess benefits and risks. By linking the registration of new

trials with final outcomes, this database also could help prevent selective reporting

of positive results and the problems that have resulted from the withholding of negative trial results. And, not incidentally, given that clinical trials could not exist

without patients’ willingness to give of their time and health, such a mechanism

could help restore patients’ trust in the integrity of the clinical trials process.

While we work toward providing the FDA additional authorities and enforcement

tools, we must acknowledge that chronic under-funding is severely straining the

ability of the Agency to perform even its current functions. Years of essentially flat

funding, coupled with new challenges such as increasingly global markets, the

threat of bioterrorism, and the promise of personalized medicine, have left the Agency struggling to meet its obligation to protect the public health. We—Congress, the

Administration and patients—must work together to give the FDA the resources it

needs to accomplish its critical mission. We suggest the combination of an increase

in user fees targeted to drug safety activities and an increase in appropriations. Because we believe that the need for new authorities and for increased funding are

so inextricably linked, we strongly recommend the subcommittee consider these

issues, along with legislation to improve the safety and availability of pediatric

drugs and devices, as part of a single legislative package.

Mr. Chairman, you have before you a historic opportunity to finally match our nation’s success in speeding new therapies to patients with a system that can better

ensure the safety of those products once on the market. We appreciate your interest

in patients’ and providers’ perspectives on these critical issues and look forward to

working with you to accomplish these goals.

Thank you again for the opportunity to share our views.

Mr. PALLONE. Thank you. Thanks a lot. Mr. Theriault.

STATEMENT OF JOHN THERIAULT, CHIEF SECURITY OFFICER

AND VICE PRESIDENT, GLOBAL SECURITY, PFIZER

Mr. THERIAULT. Thank you, Chairman Pallone and Ranking

Member Deal and members of the subcommittee. My name is John

Theriault. I am the vice president of global security at Pfizer. Prior

to joining Pfizer, I was a special agent with the FBI for 25 years,

retiring in 1995 as a member of the Bureau’s Senior Executive

Service. It is a pleasure to appear before you today to talk about

a critical issue: drug safety and efforts to protect the U.S. pharmaceutical supply from counterfeit medicines.

When I joined Pfizer in 1996, the company did not have an anticounterfeiting program, frankly because there were no indications

that any of our products were being counterfeited. That changed in

1998 when we launched Viagra, and I think that understanding

what happened with that product at that time will help in understanding the counterfeit medicines industry that has evolved since

then.

Viagra was a unique product in 1998, and it was in great demand all over the world. But because of regulatory requirements,

it was not legally available in many countries. So what we saw imVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00131 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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mediately was a global demand that was filled by entrepreneurs

who purchased the product in a country where it was available and

resold it sometimes at 10, 20 times what they had paid for it in

countries where it was not available.

Very soon thereafter, we saw our first counterfeiting case. It involved a UK organized crime figure who was convicted of conspiring to import counterfeit Viagra from a legitimate Indian company.

Now, over the next few years, we conducted several investigations

to identify Viagra counterfeiters and distributors. But in doing so,

what we discovered was that they were counterfeiting and distributing other counterfeit medicines that we were not aware of. The

Viagra investigations actually opened a door for us to look into a

very robust counterfeiting industry that we didn’t know existed.

Since the inception of our anti-counterfeiting program, we have

discovered counterfeit versions of our medicines in more than 60

countries. The medicines span a wide range of therapeutic areas,

and they include Aricept, Lipitor, Norvasc, Diflucan, Ponstan,

Cabaser Celebrex, Dilantin, Vibramycin and Zoloft. This is an issue

that goes well beyond erectile dysfunction drugs. It is a counterfeiting issue that affects virtually every therapeutic area you can think

of.

Now, it is Pfizer’s goal to make sure that every patient who buys

a Pfizer product receives an authentic Pfizer product, and we consider the counterfeiting problem to be so serious today that our

program to investigate and deal with it has increased from one security professional in New York in 1999 to 17 security professionals

based in the United States, Mexico, the United Kingdom, Germany,

Turkey, mainland China, Hong Kong, India, Thailand, and Malaysia.

To give you some idea of the scope of the problem, in 2006 alone,

law enforcement and customs authorities, with whom our investigators are working, conducted 238 raids, made 501 arrests, seized

over 8.1 million units of counterfeit Pfizer products and enough active pharmaceutical ingredient to manufacture more than 15 million counterfeit Viagra tablets and more than 20 million counterfeit

Norvasc tablets.

During those raids, counterfeit versions of other companies’

medicines were discovered as well. Counterfeiting is a serious

crime, and as you can see from this display, counterfeiters take

great care in replicating the appearance of genuine product. The

counterfeit product there is on the left. The authentic is on the

right, and it is virtually impossible to differentiate those by visual

inspection.

But what you can see from the next display is that the counterfeiters don’t really take quite as much care in the manufacturing

process. Counterfeits are inherently dangerous. They are manufactured in unknown locations using unknown ingredients. We have

seen counterfeits that contain no active pharmaceutical ingredient

and therefore did not deliver the therapeutic benefits for which

they were prescribed. Some contain super potent amounts of active

ingredient, which increase the risks of adverse events, and yet others contain toxic ingredients that are harmful in themselves.

Our experience indicates that the counterfeit medicines problem

is growing, and it is being facilitated by the Internet, which proVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00132 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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vides both business-to-business distribution capabilities as well as

retail opportunities, via bogus online pharmacies.

Counterfeiters are also exploiting a loose distribution channel to

get their bad medicine into the hands of patients. The evidence

clearly reveals that the more times medicines change hands in the

distribution system, the more opportunities there are to introduce

counterfeits.

Now, I said the problem is growing, and the reason for that is

simple. This is a very, very high-profit, low-risk criminal enterprise, and we shouldn’t lose sight of the criminal nature of this as

we debate drug safety. How profitable is this for counterfeiters?

That graphic shows that if you were to invest $20,000 in a kilo of

cocaine—not that anybody would do that, but that is about what

it costs these days. $20,000 for a kilo of cocaine would yield $60,000

in sales. Subtract the cost, and you have got a $40,000 profit. You

can buy from any Indian company on the Internet the active ingredient for Viagra, $64. That would produce 14,000 50-milligram

Viagra tablets at $10 apiece, $140,000 in revenue. Subtract the

$64, and you have got a much greater profit margin doing counterfeit drugs. This is a crime that attracts serious criminals.

Now, the facts here are irrefutable. The importation of counterfeit, infringing, misbranded, non-approved, pharmaceutical products in the United States is increasing exponentially. Those products, by definition, pose a risk to public health and safety. The response by regulatory and law enforcement agencies to this growing

crisis has to be reviewed, analyzed and modified at all levels.

To sum up quickly, instead of discussing ways to deregulate the

current safety system, we think that we ought to be discussing

ways in which the current system could be improved to mitigate

these threats to patients. Mr. Chairman, Ranking Member, members of the committee, thank you for the opportunity to share this

with you.

[The prepared statement of Mr. Theriault follows:]

STATEMENT OF JOHN THERIAULT

Chairman Pallone, Ranking Member Deal, and members of the subcommittee, my

name is John Theriault. I am the chief security officer and vice president of global

security at Pfizer Inc, the world’s largest pharmaceutical company. It is a pleasure

to appear before you today to discuss an issue of critical importance: drug safety

and efforts to protect the United States pharmaceutical supply from contamination

with counterfeit products.

Prior to joining Pfizer, I spent more than 25 years as a Special Agent of the Federal Bureau of Investigation. During my FBI career I had substantial experience in

international law enforcement and served for a number of years as the Legal Attache in Ottawa, Canada and London, England.

Mr. Chairman, while my testimony today focuses on our experience with counterfeit Pfizer products, I wish to impress upon the subcommittee that these problems

are not limited to Pfizer. They threaten the entire pharmaceutical industry and

most importantly, the U.S. patients who depend upon that industry.

As the subcommittee is well aware, there is already importation of counterfeit and

diverted medicines into the United States through the mail, courier services, and

some unethical re-packagers and wholesalers. Millions of Americans who assume

that the prescription medicines they buy online are safe and effective are at risk.

Regardless of the method of obtaining drugs from Canada or other countries, there

is a real potential for fraud or harm. I would emphasize that every time a medicine

changes hands represents—an additional opportunity for counterfeit products to be

introduced into distribution.

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COUNTERFEIT PHARMACEUTICAL PRODUCTS: WHAT IS THE SCOPE OF THE PROBLEM?

The problem of counterfeit medicines, once thought to be limited to developing

countries with weak regulatory systems, is now recognized as a global problem from

which no country is immune. The manufacture of counterfeits is not limited to

China and India. They are produced in at least twenty-four countries, including

Canada, the United Kingdom, and four other members of the European Union—Belgium, the Netherlands, Poland, and Portugal.

Since 1998, when the first counterfeit Viagra tablets were discovered in the

United Kingdom, Pfizer has developed a focused anti-counterfeiting program to protect the integrity of our products and supply chain. Staffing for that program has

increased from one security professional based in New York, to seventeen security

professionals based in the United States, Mexico, the United Kingdom, Germany,

Turkey, China, Hong Kong, India, Thailand, and Malaysia. Our Product Integrity

Steering Committee has set as Pfizer’s goal ensuring that every patient who buys

a Pfizer product receives an authentic Pfizer product.

We are waging a fierce battle against these counterfeiters. Pfizer products targeted by counterfeiters now include Aricept (Alzheimer’s disease), Lipitor (cholesterol), Norvasc (hypertension), Diflucan (antifungal), Ponstan (anti-inflammatory)

and Viagra (erectile dysfunction), Cabaser (Parkinson’s disease), Celebrex (pain),

Dilantin (epilepsy), Vibramycin (antibiotic), and Zoloft (depression).

Although it is difficult to measure the true scope of the counterfeiting problem,

the number of reported seizures by law enforcement of Pfizer products serves as a

useful baseline. During 2006, authorities from 36 countries reported seizing more

than 8.1 million counterfeit tablets, a 20.8 percent increase over 2005. That increase

was most significant in Europe, the Middle East and Africa, where seizures increased by more than 332 percent

A CASE IN POINT: DEADLY POISON MASQUERADING AS MEDICINE

Fake medicines are costing lives. In March 2007, we heard of a tragic story of a

woman’s death which, according to press reports, was caused by drugs she ordered

online from a bogus Canadian pharmacy. Instead of treatment for her arthritis and

allergies, Ms. Marcia Bergeron was slowly poisoned by products that contained dangerously high levels of strontium, uranium, and lead, heavy metals that had apparently been used as a cheap filler. Ms. Bergeron started losing her hair and had

blurred vision and died a few days after Christmas in 2006.

We fear that there may be more terrible stories like this one. I’m sure you all

have read the story from Sunday’s New York Times about the hundreds of deaths

in Panama from cough syrup from China that contained diethylene glycol.

It is virtually impossible to see differences between counterfeit and genuine medications. If you visited the manufacturing facilities, the differences would be

shockingly obvious. Drug counterfeiters do not care about safety or sanitation. They

only care about profits, and counterfeiting is highly lucrative. The profitability of

drug counterfeiting far exceeds that of the illicit drug trade. However, there is a

lower chance that these counterfeiters will get caught, and if they do, the penalties

are less punitive.

RXNORTH: PROFITS BEFORE PATIENTS

Another case involves the Internet pharmacy RxNorth. A company whistleblower

told a Canadian Television (CTV) news program that customers had received expired drugs, and that the expiry dates had been covered up on packages. In addition, the drugs were not Canadian. In fact, RxNorth was filling prescriptions for US

citizens with counterfeit versions of Lipitor, Celebrex and other products. The CTV

news program reported that many of the drugs RxNorth sold came from sources in

the UK or Australia and were shipped to a dispensing facility in Freeport, the Bahamas, where Internet orders were filled and shipped to US customers.

Counterfeiters often use a convoluted shipping path to evade the authorities and

trick customers. For example, on May 22, 2006, UK Customs intercepted a four-pallet shipment of pharmaceuticals, which had come to the UK from the United Arab

Emirates (UAE). The shipment consisted of eight products manufactured by five

major pharmaceutical companies: Pfizer, AstraZeneca, Novartis, Merck, and Proctor

& Gamble. The shipper was the Oyster Corporation, of Sharjah, UAE. The intended

recipient was Missouri-Bain Thomson, of the Personal Touch Pharmacy, in Freeport,

the Bahamas. Investigation by the authorities determined that Personal Touch

Pharmacy computers were connected to Rx North’s servers. This is commonplace:

according to a 2005 FDA study, fewer than two percent of the thousands of Web

sites advertising cheap Canadian drugs are actually based in Canada.

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Our infrared spectral analysis of the seized Lipitor tablets showed that the Lipitor

was counterfeit, and contained about 82 percent–86 percent of the claimed concentration of active pharmaceutical ingredient (API). The lot number printed on the

packaging of the counterfeit Lipitor’ was legitimate for a product produced for the

Middle East market, and the counterfeit packaging was elegant. Pfizer analysts examined the packaging and determined that the ‘‘i’’ in the word ‘‘atorvastatin’’ on the

blister foil was placed differently, indicating a difference in font size; and the breakage-line between the single cavities showed that the authentic blister has a tighter

punching line than the sample. The counterfeit packaging also contained a patient

information leaflet, although it was smaller than a genuine leaflet, and missing a

page. The fact that the counterfeiters are using legitimate lot numbers is concerning, since it demonstrates a level of sophistication in their deception that makes the

counterfeits that much harder to detect.

On June 1, 2006, Pfizer investigators notified the Bahamian authorities of the

facts in this case, and on June 9th the Bahamian authorities raided the Personal

Touch Pharmacy in Freeport. There they seized $3.7 million worth of products,

spanning numerous different brands from 13 different manufacturers. The total

amount of product seized amounted to 3.025 million dosage units of products. The

Bahamian investigation determined that approximately $8 million worth of business

was conducted at Personal Touch Pharmacy on a yearly basis. The investigation is

ongoing.

We remain concerned that there are thousands of similar situations that remain

undetected, and that consumers like Ms. Bergeron will be victims to this fraud and

greed. As Congress develops drug safety legislation, it is essential that you carefully

consider this very dangerous situation that has yet to be adequately addressed.

The facts are irrefutable. The importation of counterfeit, infringing, misbranded,

and unapproved pharmaceutical products into the United States is increasing exponentially, and those products, by definition, pose a risk to public health and safety.

The response by regulatory and law enforcement agencies to this growing crisis

must be reviewed, analyzed, and modified at all levels. The public health and safety

depend upon the FDA’s vigilance. The FDA and Customs must receive the additional resources necessary to fulfill their current mandate. Regulations currently in

existence must be fully funded and fully enforced. The notion that somehow importation can be done safely by implementing so-called anti-counterfeit technology is

to ignore everything we know about counterfeiting and counterfeiters. Similarly, the

notion that importation on any scale will be as safe as the current system is to ignore all of the available evidence. Again, any time a medicine changes hands presents a new opportunity for the introduction of counterfeits into distribution. Instead of discussing ways to ‘‘de-regulate’’ the current safety system, we ought to be

discussing ways in which the current system can be improved to mitigate these

threats to patients.

Mr. Chairman, Ranking Member Deal, and distinguished members of the subcommittee, thank you for this opportunity to express our concerns about this critical

issue. I would be happy to answer your questions.

Mr. PALLONE. Thank you. I recognize Dr. Levine.

STATEMENT OF SHARON LEVINE, M.D., ASSOCIATE EXECUTIVE DIRECTOR, PERMANENTE MEDICAL GROUP, SPEAKING

ON BEHALF OF THE KAISER PERMANENTE MEDICAL CARE

PROGRAM

Dr. LEVINE. Mr. Chairman, distinguished committee members, I

am a physician with Kaiser Permanente in northern California,

and I oversee the Permanente Medical Groups’ efforts on drug use

management in partnership with my Kaiser pharmacist colleagues.

Our shared goal is the delivery of high-quality, safe and effective

drug therapy and pharmaceutical services to our members. In order

to do this, our physicians and pharmacists need the best available

information on the safety and effectiveness of the drugs we prescribe and dispense. The importance of this issue is increasing

every year. New, more powerful drugs are being approved and released to the market, and prescription drug therapy is playing an

ever-increasing role in therapy.

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An important benefit of our efforts to fully integrate pharmacy

services with health care delivery is that we are able to capture detailed and very complete information about the drugs we prescribe

and dispense since almost 98 percent of prescriptions written for

Kaiser members are filled in our pharmacies at our facilities, and

we are able to match that information with robust clinical and demographic data that is captured in our delivery system and our

health plan.

Because of our large and stable population, we have the ability

to generate enormous statistical power in research studies that we

do. We have begun in earnest to utilize these data to learn more

about the safety and effectiveness of specific prescription drugs and

to answer questions which, when applied clinical practice, will protect consumers from drugs that pose an unacceptable risk compared to the benefits the drugs provide.

We believe strongly that there is a need for an intentional, careful, and systematic data collection and review of a drug’s use,

which begins with its introduction into the market. This will enable

faster identification of safety problems that result from the use of

the drug outside the carefully controlled circumstances of phase

one through three trials—ideally before rapid uptake of the drugs

in the market exposes more people than necessary to unanticipated

risks.

Our researchers have access to and analyze data from multiple

sources; membership records, hospital discharge records, outpatient

and inpatient prescription data, outpatient clinic data, and laboratory and x-ray results. My written testimony provides detailed information on these data sources and how they are used. And I

want to share with you today two examples.

The Vioxx story is obviously very well known to this committee.

Almost everyone has mentioned it, and it has become the poster

child for the call to protect the public from unacceptable risk. A relatively limited population of Kaiser Permanente members were exposed to this drug. We had in place a Web-based tool to enable

physicians to identify the small subset of patients who actually

stood to benefit from the theoretical advantage that the drug provided, that of avoiding serious gastrointestinal side effects Yet millions and millions of patients in the general population received

this drug. Almost 107 million prescriptions for Vioxx were filled before the drug was pulled from the market.

In collaboration with the FDA, Kaiser Permanente researchers

and clinicians were able to confirm that Vioxx increased significantly the risk of coronary events, 5 years after introduction of the

drug into the market and 5 years after the VIGOR trial which first

raised the issue of vascular events.

Equally important, the same prescription drug and clinical data

can be used to erase safety concerns that are raised by spontaneous

reports of adverse events. In March 2005, the FDA issued an advisory to physicians urging caution in prescribing topical tachrolinus

and pimecrolimus, two topical agents used to treat eczema and

other skin conditions, because of concerns raised by animal studies

and isolated case reports in a small number of patients. Matching

up our pharmacy database with our cancer registry, we were able

to identify those patients who had received those two drugs and

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were also diagnosed with cancer. Our researchers actually found no

increase in the overall cancer rates but did find an increase in cutaneous T-cell lymphoma, a skin malignancy, among the drug

users.

By examining the medical records of these patients, and excluding those that the physicians suspected of having cancer prior to

the drugs, our researchers were able to find no increased risk either of cancer in general or of cutaneous T-cell lymphoma.

These are just two examples of what is possible using existing

data, and my written testimony contains many more examples. In

systems like Kaiser Permanente and the Veterans Administration

today, the rapidly approaching future of complete clinical data capture with electronic medical record systems will significantly enhance the ability of researchers to identify and quantify problems

and assess associated risk, which will inform better risk/benefit

analysis.

I want to thank the committee for taking these issues under consideration and for your interest in this, and I look forward to answering your questions.

[The prepared statement of Dr. Levine follows:]

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Mr. PALLONE. Thank you, Doctor. Dr. Powers.

STATEMENT OF JOHN POWERS, M.D. ASSISTANT PROFESSOR

OF MEDICINE, THE GEORGE WASHINGTON UNIVERSITY

SCHOOL OF MEDICINE, AND UNIVERSITY OF MARYLAND

SCHOOL OF MEDICINE

Dr. POWERS. Thank you, Mr. Chairman and members of the committee. My name is John Powers, and I am a physician scientist

who worked at the Food and Drug Administration for the last 8

years. My background is that of a practicing clinician and academic

investigator and researcher, a scientist in the field of drug development, a consultant for several drug sponsors, and most importantly, I have been a patient myself. I would like to thank you for

the opportunity to discuss with you today my perspective on the

issues of evaluating the risks and benefits of medical intervention.

The Institute of Medicine report on drug safety points out that

the current reauthorization of the Prescription Drug User Fee Act

is a golden opportunity to address long overdue improvements

needed in our system of evaluating drug safety. The GAO report

points out that there have been at least five separate reports since

1971 related to these issues. Therefore PDUFA should not be reauthorized without simultaneously addressing the important public

health issues related to drug safety that have persisted for some

time.

Previous drug legislation addressed the issues of pre-approval

safety in 1938 and pre-approval effectiveness in 1962. But it is now

clear that we need more focus on continuously evaluating drugs

even after approval.

For instance, the example of the inevitable emergence of antibiotic resistance points out how the assessment of both safety and

effectiveness of drugs can change over time. The standard we

should use to judge proposed changes in drug safety should be

would these changes prevent another safety episode like Vioxx of

Ketek? Tying pre-approval review that brings medical interventions to patients and appropriate post-approval evaluations of those

same interventions are not mutually exclusive goals, and we can do

both.

I would like to divide the issues related to addressing drug safety

into three categories. First, inputs of resources in authority into

FDA. Second, internal use of science resources and processes inside

FDA. And third, outputs of decisions and communications with the

public from FDA.

In terms of inputs into FDA, Congress should authorize adequate

funding for general appropriations, and any PDUFA fees should

have no strings attached, and their use should not be negotiated

with regulatory industry. FDA needs the authority to require postapproval studies, to mandate labeling changes, and to assess simple monetary penalties for not fulfilling risk management activities.

The legislation proposed by Mr. Markey and Mr. Waxman is a

start in this direction by providing more meaningful penalties. FDA

needs access to modern databases and active surveillance to more

efficiently gather information on drug use and potential adverse

events.

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Any organization is only as strong as the people who work there,

so FDA needs to hire adequately trained staff and ensure the staff

remain engaged as a part of the scientific community. This leads

to issues involving science and process inside of FDA. FDA scientists should be free to participate as members of the scientific

community by having the right to publish and share their information and participate in scientific meetings.

There needs to be a culture of professionalism at FDA. And if,

on rare occasions, after attempting to reach internal agreement,

FDA staffers need to seek help outside of FDA in order to protect

the public’s health, there needs to be enhanced whistle-blower protections, such as those outlined in Mr. Markey’s Swift Approval

Full Evaluation Act.

There also needs to be accountability for FDA staff who attempt

to retaliate against their colleagues or who do not uphold the laws

and regulations. For instance, in cases where drugs have been

knowingly approved without substantial evidence of effectiveness.

Any system should have checks and balances, and the Office of

New Drugs and the Office of Surveillance and Epidemiology should

have joint decision-making authority regarding post-approval decisions. FDA needs to define what they mean by best use of science

and define the criteria used for making risk/benefit decisions in

general.

In terms of outputs from the FDA, we need transparency of decision making in the form of summary bases of approval published

on the FDA Web site in a timely fashion, which explain the scientific rationale for regulatory decisions. This would be helpful for

both regulated industry and for patients. All clinical trials and

their results should be included in a registry.

It is FDA’s job to communicate with the public, and FDA needs

the resources to evaluate the effectiveness of all of the methodologies used to try to accomplish this goal, as it is well known that

changes in labeling alone have little effect on prescribing behavior.

The IOM report reinforces that now is the time to address sorely

needed improvements in evaluating drug safety. Congress should

include provisions for strengthening drug safety in any reauthorization of PDUFA. We can address issues in evaluating drug safety

in an efficient way without hindering access to important medical

advances for patients.

Making these changes today will help us to avoid another Vioxx

or Ketek tomorrow. Congress can help FDA start down the road of

being the foremost authority on pharmacoepidemiology, to help

them work closely with the scientific community, and to develop

scientifically-based approaches to evaluating the balance of risk

and benefits for drugs.

This will help FDA achieve its stated mission of protecting and

advancing the public health. Most FDA staffers are incredibly hard

workers and courageous public health servants. Please give them

the tools they need to do their jobs for all of us. Thank you.

[The prepared statement of Dr. Powers follows:]

STATEMENT OF JOHN H. POWERS, M.D.

Good morning Mr. Chairman and members of the committee. My name is John

Powers. I am a physician-scientist who worked at the Food and Drug AdministraVerDate 11-SEP-98 10:21 Oct 16, 2008 Jkt 000000 PO 00000 Frm 00150 Fmt 6633 Sfmt 6633 Q:\DOCS\110-43 SCOM1 PsN: SCOM1
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tion for the last 8 years. My background is that of a clinician in internal medicine

and infectious diseases, an investigator and researcher in clinical trials, a scientist

in the field of drug development, and a consultant for several drug sponsors. Perhaps most importantly, I have been a patient myself. I would like thank you for the

opportunity to discuss with you today my perspective on the issues of evaluating the

risks and benefits of medical interventions.

As the Institute of Medicine report on drug safety points out, the current reauthorization of the Prescription Drug User Fee Act is a golden opportunity to address

long-overdue improvements with drug safety in order to adequately protect the

public’s health. PDUFA should not be reauthorized without simultaneously addressing the important public health issues related to drug safety. The standard we

should use to judge proposed changes to the evaluation of drug safety should be:

Would these changes prevent another drug safety episode like Vioxx or Ketek?

Bringing medical interventions to patients in a timely way and appropriate post-approval evaluations of those same interventions are not mutually exclusive goals, and

addressing post-approval drug safety need not slow bringing new medications to patients. Indeed, the FDA Critical Path initiative points out that better tools for preapproval evaluation of potential safety issues may allow more efficient drug development, earlier cessation of drug development programs of drugs with toxicities before

spending precious resources, and more focused evaluation of drug toxicities post-approval.

The passage of the Food, Drug and Cosmetic Act (FD&C) in 1938 shifted the burden of the evaluation of pre-approval safety of drugs from the government to drug

sponsors. From that time forward there was no assumption that a drug was safe,

and sponsors had to provide evidence of the potential adverse events associated with

drug use. This reflected a notion that is clear today; no drug is completely safe in

that all drugs are associated with some adverse events. In 1962, Congress amended

the FD&C Act to require substantial evidence of effectiveness based on adequate

and well-controlled trials, codifying the logic that there must be evidence of benefit

in order to justify any risks of drugs, no matter how rare.

Both these provisions focused on the pre-approval evaluation of medical interventions, which was appropriate for that time. However, it is now clear that we need

to focus on the entire life-cycle of medicines with a greater focus on post-approval

evaluations. This is eminently sensible as we cannot learn all we need to know

about medical interventions given the limited number and types of patients and the

short time span in which drugs are studied pre-approval. The vast majority the lifecycle of a drug is spent post-approval, and it follows we can learn much about a

drug during this time. FDA must play a crucial role in continuing to evaluate drugs

once they are approved.

The need for regulation is two fold: first, regulation is needed when market forces

tend to guide businesses in a way that may be contrary to public interest, and second, regulation provides a uniform standard for public health and consistency and

fairness for the regulated industry. In regards to the first point, there is little incentive for drug sponsors to rigorously evaluate potential safety issues with a drug once

it is approved since from a business perspective this evaluation has the potential

to decrease sales. This is in contrast to providing evidence of drug effectiveness prior

to approval which is necessary both for FDA approval for marketing and to convince

clinicians to use the drug. Many drug sponsors certainly do include protecting the

public’s health in their decision making. But as James Madison stated in the Federalist #51 in 1788, if all men were angels no government would be necessary. Even

one sponsor who decides that profits trump public health is one too many and it

is the FDA’s job to ensure all sponsors are held to the same standard. This relates

to the second point, which is that FDA is supposed to ensure a scientifically based

and consistent standard of public health both for the sake of the public health, and

out of fairness to drug sponsors so that every sponsor is subject to the same rules.

This allows less uncertainty in drug development, and allows sponsors to plan their

studies accordingly. The only way to ensure both protecting and advancing the public health and fairness to drug sponsors is to base laws and regulation upon the best

science. Since science changes over time as we learn new things, regulations need

to adapt as well. The prior focus on pre-approval evaluations is still needed, but we

now need to focus our attention of post-approval evaluations as well.

One can view the issues related to addressing drug safety as divided into three

categories: inputs of resources and authority into FDA, internal use of resources,

science and functioning inside FDA, and outputs of decisions and communications

with the public from FDA.

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I. INPUTS INTO FDA

FDA staff need the resources in terms of funding, manpower, knowledge, data and

authority to do its job properly.

Congress should authorize adequate funding for FDA from general appropriations

and PDUFA fees should have ‘‘no strings attached’’ and not be negotiated with regulated industry: FDA has been severely under-funded for some time, even to do the

job it already has to do. Indeed, the original intent of PDUFA in 1992 was to bring

greater funding to FDA to provide it the resources it needed at that time. To address the larger issues of post-approval evaluations of drugs it will need greater

funding. It seems logical that regulated industry should pay for a fee for licensing

of drugs to defray the costs to the government, similar to how drivers pay a fee for

their drivers’ license of doctors pay a fee to State medical boards for a license to

practice medicine. However, drivers and doctors do not negotiate the uses to which

those fees are put with Division of Motor Vehicles or the State Medical Board. In

addition to the obvious appearance of conflict of interest of allowing the regulated

to help decide where the regulator appropriates funds, the long time frame between

PDUFA negotiations—done only once every 5 years—does not allow FDA to adapt

and shift resources to where they are most needed. Again, there is a need for regulation when there is no incentive for the regulated to address issues of public health,

and previous negotiations of PDUFA in which FDA was barred from applying fees

to post-approval safety evaluations are evidence of a desire by some to avoid performing these evaluations.

FDA needs adequate authority to ensure the public health including ability to assess sufficiently stringent civil monetary penalties for non-adherence and sufficient

authority to ensure device effectiveness—FDA needs the authority to require postapproval studies and ensure sponsors complete those studies. As noted previously,

there is an obvious incentive for drug sponsors to submit data in support of drug

effectiveness. Since there is less incentive to perform post-approval studies, FDA

needs the ability to require studies and impose meaningful penalties on drug sponsors who do not fulfill their stated commitments. The Enhancing Drug Safety and

Innovation Act (H.R. 1561) is a start in this direction by providing for more meaningful penalties beyond those that sponsors could just write off as the cost of doing

business. Penalties need to be appropriate in order to provide an incentive to comply. In addition, the current legally mandated standards for effectiveness of devices

are quite different for those from drugs. It is not clear from a scientific point of view

why this should be so, as patients who receive devices should receive the same protection under the law as those who receive drugs. Recent approvals of some devices

have left outstanding questions regarding their effectiveness, such as the vagal

nerve stimulator for depression. This seems to contradict the basic principle that

there needs to be substantial evidence of effectiveness in order to justify the risks

of any intervention. Congress should address this by changing the law to hold devices to the same standard of substantial evidence of effectiveness from adequate

and well controlled trials as for drugs.

FDA needs adequate data upon which to base decisions—The use of modern databases to more efficiently gather information on drug use and potential adverse

events is desperately needed. FDA cannot rely on the good graces of busy clinicians

for spontaneous reports of adverse events. Many medical schools do not teach their

trainees about the need to report adverse events, so there is a need for education

as well. FDA always needs to stay in touch with practicing clinicians, but they cannot be the only source of information in evaluating medical interventions post-approval. In addition, for reasons discussed previously drug sponsors cannot be the

sole source of information. There is little incentive for them to report adverse events

and there are recent unfortunate examples in which important information was

withheld from FDA. If FDA had independent sources of information this would be

less of a concern.

FDA needs to hire adequately trained staff—It is important that FDA hire, train

and keep staff who have a background and training in drug development and evaluation. It is sad to say that many in academic medicine view a career at FDA for

their trainees as ‘‘a waste of time’’ and ‘‘unscientific’’. FDA needs to be on the same

scientific par as the National Institutes of Health and the Centers for Disease Control and Prevention in terms of scientific reputation and in terms of appropriately

applying science. The only way to accomplish this goal is if the scientific community

has positive interactions with FDA staff, instead of the current ‘‘black box’’ that clinicians see as the current FDA.

FDA needs close contact with the scientific community—FDA has to have a symbiotic relationship with clinicians and scientists. As science is ever-changing, FDA

staff need to keep abreast of the latest scientific developments. In addition, FDA

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staff have much to teach the scientific community about clinical trials and the

pharmacoepidemiology, and much of the view that FDA is ‘‘unscientific’’ comes from

a lack of understanding of the scientific principles upon which appropriate drug

evaluation is based. This means that FDA staff need to be able to interact with scientist in their fields, an issue I will address in terms of outputs from FDA as well.

II. SCIENCE AND PROCESS INSIDE FDA

FDA has become too focused on ‘‘process’’ to the exclusion of the reason for why

process is needed. The process as FDA should serve good science which in turn protects and advances the public health. Science should not serve process. Appropriate

processes are needed in order to drug sponsors to submit data and for FDA staff

to review this data in an orderly way. However, on the Center for Drug Evaluation

and Research guidance page there are 53 guidances under the heading of ‘‘process’’

and 3 under the heading of ‘‘drug safety’’. Clearly this balance seems tilted in the

wrong direction. FDA managers needs to treat the scientists and review staff with

professionalism and the basis for decision making needs to be good scientific principles

FDA managers need to treat staff with professionalism—Science is based on the

scientific method, and as such, any one who uses this method, from the medical student to the senior attending, can make equally valid analyses and draw equally

valid conclusions. As with school teachers, if most of their class fails the examination, they must take part of the blame. If FDA managers believe their staff is not

using appropriate scientific analyses, then it is incumbent on these managers to

train staff in these same principles and provide mentoring for them and career development paths. It is inappropriate and unprofessional to characterize scientists

who raise scientific issues as ‘‘disgruntled’’ or to characterize a scientist work as

‘‘junk science’’. FDA managers need to realize that there are substantial issues with

the relationships between managers are staff at FDA that need to be addressed. A

Union of Concerned Scientists poll of FDA staff showed that 44 percent of FDA scientists did not respect their managers’ integrity. A substantial shift in culture at

FDA is needed, and this can be accomplished by making FDA place where people

who follow the scientific method and who treat their peers with respect want to

work and those who choose not to behave professionally don’t want to work

Joint authority of Office of New Drug and Office of Surveillance and Epidemiology

regarding post-approval decision making. It is part of the scientific method that

data, analysis and conclusions undergo peer review and re-analysis by others to confirm the conclusions of a given set of scientists. Also, it is only human nature that

when one makes an important decision that may affect the lives of thousands or

million of persons it is very disheartening to learn that decision may have resulted

in people being harmed. However, it is also part of science that we learn more as

more evidence accumulates. Lastly, systems function best when there are checks

and balances and no one person or group of persons exerts absolute authority. The

framers of the Constitution set up a bicameral legislature and three branches of

government for exactly this purpose. For all these reasons there needs to be joint

decision making authority between the Office that approves new drugs (the Office

of New Drugs) and the Office responsible for evaluating drugs after approval (the

Office of Surveillance and Epidemiology). The Enhancing Drug Safety and Innovation act could be strengthened by including provisions for this joint authority.

Accountability for decision making and behavior at FDA and increase ‘‘whistleblower’’ protections -There needs to be accountability for FDA managers who treat

staff unprofessionally, both from within FDA by senior managers and from oversight

from Congress to ensure that accountability takes place. Increased transparency of

the operations at FDA would discourage some from inappropriate behavior, and all

of FDA would benefit from changing the perception held by many clinicians, academics and those in industry that FDA is a ‘‘black box’’ in which operations, decision

making and the scientific reasoning behind decision making seem unclear. There is

no blind acceptance of data in science, and statements that ‘‘FDA cannot be secondguessed’’ do not take into account that ‘‘second-guessing’’ (also called peer review

and confirmation of evidence) is part of science. One of the basic premises of the

scientific method is we can never be sure we are correct, but we can always be proven wrong, so one needs to keep an open mind at all times. No one questions that

FDA managers have the authority to render decisions, but with the authority comes

responsibility. There is no such thing as the FDA, as FDA is made of up individuals.

It would be best if no staff person at FDA ever has to ‘‘blow a whistle’’ on inappropriate use of science or failure to protect the public’s health, but should this be necessary, FDA staff need to know they will not be risking their livelihood to protect

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patients. Therefore there needs to be increased whistle-blower protections such as

those in the legislation proposed in the Swift Approval Full Evaluation act.

Best Use of Science and Consistency of Decision Making within FDA and publication of guidance on risk-benefit analysis—One of the major complaints of drugs

sponsors is that they receive inconsistent advice from FDA. While in some cases advice can and should change as science advances during the course of drug development program, some sponsors feel that they do not receive consistent scientificallybased advice from Division to Division within FDA across similar drug development

plans in different therapeutic areas. This would seem at odds with using appropriate scientific methods to make decisions. FDA needs to train staff on the scientific and legal bases for drug evaluation, especially in that there are legally mandated standards for drug effectiveness that must be followed in order to justify the

potential adverse events of drugs. FDA needs to formulate guidance which explains

the scientific decision making process of balancing risks and benefits. While there

needs to be some flexibility to accommodate individual cases, there are some basic

principles which would apply to all situations, such as evaluating the frequency, severity and seriousness of adverse events weighed against the nature and magnitude

of the benefits of a medical intervention. FDA reviews need to explain the scientific

as well as legal basis for decision making and conclusions so that sponsors, clinicians and the public can understand the scientifically reasoning behind a decision.

FDA reviews include a tremendous amount of data and analysis but is it not always

clear how this data is synthesized into an overall decision.

III. OUTPUTS FROM FDA

FDA serves the public and therefore needs to communicate with the scientific

community, clinicians and patients as well as drug sponsors.

Transparency of decision making and reviews at FDA—The Belmont Report in

1979 on the protection of subjects in human research pointed out that research is

the pursuit of generalizable knowledge. For research to be ethical the knowledge obtained must be generalizable in order to justify exposing subjects to the risk of the

research. If research is not generalized, that is, shared with others in the scientific

community then it is inherently unethical. Therefore it is incumbent upon FDA and

drug sponsors to share the information from all clinical trials. A registry that includes a listing of all clinical trials including the results of these trials would allow

knowledge to be generalized. The Enhancing Drug Safety and Innovation Act includes such a provision. It is important that data from earlier phase trials be included in such registries and databases as these earlier phase trials often form the

basis for evaluation of further adverse events post-approval. In addition the results

of these trials, not merely that fact that they are ongoing or completed, need to be

included in any database in order for the results to be generalizable. FDA reviews

should be published on the FDA website within a reasonable period of time (no

longer than a few weeks) in order for the scientific community to evaluate the basis

for FDA decision making. This form of peer review is part of the scientific process.

FDA staff should have a right to publish and participate in scientific meetings—

As noted previously, FDA reviewers need to keep current with the science in their

field. This means FDA staffers need to share their knowledge with those outside

FDA as well as gaining knowledge themselves from scientists outside FDA. FDA reviewers need to be able to share their analyses with the scientific community and

the need to FDA managers to ‘‘make one decision’’ should not bar a scientific discussion among the scientific community. The Supreme Court ‘‘make one decision’’ and

yet members of the Court still publish a minority as well as a majority explanation

of their findings. Therefore, FDA should publish a Summary Basis of Approval

(SBA) for each medical intervention which would include a discussion of any and

all scientific differences during the review process and an explanation and scientific

reasoning for the final conclusions.

The IOM report tells us that now is the time to address the important issues in

evaluating drug safety that have needed to be addressed for some time. In order

to address this urgent public health issue, we need to act now. Congress should include provisions for strengthening the evaluation of drug safety in any reauthorization of PDUFA. A recent Harris poll showed that the public is losing confidence in

FDA, and the only way to restore that confidence is by action, not merely by words

or reshuffling of the structure of FDA and without new resources and authority. We

can address the important issues in evaluating drug safety in an efficient way without slowing bringing important medical advances to patients. Safety and efficiency

and not mutually exclusive goals and more focus on post-approval activities need

not slow pre-approval evaluations. However, we need to learn from recent events

and take action today to avoid another Vioxx or Ketek tomorrow. Congress can help

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FDA start down the road to being the foremost authorities on

pharmacoepidemiology, to work closely with the scientific community to gather data

and to develop new methods and analyses, to come up with cogent scientifically

based approaches to evaluating the balance of risks and benefits of drugs, and help

FDA achieve its stated mission of protecting and advancing the public health. Most

FDA staffers are courageous public health servants. Please give them the tools they

need to do their jobs for all of us.

Mr. PALLONE. Thank you. And we will take questions of the

panel now. Thank all of you again for being here. I am just going

to recognize myself for 5 minutes for some questions, and I wanted

to ask a couple questions of Ms. Thompson.

First of all, let me thank you for all the good work you do with

the Elizabeth Glaser Pediatric AIDS Foundation. I am familiar

with it, and I really know that you do a great job. But I found your

testimony interesting because you suggest that the goals of a

strong and robust drug safety system and at the same time, innovative medicines are not necessarily mutually exclusive, that you

could possibly do both. And I am wondering if you could elaborate

more on why you think that doesn’t have to be an either/or scenario? In other words, if we were to pass drug safety legislation

that built upon what is already included in the PDUFA IV proposal, that included stronger monitoring and enforcement provisions—in other words, like if we did what Mr. Waxman and Mr.

Markey have included—do you think that would kill innovation?

Or would we still be able to be innovative, so to speak?

Ms. THOMPSON. Well, I think we strongly believe that it won’t,

in fact, kill innovation. What the IOM has proposed and what, I

think, has been picked up both in the Waxman-Markey bill and the

Kennedy-Enzi bill is to address this new paradigm of looking at

safety concerns throughout the life cycle of the drug. So it is really

taking the FDA back, in some senses, to its roots under the original

1938 statute, which was all about safety. Of course, efficacy wasn’t

added until 1962.

So by providing FDA the resources that it needs to maintain its

scientific excellence, the resources that it needs to integrate more

fully safety concerns both into the drug review process and into the

post-market surveillance process, I think you have got the perfect

recipe for enabling innovation to continue and, in fact, supporting

it because one of the areas that has suffered under PDUFA is the

FDA science base.

And FDA, in order to support the innovation that is coming out

from industry, needs to be the leader in terms of regulatory science

and in terms of advancing the tools and techniques that are going

to support regulatory discovery and how that discovery gets translated into new therapies.

Mr. PALLONE. Thank you. In your testimony, you call for giving

FDA authority to require testing for off-label uses of drugs. But if

Congress granted FDA such authority, how would that match up

with the Pediatric Incentive Program? How exactly would those

two programs work together? Would granting such authority obviate the need for the incentive program? If you would explain.

Ms. THOMPSON. Well, the answer is no, it would not obviate the

need, but we begin with the position that three-quarters of the prescriptions that are written for children are written off label. And

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the Pediatric Incentive Program, the program you referred to,

BPCA, Best Pharmaceuticals for Children Act, provides a voluntary

mechanism where FDA can go out and, if the drug is still on patent, it can recommend to a manufacturer that the manufacturer

conduct certain studies to determine effectiveness and/or safety in

children.

But that only applies on a voluntary basis. Obviously under the

stick part of that equation, the pharmaceutical research side, that

legislation for the most part applies only to new drugs. And there

is a very high standard that FDA has to meet to require studies

now, very high safety finding or danger finding that the FDA has

to make.

So providing new authorities in combination with the existing

carrot-and-stick approach under pediatrics is really essential if the

FDA is going to be able to identify safety and effectiveness for children.

Mr. PALLONE. Thank you. I am just going to try to get in a couple

questions here to Ms. Van Syckel. Thanks again for being here. But

in your testimony, you don’t specifically call for the repeal of the

user fee system. In fact, you suggest that it should be expanded,

but you call for it to be decoupled from obligations made to the industry. Would you just comment further on that? And then I am

going to ask you also a second question. You have been very vocal

about improving communications about medications to patients and

providers, and you have focused on the availability of the distribution of med guides. Is there something that you think Congress

could do to improve communications about medication risks

through changes to the med guide system? So second, the med

guides, and third this whole idea of decoupling the user fee system.

Ms. VAN SYCKEL. OK, let us start with the med guides first.

Mr. PALLONE. OK.

Ms. SYCKEL. First we have a bill, S. 2364, in New Jersey that

is sponsored by Senator Codey and Senator Lance. We have got two

good guys there. And what we are trying to do is these medication

guides, we don’t want to find them, if we get them, in the bottom

of a pharmacy bag. So what we would like is to have parental informed consent. Look at the med guide with the doctor, go over the

med guide, don’t just put it in the bottom. I took this off the Internet. It is that simple. Doctors can do that.

And I asked Assemblyman Conaway, because we had discussed

this issued. And I said Doctor, have you seen the med guide? And

he said yes, and I guess he assumed he had. And I said well, could

you please tell me what to look for? And he couldn’t tell me, and

this is a doctor within New Jersey on the assembly.

And I think it is important because everybody is so concerned

about the thoughts of suicide. There is a lot more of side effects

than just the thoughts of suicide, and those are newer, worse irritability, acting aggressive, being angry or violent, and acting on dangerous impulses. And I will give you an example from New Jersey.

There was a young teenager who was an honor roll student, participated in peer groups. He was over-medicated, and he brought

a cache of weapons to school, loaded guns, to even the point that

the father, the parents didn’t even know where he got the guns.

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So violence issue with the anti-depressants has become very—is

something that we should all be concerned about, and I was so concerned that I attended a White House conference on school violence

and school safety. And I did have an opportunity to speak to Attorney General Alberto Gonzales concerning this issue, and I have

even spoken to Mr. Ferguson because I saw how my daughter attacked three police officers, assaulted her brother. I see how violent

the children become. And the Attorney General asked Secretary

Leavitt, sent him a letter back in October to look at the violence

issue concerning the antidepressants.

So if parents don’t have this med guide, and I think it is very

insulting for the FDA to say that there are some outsiders who

should determine what parents need to know. This is what we need

to know so if we make a decision to give them an antidepressant,

we can monitor them. The doctor can’t do it. The school district

can’t do it. It is up to the parents, and we need this vital information.

I guess I was kind of being diplomatic with PDUFA. If it were

up to me in the great world, I would like to have it repealed. But

it is not the perfect world, and I believe we need to focus more on

an independent office of drug safety. I am trying to be diplomatic

but I sometimes can’t. I truly believe we need an independent office

of drug safety. I agree with Senator Grassley and Senator Dodd on

this issue. They have been at this issue for 4 years. They are

knowledgeable.

Mr. PALLONE. OK, thank you so much. Mr. Deal.

Mr. DEAL. Mr. Theriault, I share your concern for counterfeit

drugs. In a previous hearing that we had where the issue came up

about adverse events, a questions was asked as to whether or not

there was any way, with our current information, to distinguish adverse events that might have been caused by counterfeit drugs as

opposed to brand-name drugs. And the general answer was no,

there was not. Is there anything that we should to do to try to deal

with that particular issue? And are there things that we might do

that would—might have adverse consequences, thinking we were

doing the right thing?

Mr. THERIAULT. The adverse event reporting issue is something

that I think is difficult, and I am not sure how you can differentiate between adverse events that are caused by counterfeits as opposed to legitimate medicine. From our point of view, the safety

issue is addressable on a number of fronts. I think that stopping

these personal use amounts of prescription medicines that come

into the country, via the mail services and that sort of thing, is almost a no-brainer.

We conducted a study about 2 years ago, and at the New York

City mail facility alone, there were over 40,000 packages a day

coming into that one mail facility that were identified as unapproved pharmaceuticals. Tightening the supply chain, requiring

pedigrees, enforcing the pedigree aspect of PPNA. I think you can’t

regulate the Internet, but I think you can regulate the flow of products that are ordered on the Internet.

Mr. DEAL. Could you give us some idea what proportion you

think are coming in from outside of the country versus counterfeiters who are operating within our own country?

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Mr. THERIAULT. In the last 10 years that I have been at Pfizer,

we have had probably the most aggressive anti-counterfeiting program in the industry. And I can’t recall one counterfeiting manufacturing operation that we found in the United States. I would say

the very, very high percentage of counterfeits in the 1990s comes

from outside the United States. And that is why, when we address

importation and issues like that, I think that unless we deal with

the drugs coming in from outside the United States we are going

to have a problem.

Mr. DEAL. Your written testimony indicates one particular, I

think it was an Internet pharmacies supposedly in Canada. How

big a problem is Internet pharmacy in this overall problem of counterfeiting?

Mr. THERIAULT. Well, I think it is a huge problem. And to your

earlier point, the woman who died in Canada, I think, was a U.S.

citizen residing in British Columbia. As I understand the facts, the

medicine she received came in an unmarked vial. There was no

label, no safety information. There was very little possibility to determine where she bought those, and the Internet pharmacy that

sell those things are up and down in a matter of days.

So I think if you buy prescription drugs on the Internet, you are

taking about a 50 percent chance of getting either counterfeit or

unapproved generic medicines.

Mr. DEAL. And I suppose you would support increasing the penalties for the counterfeiting of drugs, would you not?

Mr. THERIAULT. Yes, sir, I would. I think Congressman Rogers’

bill is an excellent step in that direction.

Mr. DEAL. OK, I would like to briefly explore the procedures that

are embodied at FDA now. I believe we refer to them as the critical

path. Dr. Powers, since you have worked there, would you briefly

comment on that initiative and whether you think it is appropriate?

Dr. POWERS. Sure, the critical path was initiated in March 2004,

which is an attempt for FDA to partner with folks outside the FDA,

both academics and people in practice, to try to develop tools that

would more efficiently help drug development, both in terms of

measuring safety and effectiveness. It is a great idea, but it is one

in which FDA is left in the position of having to suggest things to

people outside the agency and really doesn’t have funding at this

point to be able to accomplish those things.

So they published several, including one last week on generic

drugs, saying here are some great things we would like to know the

answers to, but are left without the resources to be able to do that

in a lot of cases.

For instance, let us take the issue of biomarkers. The way for us

to explore whether those biomarkers are helpful in selecting which

patients may benefit or which patients are at risk would mean

looking at studies to see whether those biomarkers make any sense

or not. And right now, FDA is left in the position of suggesting saying wouldn’t this be a good idea.

Mr. DEAL. Money would help.

Dr. POWERS. It sure would.

Mr. DEAL. Thank you.

Mr. PALLONE. Mr. Ferguson.

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Mr. FERGUSON. Thank you, Mr. Chairman. Thanks to all of our

witnesses on our second panel. As most or some of you know, I

spent my time in the first panel talking about medication guides.

It is something I have spent a great deal of time on, and Lisa and

I have actually worked on the issue a lot together.

Lisa, we have heard your testimony today. Of course, I am very

familiar with your own family’s story. It is important that you continue to share that with folks, including in this setting, so people

can just understand one family’s situation and ordeal. And you had

said before you represent kind of families in New Jersey, but you

are not an official organization or group.

Ms. VAN SYCKEL. No, I am a mom.

Mr. FERGUSON. You are a mom. You are a parent like I am and

so many of us are, trying to make sure you are taking care of your

child and having information to take care of Michelle——

Ms. VAN SYCKEL. And Chris who is down in Florida.

Mr. FERGUSON. Yes. Now, with regard to the medication guides,

you know that in 2004, we had our Oversight and Investigation

Subcommittee hearings and investigations into this particular

issue. And subsequent to that, these medications, SSRIs, who are

prescribed for kids now are accompanied by or supposed to be accompanied by medication guides. That was after your family situation.

Ms. VAN SYCKEL. That is right.

Mr. FERGUSON. If you can hypothesize, I guess, or——

Ms. VAN SYCKEL. Finding out that the med guides weren’t being

distributed?

Mr. FERGUSON. Well, actually how would that have affected your

own family situation? If you had been presented with a med guide

when you filled that prescription for your daughter—I mean it is

tough in hindsight to be able to go back and figure out what you

would have done but——

Ms. VAN SYCKEL. And I don’t believe I, at that time, would have

known what to do because Michelle really didn’t have depression

or anorexia. It turned out she had Lyme disease, so we were desperate to help her. So would I have done this? I don’t know. I may

have, but armed with this information at least, I could have prevented the self-mutilation, the scars that are on her body today.

We have a young girl who came to your office, and no one is immune to the side effects of the antidepressants, and this young girl,

both of her parents work for the pharmaceutical industry. And if

you look at her arms, do those look like little scratches to you? Cutting the word ‘‘die’’ onto the inside of your arm? Is that an acceptable side effect? I don’t think so.

Mr. FERGUSON. Now, you——

Ms. VAN SYCKEL. But it is not here.

Mr. FERGUSON. You obviously are in touch with and work with

other families who have had similar situations that we have met

with.

Ms. VAN SYCKEL. They call me desperately seeking answers because they said my doctor told me it was safe and not to listen to

the stories in the media, that they are parents that are—they are

actually labeling parents like me.

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Mr. FERGUSON. What do they say? And I have heard some of

them talk. But what is the general sense among some of the families and parents that you know about the specific information that

they could have with medication guides if they were being gotten

into their hands properly?

And we have obviously had a breakdown in the system, and it

is normal and natural for parents or anybody who is concerned,

who has a conscience, to want to try and figure out who is to blame

and where to lay blame about this whole problem. But as we have

found, there is a big breakdown in communication and responsibility and jurisdiction.

And that is what we are trying to get to the bottom of. But at

the end of the day, what we are finding is that there aren’t assurances in the system as we would like them to be today, that every

parent who has an SSRI prescribed for their child is getting this

information.

Ms. VAN SYCKEL. Right, actually the parents in New Jersey are

angry with the doctors because they said the doctors should know

when they say it has a black box warning, I heard about increased

risk of suicide, and the doctor downplays the side effect. But both

parents, one who is a pediatric emergency room nurse at a large

hospital in New Jersey, who lost her niece Brittany to a Prozac-induced cardiac arrest and then, of course, with the other teenager,

they said had they been provided this information, the horror and

the tragedy they endured never would have happened.

And it has weakened the parents who have to make the decisions

with their children. It is not the FDA’s job. It is not the pharmaceutical companies’ job. Parents, we don’t want to harm our children. We want the best medical care for them, but I find it insulting that they believe that we don’t know how to handle this type

of information. Give me the worst scenario, and I will always pray

for the best scenario.

Mr. FERGUSON. Mr. Chairman, I know I am out of time, but I

think one of the reasons we work so hard on this issue is because

at the end of the day, parents are ultimately responsible for the

health care of their children. And that is why they go to doctors.

That is why they perhaps take medications. That is why you consult with the widest variety and try and gather as much information as you possibly can to make the right decision for your own

child. But you are handicapped from making that decision if you

don’t have all the information. That is why I think this med guide

issue is so important.

Ms. VAN SYCKEL. Or if they choose to try the medication at least

they have the information to monitor their child.

Mr. FERGUSON. That is right.

Ms. VAN SYCKEL. Because that is really important because we

are with our children, 24/7. It is that important, and I have to say

this because I believe it is very important. But back during the

2004 oversight and investigation, it was determined by the FDA

and by Congress that antidepressants was a causal role in suicide.

They used the word causal, but FDA negotiated the label.

And now it is increased risk, and then we have the JAMA study

that just came out where they say there is no increase and that the

benefits outweigh the risks. But what that JAMA study failed and

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what the FDA failed to do was when the child stops taking the

medication abruptly, cold turkey, that is when we see our suicide

attempts. That is when we see our violent behavior. And FDA, during the adult hearings in this past December, they stopped with

their method analysis, their investigation, day 1 of withdrawal.

Now if they went for the next 30 days or 4 to 6 weeks, you would

have seen some violent behavior, and you would have seen suicide.

And we also have 150 percent increase of prescribing

antipsychotics and Strattera to our kids. They also carry suicide labels, and I mean it is pretty sad when I look at the Medechi record

in New Jersey and our new doctors, a psychiatrist, is giving it to

newborn babies. Risperdal and Effexor, two deadly drugs, how were

they administering that to a baby? We need to look into Zyprexa

and Risperdal and why they feel the need that they have to medicate our toddlers.

Mr. PALLONE. Thank you so much. Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman. Dr. Ellenberg, I want

to ask you what are the provisions in the administration’s PDUFA

proposal that allow user fee dollars to be put toward increasing

FDA’s access to outside population-based epidemiological databases. Information from these databases would obviously be useful

for FDA in its efforts to detect safety signals earlier. This is an extremely positive development, and I am encouraged to see that it

was included in the negotiated package.

But I think we need to go further in terms of providing FDA with

additional tools and authorities. One of IOM’s recommendations to

Congress was to provide FDA with the authority to require postmarket studies. Can you tell us about the benefits and limitations

of data mining? Can you also explain why, even if it has the enhanced ability to conduct this so-called data mining, FDA still

needs to have the ability to require post-market studies?

Ms. ELLENBERG. Yes. Well, there are a number of different facets

to understanding of risks of drugs post-marketing. Data mining is

a tool that people have been trying to implement with the passive

surveillance system, the reports that people send in. And that can

be a useful tool. With several hundred thousand reports coming in

every year, you can appreciate there has got to be some kind of

automated way to pull out patterns that might need further investigation. And that is what data mining is. So that is one piece of

post-marketing surveillance. And that might be the fastest way to

actually identify a very, very strange, unusual, very rare adverse

event because it could be reported from anywhere.

That is not a good way to identify an increase in a fairly common

background rate. So, for example, increased rates of heart attacks

with a widely-used drug, you will not find that from a passive reporting system with data mining.

Access to health care databases where you have information on

thousands or hundreds of thousands of people and their ability to

follow them over time, taking drugs, you might be able to get some

information there. So I don’t think it is one or the other. And sometimes——

Mr. WAXMAN. You think both are very——

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Ms. ELLENBERG. You need both, and you need the ability to

sometimes carry out perspective studies that might even need to go

beyond existing databases.

Mr. WAXMAN. IOM also concluded that Congress needs to provide

FDA with other authorities the agency currently lacks. For example, one, the authority to place a moratorium on DTC advertising

and to require the specific warnings be incorporated into DC ads.

Two, the ability to require that labels of new drugs carry a special

symbol to indicate their newly approved status. Three, the ability

to require that companies make label changes instead of just asking them to do so.

Additionally, the IOM has said Congress should enhance FDA’s

enforcement tools to include things like civil monetary penalties, so

that the FDA had other choices besides using its bully-pulpit to

threaten using its only real enforcement tool, the nuclear option of

removing the drug from the market. Obviously the administration’s

PDUFA legislation proposal does not incorporate these recommendations.

In your view, if Congress were to act this year only on the drug

safety-related provisions included in the administration’s PDUFA

proposal, would the very serious drug safety oversight problems

that the IOM describes in its report be resolved?

Ms. ELLENBERG. Well, as a member of the IOM committee that

put the report together, we all felt strongly that the whole package

really ought to be adopted, and it was not something to pick and

choose, use this one, use that one. So I do believe that these authorities would be helpful.

It is very hard for me or probably anybody to assess really what

will happen with this aspect, without this aspect. It would be very

hard to predict, but it seems to me that those additional tools could

be used by the FDA. Most of the things that you mentioned relate

to adequate communication of risk to the public and the issues of

what is in the label, ability to regulate DTC advertising. Those are

all how do we get information on risks out to the public.

Mr. WAXMAN. Well, along those lines, IOM recommended Congress pass legislation that would require companies to register and

report the results from their clinical trials and public available

database. Can you tell us what lead to this recommendation and

why the IOM felt it was necessary to create a mandatory system?

Ms. ELLENBERG. Well, the concern is that studies may be done

that suggest that there may be an increased risk or suggest something that is not favorable about a drug and that if nobody knows

that study was done, if that is hidden under regulations, and then

other studies are done that maybe don’t show that, well it would

be hard to know if you have a whole picture, whether this is something we should worry about or not. If we don’t see the studies that

suggest that there might be a problem, they don’t know that there

might be a problem.

So there certainly has been a move toward making these public.

I think there was a provision——

Mr. WAXMAN. But do you think it ought to be mandatory? Because it could be voluntarily be made public.

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Ms. ELLENBERG. I think that many companies are voluntarily

making these public. I don’t know the extent to which they are

doing that now so——

Mr. WAXMAN. Mr. Chairman, if you permit, I have one last question, and I would like to pursue it. We heard from Dr. Galson on

the first panel about FDA’s system for handling the steadily increasing number of AERs the agency receives, and you describe

this trend in your testimony also. He told us they got a half million

AERs, and I understand that approximately 200,000 were for serious and unexpected conditions. He said that the staff available to

review those reports has been limited by resources. In fact I understand that there are only 20 epidemiologists who review all of those

reports.

Dr. Galson also described the upgrades to the agency’s IT system

that would help to review these reports that FDA would make with

an increase of PDUFA dollars for that purpose. But he said it

would be only $4 million. I am concerned that that may not be

enough. Can you describe in more detail the situation with respect

to the agency’s review of AERs and comment on whether you think

$4 million would be enough to complete what would be a massive

overhaul of FDA’s IT infrastructure?

Ms. ELLENBERG. No, I don’t think $4 million would be enough at

all. I think you need probably more than that just to do a reasonable overhaul, a reasonable redo of the adverse event reporting system to incorporate the data mining, making that routine, training

reviewers, having enough reviewers to look at it. But as I said before, that is just a single piece, a single component of the needed

system. The Centers for Disease Control has a series of databases

that they use from the Kaiser Permanente system, and I think they

spend something like $10 or $15 million a year to maintain that

system so that if there are vaccine adverse events that people are

concerned about, vaccine safety issues, they can really go right to

that system and try and get answers very, very quickly.

And it is that kind of a linkage of databases that FDA needs to

have access to investigate drug safety problems as well.

Mr. WAXMAN. OK, thank you. Thank you, Mr. Chairman.

Mr. PALLONE. Thank you. Dr. Burgess.

Mr. BURGESS. Thank you, Mr. Chairman. Dr. Levine, let me just

ask you since this question just came up and you were referenced,

do you have a concept of what the dollar expenditure was to develop the data operation that you have at Permanente?

Dr. LEVINE. To develop the data operation?

Mr. BURGESS. Right, the continual data observation that you

have.

Dr. LEVINE. I know that the development of our fully automated

medical record system, including the inpatient and outpatient

pharmacies, is in the billions of dollars. The piece in terms of vaccine safety, which was developed with our Vaccine Center and the

CDC, I don’t know the cost of the implementation. That was a

stand-alone system.

We are currently involved in trying to roll all of our legacy and

stand-alone systems into a single fully-automated medical record,

which will actually enable projects like the one we did with the

FDA and the ones we are doing with the CDC to be done much less

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expensively because the maintenance of those legacy systems is extraordinarily expensive. And I share the concern about what you

can do with $4 million, just based on what it costs us to do anything in IT.

Mr. BURGESS. Let me ask you a question just to put it in context.

How many covered lives are there in Permanente?

Dr. LEVINE. In the present Kaiser Permanente Medical Care Program, there are 8.7 million covered lives. In northern California, it

is about 3.35 million.

Mr. BURGESS. But that system which you described that cost X

million dollars, that covers——

Dr. LEVINE. All 8.7.

Mr. BURGESS. How long did it take to develop that?

Dr. LEVINE. We are midway through the implementation, and development is going hand and hand. We are using software from the

Epic Systems, which is one of the largest medical record systems

based in Madison, Wisconsin. It was developed for outpatient systems, and we are working with Epic to adapt their product to our

very large population.

Mr. BURGESS. And that is probably a topic for another hearing,

Mr. Chairman, but it does show the size and the scope of the problem. Dr. Loew, let me ask you, you referenced a figure of 3 percent

of medications that were taken off the market. Is that the correct

way to phrase that?

Ms. LOEW. That is correct. In the past 20 years, the withdrawal

rate has been consistently around 3 percent.

Mr. BURGESS. The withdrawal rate. That is the term you used.

Now, of that, can you just give us an idea of what the number of

products were that were withdrawn, say, in the last 5 years?

Ms. LOEW. Actually, I don’t have that figure, but we can get that

data.

Mr. BURGESS. Can you get that for us?

Ms. LOEW. Absolutely.

Mr. BURGESS. And would you have an idea as to how many of

those were voluntarily withdrawn by the manufacturer, what problems came to light, and how many of those were enforcement actions by the FDA?

Ms. LOEW. I believe that in many situations, it is a voluntary

withdrawal on the part of the manufacturer. A safety issue comes

to light. They discuss it with the FDA and decide to withdraw the

product from the market, but we will get you the exact data on

that.

Mr. BURGESS. OK, I was just thinking back, and I can’t recall an

instance where there was an actual FDA recall. But I am sure it

must have happened, but most of——

Ms. LOEW. The majority of the situations, if I recall, were all situations where the manufacturer had voluntarily taken it from off

the market. But I can’t verify that.

Mr. BURGESS. Great. If you could get that for us, that would be

wonderful. We heard testimony from another witness on the panel

that the drug manufacturers, in fact, they don’t even pay attention

to safety issues after the product has been approved because they

have no incentive to do so. Is that an accurate statement?

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Ms. LOEW. I would argue that the opposite is completely true.

Pharmaceutical manufacturers take the safety of our products extremely seriously. There are, in fact, some extensive requirements

for manufacturers to monitor their products in the marketplace,

and there are a number of different tools. There are, of course, the

adverse effects reporting systems that we have heard about today.

If there is a serious adverse event that is detected that is an event

that hasn’t been previously seen, manufacturers have an obligation

to report that to the FDA within 15 days and then to follow up 15

days later with a full report. An additional report quarterly in the

first 3 years of production on the marketplace, to quarterly submit

reports to FDA on the adverse events that have been detected

around the product.

In addition to that, there is an annual report requirement where

companies submit all new information that has become available

on the product. The manufacturing rate of information, new clinical

data, observational data, and so on. They are required to report

that, so they take the obligations of monitoring the product in the

marketplace extremely seriously. And it is, of course, in their best

interest to ensure that is the case and, of course, the best interest

of the patients.

Mr. BURGESS. Thank you. Mr. Theriault, let me just ask you, you

talked about a number of things that are being done. A company

that I became familiar with several years used a labeled isotope in

like the parts per billion range to ensure that products were what

they said they were, and I think they were talking about rap CDs

at the point that they could put this isotope in ink that was on the

label and that way, detect whether or not the counterfeit product

had found its way into the supply chain.

And I asked the question at that time could this apply to pharmaceutical agents as well because we are talking about a molecule

that again would be in the parts per billion range. And the question obviously came up, well, how would the FDA look upon that?

Have you had any experience with investigating those types of

technologies?

Mr. THERIAULT. We haven’t looked at that technology. I think the

FDA’s preference right now is for RFID tracking, and we have got

a pilot project around that right now. But I think one of the issues

there is where does the authentication occur? Is it the patient who

authenticates the product, the pharmacist, or somebody else in the

supply chain? But to answer your question directly, I think that

technology probably could apply.

Mr. BURGESS. There was a news story probably 4 or 5 years ago

now from New Orleans where they did an analysis of not so much

the active ingredient of the medication, but just the inert part of

the pill, the vehicle that the medicine was contained in and found

significantly high—for medicines purchased over the Internet—and

found significantly high quantities of heavy metals, cadmium, liquid chromium. To your knowledge, is that still an ongoing problem?

Mr. THERIAULT. It is. We have seen a number of cases involving

heavy metals recently, and I think that the woman who died in

British Columbia, I think the coroner said her death could possibly

be related to heavy metals that probably she was taking.

Mr. BURGESS. Thank you, Mr. Chairman.

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Mr. PALLONE. Let me thank our entire panel for being here this

afternoon. I felt this was a good opportunity to hear from you and

ask some questions that were really pertinent, and we appreciate

it. A number of people asked if they could submit things for the

record, both members and panelists. And, of course, we will do

that. We will include those things in the record. And you may get

additional written questions from some of us in the next 10 days,

which we would like you to answer as well in writing. And again

thank you all, and I thought it was very good today. We appreciate

your help. And with that, the subcommittee meeting is adjourned.

[Whereupon, at 3:05 p.m., the subcommittee was adjourned.]

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