U.S. GOVERNMENT PRINTING OFFICE

61–435 CC WASHINGTON : 2000

HOW ACCURATE IS THE FDA’S MONITORING

OF SUPPLEMENTS LIKE EPHEDRA?

HEARING

BEFORE THE

COMMITTEE ON

GOVERNMENT REFORM

HOUSE OF REPRESENTATIVES

ONE HUNDRED SIXTH CONGRESS

FIRST SESSION

MAY 27, 1999

Serial No. 106–60

Printed for the use of the Committee on Government Reform

(

Available via the World Wide Web: http://www.house.gov/reform

(II)

COMMITTEE ON GOVERNMENT REFORM

DAN BURTON, Indiana, Chairman

BENJAMIN A. GILMAN, New York

CONSTANCE A. MORELLA, Maryland

CHRISTOPHER SHAYS, Connecticut

ILEANA ROS-LEHTINEN, Florida

JOHN M. MCHUGH, New York

STEPHEN HORN, California

JOHN L. MICA, Florida

THOMAS M. DAVIS, Virginia

DAVID M. MCINTOSH, Indiana

MARK E. SOUDER, Indiana

JOE SCARBOROUGH, Florida

STEVEN C. LATOURETTE, Ohio

MARSHALL ‘‘MARK’’ SANFORD, South

Carolina

BOB BARR, Georgia

DAN MILLER, Florida

ASA HUTCHINSON, Arkansas

LEE TERRY, Nebraska

JUDY BIGGERT, Illinois

GREG WALDEN, Oregon

DOUG OSE, California

PAUL RYAN, Wisconsin

JOHN T. DOOLITTLE, California

HELEN CHENOWETH, Idaho

HENRY A. WAXMAN, California

TOM LANTOS, California

ROBERT E. WISE, JR., West Virginia

MAJOR R. OWENS, New York

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

PATSY T. MINK, Hawaii

CAROLYN B. MALONEY, New York

ELEANOR HOLMES NORTON, Washington,

DC

CHAKA FATTAH, Pennsylvania

ELIJAH E. CUMMINGS, Maryland

DENNIS J. KUCINICH, Ohio

ROD R. BLAGOJEVICH, Illinois

DANNY K. DAVIS, Illinois

JOHN F. TIERNEY, Massachusetts

JIM TURNER, Texas

THOMAS H. ALLEN, Maine

HAROLD E. FORD, JR., Tennessee

JANICE D. SCHAKOWSKY, Illinois

———

BERNARD SANDERS, Vermont

(Independent)

KEVIN BINGER, Staff Director

DANIEL R. MOLL, Deputy Staff Director

DAVID A. KASS, Deputy Counsel and Parliamentarian

CARLA J. MARTIN, Chief Clerk

PHIL SCHILIRO, Minority Staff Director

(III)

C O N T E N T S

Page

Hearing held on May 27, 1999 ............................................................................... 1

Statement of:

Levitt, Joseph A., Director, Center for Food Safety and Applied Nutrition,

Food and Drug Administration .................................................................... 8

Soller, R. William, Ph.D., senior vice president and director of scientific

and technical affairs, Consumer Health Care Products Association;

Theodore M. Farber, Ph.D., principal, Toxachemica, International; Daniel B. Mowrey, Ph.D., president, American Phytotherapy Research Laboratory; Annette Dickinson, Ph.D., vice president for scientific and

regulatory affairs, Council for Responsible Nutrition; Karen Schlendorf;

Barbara Michal, H.E.A.T.; and Raymond Woosley, Ph.D., professor of

pharmacology and medicine, Georgetown University ................................ 82

Letters, statements, etc., submitted for the record by:

Dickinson, Annette, Ph.D., vice president for scientific and regulatory

affairs, Council for Responsible Nutrition, prepared statement of ........... 138

Farber, Theodore M., Ph.D., principal, Toxachemica, International, prepared statement of ........................................................................................ 97

Levitt, Joseph A., Director, Center for Food Safety and Applied Nutrition,

Food and Drug Administration, prepared statement of ............................ 12

Michal, Barbara, H.E.A.T., prepared statement of ........................................ 151

Mowrey, Daniel B., Ph.D., president, American Phytotherapy Research

Laboratory, prepared statement of .............................................................. 110

Schlendorf, Karen, prepared statement of ..................................................... 146

Soller, R. William, Ph.D., senior vice president and director of scientific

and technical affairs, Consumer Health Care Products Association, prepared statement of ........................................................................................ 85

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

of California, summaries of complaints ....................................................... 53

Woosley, Raymond, Ph.D., professor of pharmacology and medicine,

Georgetown University, prepared statement of .......................................... 183

(1)

HOW ACCURATE IS THE FDA’S MONITORING

OF SUPPLEMENTS LIKE EPHEDRA?

THURSDAY, MAY 27, 1999

HOUSE OF REPRESENTATIVES,

COMMITTEE ON GOVERNMENT REFORM,

Washington, DC.

The committee met, pursuant to notice, at 1:30 p.m., in room

2154, Rayburn House Office Building, Hon. Dan Burton (chairman

of the committee) presiding.

Present: Representatives Burton, Morella, Horn, Waxman, Norton, Cummings, Kucinich, Tierney, Schakowsky.

Staff present: Kevin Binger, staff director; Daniel Moll, deputy

staff director; Beth Clay, professional staff member; David Kass,

deputy counsel and parliamentarian; Mark Corallo, director of communications; Corinne Zaccagnini, system administrator; Carla Martin, chief clerk; Lisa Smith-Arafune, deputy chief clerk; Phil

Schiliro, minority staff director; Phil Barnett, minority chief counsel; Kristin Amerling, Cherri Branson, Sarah Despres, and Michael

Yang, minority counsels; Karen Lightfoot and Denise Wilson, minority professional staff members; Ellen Rayner, minority chief

clerk; Earley Green, minority staff assistant; and Barbara Wentworth, minority research assistant.

Mr. BURTON. The committee will come to order.

I want to apologize for a lot of Members not being here. We had

a rule on the floor that went down just a short time ago, and there

is a conference going on with a large number of our members expressing their discontent with some of the things that have happened; and I don’t know if you have ever been in a food fight, but

those things happen from time to time, and I decided to extract

myself from that and come up here to be at the meeting. I don’t

know what the Democrats are doing, but we have two fine Democrat Representatives here so—— Mr. KUCINICH. We are in a supplement fight.

Mr. BURTON. We are getting ready to go on a break back in our

districts.

The Chair sees a quorum and a quorum being present, the Committee on Government Reform will come to order. I ask unanimous

consent that all Members’ and witnesses’ opening statements be included in the record, and without objection, so ordered.

We are here today to continue our dialog with the Food & Drug

Administration on their regulation of dietary supplements. Today’s

hearing will focus on the need for a better system to monitor adverse events with dietary supplements.

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The Food & Drug Administration is responsible for tracking adverse events for different products, prescription drugs, over-thecounter drugs, infant formula, dietary supplements, and even veterinary medicines.

So what is an adverse event? Clearly, if someone takes a drug

or dietary supplement and dies from it, that is a very serious adverse event. If you take a product and suffer a stroke as a result

of a heart attack, that is a serious adverse event. If you take a

product and develop a skin rash, that is an adverse event, but not

necessarily a serious event.

An adverse event can be one or more of a range of things. Why

does the Food & Drug Administration have monitoring systems?

These are early warning systems to protect the public if food or a

drug unexpectedly starts hurting people. The Food & Drug Administration has the authority to seize products which pose a public

health risk, or the FDA can propose regulations to limit the way

in which a product is used.

Obviously, it is very important that the FDA has an accurate and

effective system. People’s lives may depend on it. Companies’ reputations are at stake. Sometimes millions or billions of dollars of

investments can be affected. So it is very important that the FDA

does a good job in this area.

Today, we are going to talk about the adverse events monitoring

systems for dietary supplements. We have been looking at this system for a while now, and there appears to be some very serious

problems.

I think that the FDA will concede that this system has some

shortcomings. The point of today’s hearing is not to say that we

should not have an early warning system. The point of the hearing

is that we need to have an accurate system and that the facts need

to be checked and good information needs to be provided to the

American people. The FDA uses this monitoring system to develop

regulations. If you want to have good regulations, you have to have

good information.

Through our review, we have identified six problem areas: causality not established. There is no analysis of possible causal relationships between products and adverse reactions for dietary supplements. The FDA does not followup to make sure that an adverse

event is actually caused by a dietary supplement.

Ironically, this is done for veterinary drugs. For instance, if a dog

takes a medicine and a dog has a heart attack and dies, the FDA

evaluates this report to see if the death was related to the drug or

not. Because they followed up on the veterinary reports, the FDA

was able to determine that in 1997, of 3,000 adverse event reports

to the center for veterinary medicine, only 1 percent were definitely

associated with a product, 31 percent were probably associated, 45

percent possibly were associated, 12 percent were definitely not related to the product, and 11 percent lacked adequate information

to determine association.

With people and dietary supplements events, the FDA has not

done this analysis. They cannot provide this type of information. If

the FDA does this for animals, why not for people? On the FDA

website, two deaths are attributed to ephedra, 15 to ephedrine, and

12 to ma huang.

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I have further information on two such cases. This case states

that one death attributed to ephedra was actually attributable to

hypothermia, the other is the death of a woman who had been

using an ephedra supplement. She died after driving her automobile the wrong way on a one-way street and struck a pole going

90 miles an hour. Her blood alcohol limit was .212, more than twice

the legally intoxicated limit in most States. Are these two cases

really ephedra deaths?

No. 2, no classification of seriousness of event. The website lists

over 2,000 adverse events, but there is no evaluation of whether

these are mild events, moderate events, or serious events. The impression the FDA gives, especially in the press, is that all of these

events are serious events.

According to information provided to the committee by the FDA,

of 600 events received, 60 percent were not serious events. Additionally, it is unclear on the website what actually should be reported as an event.

On the prescription drug reporting site, a detailed explanation is

given of what an adverse event is. However, the dietary supplement site is vague and lists an adverse event as an illness or injury

associated with the use of dietary supplements.

Are there dual definitions for adverse events? This is a very important issue because the FDA frequently quotes the numbers of

adverse events in dietary supplements and uses these numbers as

a means of developing policy.

I understand my colleagues on the Science Committee have requested a General Accounting Office evaluation of the FDA’s use

of this monitoring system in the development of policy regarding

ephedra. The report is expected to be released in the coming

months, and we look forward to utilizing this report in our investigation.

Three, time lag for Freedom of Information Act requests. If someone outside the FDA wants more information on an adverse event,

they have to file a Freedom of Information Act request. This process is so slow that sometimes it takes over a year.

Can you imagine being a manufacturer of a supplement and the

FDA’s website states that someone died after taking your product,

and the FDA will not provide you information about the report for

over a year? Think about that. You could go out of business because they erroneously put something on a website about an adverse reaction to a product that you produce and they are wrong,

and you can’t get that corrected for over a year while your product

is on the market. You can bankrupt a business when the FDA is

wrong. That can’t be correct.

One case recently reported in the press was a manufacturer who

had 14 events and one death reported on the FDA website for their

product, and the FDA told the manufacturer they were too busy to

respond to his concerns. They are still waiting after 11 months for

the FDA to provide information on these events.

Another requester has still not received information after 1 year.

The industry wants to work with the FDA, but how is the industry

supposed to be responsive when the FDA will not give them any

information?

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Is the FDA’s response to the pharmaceutical industry the same

on prescription drugs or to manufacturers of infant formula and

other food products?

Fourth, timely updates to the FDA website. The current website

has not been updated since October 1998. This is over 6 months.

If the public is looking to this website for information on adverse

events and dietary supplements, they are not well served by a system that is not current, that is out of date.

No. 5, brand and corporate name identification without confirmation. The FDA identifies products and companies on the website. Is

it appropriate to do so, especially since they did not determine if

the product actually caused the event or whether the product was

actually consumed by the patient?

So you list something on the website that has not yet been documented or proven, and you put that company in jeopardy without

proper information and proper confirmation.

No. 6, incorrect information not purged. Sometimes the FDA

makes mistakes. Companies may find their name or product listed

as having caused an adverse event when they do not make a product which contains the ingredients listed.

If the FDA went back and fixed mistakes, there would be no

problem, but they don’t. The FDA commissioner alluded to this

problem in response to questions at our March 25 hearing. They

told us that it is a monumental task to have the FDA make any

changes to a report, so if they make a mistake, it is a monumental

task for them to correct the mistake.

Is it a responsible act to leave misinformation about a company

on a government website with a small footnote stating the corrected information? With the increased use of dietary supplements

by Americans and with concerns about adulterated products, drug

interactions and the need to identify public health concerns, an accurate and effective reporting system for dietary supplements

should be a high priority for the Food & Drug Administration.

Now, let’s talk about ephedra, as an example. In January, the

FDA published its priority list for 1999 activities. Resolving the

proposed rule on ephedra was listed at the top of the Center for

Food and Applied Nutritionals’ list for dietary supplements.

Ephedra has been a very controversial supplement. It has been

used for thousands of years in traditional Chinese medicine for

asthma. Approximately 15 billion servings of ephedra supplements

were used last year in hundreds of products.

The plant version of ephedra is used as a dietary supplement.

The synthetic version is used in over-the-counter medicines like

Sudafed and Primatine Mist. Sometimes it has been abused.

In the past, there have been a few unscrupulous companies that

marketed illicit street drugs containing high doses of ephedrine.

We applaud the FDA for stopping these companies. We also applaud the respectable supplement manufacturers who worked with

the government to stop this criminal activity.

We will hear today from two mothers whose sons died after taking products containing large amounts of ephedrine. Our sympathies are with them and their families.

Let me make it very clear that no one in Congress has fought

harder against drug trafficking than I and many of my colleagues.

5

We have sponsored legislation to give the death penalty to drug

pushers. It is my understanding that these products are now off

the market, the ones that we are talking about.

If they are not, the FDA clearly has the authority to seize them.

This hearing is about whether the FDA is doing a good job in

tracking adverse events; are they giving the public and the medical

community reliable information.

On the one hand, if a supplement is causing harm, it should be

removed from the marketplace. On the other hand, if the FDA is

giving the public erroneous information, then potentially good products that help people could be removed from the market and many

companies could be in jeopardy. What we need is good information

so the American people can make good decisions, and the Congress

as well.

This hearing is not about deciding whether the current proposed

rule on ephedra is the correct stand or not. It is about finding effective solutions for the obvious problem of an ineffective system so

the FDA can fulfill its mandate of protecting the public. With the

passage of the Dietary Supplement Health and Education Act, the

onus is on the FDA to determine safety of a product, and if it is

not safe to remove it from the marketplace.

Some have said that the FDA would like to use a tragedy caused

by a few unscrupulous manufacturers to change how we regulate

an entire industry, retract the Dietary Supplement Health and

Education Act and regulate dietary supplements as drugs, not

foods. I hope that is not the case. That is not the right way to make

policy.

We are pleased that Dr. Joseph Levitt, Director of the Center for

Food Safety and Applied Nutrition at the Food & Drug Administration will be addressing us on the development of the special nutritional adverse events monitoring system. He will detail how this

system functions and how it compares to other monitoring systems

within the FDA and other HHS organizations.

I have been told by my staff that Mr. Levitt and staff from the

FDA plan on leaving after the first panel is finished. I would request, Doctor, that you stay to hear the other witnesses and be

available to answer questions that may arise as a result of the

other testimony.

Mr. Levitt, I appreciate that you are here today, but these people

represent the public that both you and I serve. I really think if it

is at all possible that it is valuable for you to stay and hear what

they have to say, especially considering that we have two mothers

who have lost their sons to adverse events.

We will hold the record open until June 10 to allow written submissions to the record. I will wait until the second panel comes to

the table to introduce them. But before I introduce our first panel,

I would like to recognize our ranking minority member, Mr. Waxman, for his opening statement.

[NOTE.—The submissions referred to may be found at the end of

the hearing.]

Mr. WAXMAN. Mr. Chairman, today’s hearing raises important

questions about the regulation of dietary supplements. The Food &

Drug Administration [FDA] is supposed to ensure the safety and

effectiveness of an enormous range of health products, including

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supplements. To do so, it is essential that manufacturers report

deaths and other adverse events to the FDA. This is the rule that

applies in the case of drugs and medical devices.

But the public will be surprised to learn that manufacturing of

dietary supplements are exempt from the most basic public health

protection. When Congress enacted the Dietary Supplement Health

and Education Act of 1994, we severely limited FDA’s authority

over supplements. FDA may not approve supplements before they

are marketed and FDA is held to the very high threshold of demonstrating a ‘‘significant or unreasonable risk of illness or injury

before it can remove an unsafe supplement from the market.’’ This is a higher threshold than FDA has for dealing with foods,

drugs, or medical devices. This means it is up to the supplement

industry to ensure that the products that they are making are safe.

But here, too, we have restricted the FDA.

We require all drug and medical device companies to report any

adverse events they learn of which are associated with their products, but not dietary supplement companies. Instead, we rely on

them on a wholly voluntary system of reporting.

This system is not adequate to protect public health. There are

many unavoidable problems with a voluntary reporting system, not

least of which is the possibility that manufacturers become aware

of problems with products and choose not to share that information

with the FDA.

I am interested in learning from today’s witnesses how reliable

the current system has been and how the system can be strengthened.

I want to commend the chairman for his balanced approach in

putting this hearing together. He has graciously and appropriately

agreed to allow three witnesses that we have requested to testify.

As a result, we are going to have witnesses here today who can tell

both sides of the story, including witnesses who have lost family

members because of ephedra products.

I look forward to hearing their stories and to learning from their

firsthand experience about the need for a strong monitoring system, especially for dietary supplements that do not have to undergo

any premarketing testing for safety.

Let me make a final comment about FDA’s regulation of ephedra.

Ephedra is practically a molecular twin to methamphetamine, or

speed. The DEA already has restricted its availability. And, in response to hundreds of adverse events related to ephedra supplements, including several deaths, the FDA proposed to limit the

amount of ephedra permitted in supplement doses and to require

labeling to fully inform consumers about their risks.

This seems to me sensible. Despite the industry’s claims, there

is no ephedra ban. No one is going to burst into your home to take

away your ephedra. Instead, the regulation appears to contain

minimal, common sense health safeguards.

There is a lot of misinformation about ephedra. That is why I

found Dr. Tim Johnson’s comments this morning on Good Morning

America to be so helpful, and I would like to play his comments

for the committee. I think he cuts through a lot of false claims and

provides a balanced analysis.

[Video tape played.]

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Mr. WAXMAN. I hope that we can approach this issue with the

same kind of objectivity that Dr. Johnson displayed in his presentation. I welcome our witnesses, and I look forward to their testimony. I hope that out of this hearing we will get information that

will help us do our jobs better.

Thank you, very much, Mr. Chairman.

Mr. BURTON. Did you have an opening comment?

Mr. KUCINICH. Just for a minute.

Mr. BURTON. Let me yield to Congresswoman Morella.

Mrs. MORELLA. I want to thank you for calling for this hearing

because I look forward to hearing about the adverse event reporting system. But I was just reminded of the fact that recently I had

a group of school students who came in and I took them on the

floor of House.

I showed them where the Speaker stands; and during the Q and

A one of them said, You have a speaker, but do you have a listener? So I am going to be a listener today, and I hope to learn a

great deal. Thank you.

Mr. BURTON. That is refreshing.

Mr. Kucinich.

Mr. KUCINICH. Thank you very much, Mr. Burton. I want to

thank you, Mr. Burton, for your continuing efforts to provide a balanced public presentation of the possibilities of alternatives of

health care in this country.

I think that all of us appreciate the opportunity to look at not

only the challenges which face health care but also the possibilities

of new approaches that people might use in order to expand their

own health and to improve the quality of their lives.

I support your endeavors in looking at alternative medicine, and

I know that the concerns that are expressed today about the use

of supplements are concerns that ought to be taken with a great

deal of seriousness.

It is my view that while food supplements can provide many useful opportunities for people to have better health, I think we are

starting to gather a lot of information that would suggest that

some degree of professional supervision may be helpful in order to

protect the health of the consumer.

Not every consumer has the kind of background that would enable them to be safe in the consumption of some of these products.

On the other hand, I don’t think that products ought to be withheld

from the market simply because they are not approved by the FDA.

Now, this is a very difficult matter that we face, and I know that

the testimony will help to resolve some of it, at least for the moment. So I thank you again, Mr. Chairman. Thank you, Mr. Waxman, for your leadership on this issue.

Mr. BURTON. Do other Members wish to be heard?

Mr. Cummings.

Mr. CUMMINGS. Mr. Chairman, thank you very much. I join with

my colleagues in expressing appreciation to you for this hearing.

Whenever I go to the health food stores, the place is packed with

people trying to improve their health, trying to deal with health

problems, and so this hearing is quite appropriate.

The Food & Drug Administration is the governing body charged

with the responsibility of regulating the production, distribution,

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and consumption of prescription and over-the-counter drugs. In

keeping with its general purpose, it seems only natural that the

FDA has an adequate system of monitoring the adverse effects of

dietary supplement products that are not FDA regulated, specifically those like ephedra.

The need for a careful examination and assessment of the Food

& Drug Administration’s AER reporting system, particularly in the

way of stimulus-like drugs, like ephedra, is evidenced by not only

the 38 deaths and the several hundred voluntarily reported cases

of adverse events caused by ephedra or synthesized versions, but

also in the history of the Federal action involving ephedra, which

dates back as early as 1983.

In addition, after giving consideration to the fact that in 1998 the

DEA noted an increased relationship between synthesized ephedra

and the street drug methamphetamine, it becomes obvious that the

nature of this stimulant is one that necessitates mandatory monitoring and reporting of its adverse effects.

I am interested to hear Mr. Levitt’s testimony concerning the

AER system and how the FDA seeks to modify the process toward

making it a more efficient and effective means of monitoring

ephedra and other dietary supplements which might have adverse

effects to the public. Thank you very much.

Mr. BURTON. I thank the gentleman.

Are there further Members that want to be heard? If not, Mr.

Levitt would you come forward.

[Witness sworn.]

Mr. BURTON. We welcome your opening statement, Mr. Levitt.

STATEMENT OF JOSEPH A. LEVITT, DIRECTOR, CENTER FOR

FOOD SAFETY AND APPLIED NUTRITION, FOOD AND DRUG

ADMINISTRATION

Mr. LEVITT. Thank you, Mr. Chairman and members of the committee. My name is Joseph A. Levitt. I am Director of the FAA

Center for Food Safety and Applied Nutrition, often referred to as

CFSAN.

Joining me today at the table is Janice F. Oliver, my Deputy Director in the center, and on my right, Dr. Elizabeth A. Yetley, who

is Director of the Office of Special Nutritions within our center and

it is their office that we regulate dietary supplements.

I am pleased to be here today to discuss FDA’s adverse event reporting systems generally, and specifically CFSAN’s adverse event

monitoring system, referred to by the initials SN/AEMS, which

stands for special nutritionals adverse event monitoring system,

and this includes dietary supplements.

Mr. Chairman, if I may respond to your request that you made

in your statement about my staying at the hearing, while I had not

planned to, at your request I will be glad to with the one request

that I be allowed a 2-minute break between panels in order to rearrange my schedule.

Mr. BURTON. That is fine.

Mr. LEVITT. Let me begin by saying that we are here today to

focus on FDA’s adverse event reporting system for dietary supplements. As Dr. Henney stated when she testified before this committee on March 25, 1999, the intent of the Dietary Supplement

9

Health and Education Act [DSHEA], was to provide consumers

with broad access to dietary supplements while at the same time

to assure the safety and proper labeling of those products.

The adverse event monitoring system for dietary supplements is

a critical part of FDA’s ability to meet the consumer protection provisions of the law. We believe the current system serves as a valuable source of information to signal—and we will be hearing that

word a lot today—to signal potential hazards associated with the

use of dietary supplements.

However, we agree with what you said, Mr. Chairman, in your

opening. We believe there are both enhancements and refinements

to the current system that need to occur.

As we move ahead, we want to learn from our experience to date,

including our experience with ephedra-containing products, which

I know that the committee is particularly interested in. We welcome this opportunity to continue a dialog with the committee on

this important issue and how we approach this task.

Mr. Chairman, if I may just divert for one moment with your indulgence, since this is my first time for appearing before your committee as a principal witness, let me just share for a moment some

of the overall themes that I have tried to bring to the center in the

leadership position that I have been at for a little over a year now.

One thing that people are very curious about when somebody

takes a new job, is what does that person really stand for? What

values does that person bring to the job? And I have over here a

poster on my right which stands in our lobby. It is a little faded

because it has been there for a year, but it lays out five major values that I have tried to stress in the year that I have been at

CFSAN and which I think are very applicable here today.

No. 1 is public health and safety. We are a public health and

safety agency and that needs to be our highest priority. Clearly you

are recognizing that, and that is the subject of today’s hearing.

No. 2 is respect. I think it is very important that we at FDA and

in government as public servants show respect for all of those on

the outside that we deal with, be they from industry, health professionals, or consumers; and I think Dr. Henney tried to signal that

also in her testimony here earlier this spring.

I also think that it is important that we show respect for the law.

I am a lawyer. I think in our case the law provides both tools for

us to get our job done as well as boundaries that we must live

within. As a lawyer I have particular sensitivity to that.

No. 3 is integrity. In all that we do, what FDA needs to stand

for more than anything else is we are a group that is independent

and able to provide objective assessments for the public. That is the

groundwork on which our credibility is based, and that is paramount.

Four is dedication. I have worked at FDA for over 20 years, and

I think if there is probably one word that characterizes our work

force more than anything else, it is dedication. We have a hardworking, dedicated staff that does its best on behalf of the public.

Finally, it is not just dedication to anything; it is a dedication to

excellence—excellence in science, excellence in regulatory policy,

excellence in communication. You spell those out as you can see

and it spells out pride.

10

I have tried to bring a sense and culture of CFSAN pride to all

of the work that we do; and I have found that in the first year that

I have been there, it has been a very valuable galvanizing force to

say this is what we stand for. Thank you.

Moving back to dietary supplements, I would like to summarize

my written testimony by highlighting three main points.

First, there are inherent strengths, but also inherent limitations

in all spontaneous reporting systems, be they for drugs, biologics

devices, or dietary supplements.

The major utility of a surveillance system based on spontaneous

reports is to generate signals of potential health problems. These

signals warrant and demand further investigation and must be

evaluated in the context of other information which may include

one or all of the following: controlled clinical trials, scientific literature, market and consumer surveys and product analysis.

There are also significant limitations. The major limitations to

consider when assessing spontaneously reported information is

underreporting of adverse events, report quality, adverse event recognition or attribution, reporting biases that are inherent and estimation of population exposure.

Notwithstanding these very relevant limitations, postmarketing

surveillance based upon spontaneous report data has been a very

powerful tool for detecting adverse event signals.

Second, within the FDA the most developed system for adverse

event reporting is a system used for prescription drugs. This system, however, has had over three decades to mature and benefits

from a number of tools not available to dietary supplements, for example, premarket testing a data base, mandatory reporting by

manufacturers, and access to market exposure data, sometimes referred to as denominator data.

Moreover, even in its current state, the agency continues to incorporate enhancements into the prescription drug reporting system and to fine-tune it as necessary. By contrast, the agency’s reporting system for dietary supplements was developed only recently

in 1993. And so comparatively speaking, it is still in its infancy.

This means we are still in the process of developing the infrastructure, the resource base, and the overall framework of this adverse event monitoring system. We recognize that there are many

challenges that we face with the current system and we intend to

address each area that will make the system stronger.

The fiscal year 2000 budget request which is now before the Congress includes $2.5 million to enhance the adverse event monitoring system within the foods program. Most of these funds would

buttress reporting system for dietary supplements as these products provide the largest share of the center’s adverse event reports.

If these funds are provided, we would hire several additional

clinical staff to review the adverse event reports, and we would develop a system to integrate adverse event reporting and to modernize it for our entire center programs.

This system would also be compatible with other adverse event

systems within the agency. We are also now in the process of assessing our longer-term needs as we develop the budget for 2001.

Third and most importantly, notwithstanding its degree of development, the dietary supplement adverse event monitoring system

11

is capable of and has surfaced important safety issues for the benefit of the American public. This includes identifying a serious

manufacturing product in samples of raw material labeled ‘‘plantain’’ that contained digitalis, and more recently identifying the

basis for removing from the market products contain gamma butyrolactone or GBL.

It is critical that FDA be able to move rapidly to protect consumers when significant safety problems arise, and I believe there

is general acceptance of that principle.

In closing, Mr. Chairman, I would like to place in context today’s

subject of adverse event reporting for dietary supplements as it relates to our commitment to develop this calendar year an overall

strategy for achieving effective regulation of dietary supplements

under the law.

As part of our ongoing consultation with stakeholders, the agency

has scheduled two public meetings to solicit comments that will assist CFSAN in developing a strategy and this will include, certainly, input on adverse event reporting for dietary supplements.

The first meeting is coming up soon, July 8 in Washington, DC.

The second is on July 20 in Oakland, CA. I will personally chair

each of these two meetings. I would encourage interested persons

to attend one of these sessions.

It is not necessary to attend both, as we are essentially repeating

the same meeting on the West Coast so as to save stakeholders the

time and expense of traveling East. For those who cannot attend,

comments may be submitted in writing to the public document.

We look forward to input on development of an overall strategy

for dietary supplements. Developing the solid blueprint for implementing the DSHEA is essential. This will ensure that the implementation is guided by a framework that will both protect consumers and enable them to make informed choices by using dietary

supplements to improve their health.

Thank you, Mr. Chairman. I would be happy to respond to questions you may have. I also note I am getting a note passed to me

that I have misspoken. The two public meetings, one is in June. It

is on June 8. The second is on July 20. I am sorry if my eyes

skipped down.

Thank you very much for your attention. I will be happy, with

my colleagues, to try to answer questions.

Mr. BURTON. Thank you, Mr. Levitt, and thank you for that correction.

[The prepared statement of Mr. Levitt follows:]

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Mr. BURTON. Why is it that the FDA evaluation reports determine the causality in veterinary medicine for animals but not the

dietary supplement for humans?

Mr. LEVITT. I think the question is addressing how we evaluate

the strength of the reports. That is really what you are talking

about. In your statement you listed two main things. One is seriousness and one is what you referred to as causality. I would like

to think of that as attribution or how strong is the association.

Inherently, with any passive reporting system, whether it is veterinary drugs or human drugs, there are going to be limitations in

terms of how much information is available to us, both in terms of

how much is available and what other activities are present,

whether it is other therapies, other medical conditions, special populations. All of those have to be evaluated together.

I think it is, however, a misconception that that is not part of

the system as we have it because inherently when our medical

staff—we view reports, that is a very important part of what they

look at.

One thing that I have, I think, gleaned from, as I have looked

more into this recently, is an important lesson from what has happened is that we need to have greater transparency and understanding of the process that we have. And one thing that we will

be undertaking will be to describe better what processes that we

do use and also how can we refine those processes.

Now, if I can add—to help us do that, we have set up a working

group under the auspices of our food advisory committee to address, specifically, adverse event reporting; and this has broad

membership of health professionals as well as industry. And this

group is just getting going so the timing is very good.

They have two charges which have already been written out. I

think after this hearing we will go back and decide if we need to

broaden or refine the charge because the timing is too good not to

take advantage of that. But the charges are twofold.

No. 1, to identify medical toxicological and communication principles or guidance that could assist industry in establishing and

implementing a system to solicit, collect, evaluate, and report potential safety concerns associated with product purity and consumer complaints and reports of illness or injury. So the first

charge is what are things that the industry should be looking at

to do better.

The second is directed to FDA. Based on your knowledge or experience in other food safety or food science arenas, could you please

suggest mechanisms for FDA to share post market surveillance information with consumers, the dietary supplements industry, the

medical community, and other surveillance system.

So as I said, this group is being assembled right now and I think

that we should take advantage of what is learned today and feed

that back in so we can have recommendations.

Mr. BURTON. I glean from your answer that you are going to be

doing that in the future, and in the past you haven’t.

Mr. LEVITT. What I am trying to say is that in the past, that has

been more a part of the process of internal evaluation, and it has

been obvious to outsiders because it hasn’t been designated to 1,

2, 3, 4.

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But when I talk to the reviewers and ask them how do you

evaluate the reports, one of the most important elements that they

look at is how strong or how weak is the association with it. And

I think we need to clarify that.

For example, when we later talk about ephedra, there are large

numbers of reports that are often reported, saying FDA has so

many reports, and that is so. However, FDA within the internal

analysis breaks those down much more and tries to look at that.

So we need to spell out where and how we do it so it is better

understood. And if we are not doing it as well as we should, we

should improve that, too.

Mr. BURTON. Thank you. One of the things that concerns me—

and I mentioned it in my opening statement—is that things are

posted on your website and they may or may not be accurate. The

information that you have on there may be a conclusion that is

reached, but it takes a year or more for that to be clarified or removed. During that time the company that may be the ‘‘victim’’ or

the person who suffers from this, may not be able to get that clarified, and it may hurt the sale of their product at the marketplace.

During that time many companies have had difficulty getting the

FDA to respond to them to clear up these misunderstandings.

I know that my time has expired, and I will talk more about this

in a second round. One of the things that concern me—I take Slim

Fast. I know I look thin, strong, healthy and everything—why is

it that nobody is smiling at that?

In any event, if you look at the website that you have, you show

approximately 22 problems that are created by Slim Fast that may

or may not be accurate and probably hasn’t hurt because people

still continue to use it, but could hurt a product like that in the

marketplace.

And during the time that a company is trying to explain to the

people that buy it, who might be scared to death after reading

something like this on the website, they have no recourse because

you are not having a dialog with them and getting it cleared up.

So what’s the answer to that?

Mr. LEVITT. I think the answer to that is that we at the FDA

need to have a greater sensitivity to the manufacturers in this

whole process. We have focused primarily on our internal work.

The reports come in. We try to look at them, and making time and

resources available for getting the reports FOI purged and ready

to submit has taken a back seat.

Earlier this year, when that was brought to my attention, we

have allocated funds this year but we are terribly behind and it

will take us some time to catch up.

But if I were to paint a picture of the way that I would like to

see it, we need to have a system so that as with other product centers, if you look around within FDA, reports come in; they go

through the normal purging for names and identifiers of health

professionals and patients if they are there, and they are sent to

manufacturers because the manufacturers have an important role

to play, not just in knowing what is there but in helping and investigating what is going on with this product. And that’s something

we have to try and fix.

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Mr. BURTON. I want to go ahead and yield to Mr. Waxman, but

let me just say that I think that’s something I would like to work

with you on, and I think the committee would like to work with

you to make sure that businesses who may have been hurt by misinformation that has been put on the website or public, into the

public domain, have quicker access to the FDA so they can clarify

those things so they don’t suffer.

If a product is bad, it should be off the market. We don’t want

it to hurt the people. But at the same time in the free enterprise

system, we want to make sure that businesses don’t suffer either

because of erroneous information put on the website that they can’t

get off, and work with you to clarify those things.

Mr. Waxman.

Mr. LEVITT. Yes, thank you. And we need to be working more

closely with companies on their followup.

Mr. BURTON. OK.

Mr. LEVITT. So that we can have a stronger system.

Mr. WAXMAN. Thank you very much, Mr. Chairman. One of the

most fundamental safeguards of public health is adverse event reporting. An adverse event is a death or serious disease or injury

that’s linked to the use of a drug, a medical device, or a dietary

supplement. Adverse event reporting is required of some product

manufacturers but not of manufacturers of dietary supplements.

Can you explain why adverse event reporting is so important to

protecting the public health?

Mr. LEVITT. Well, with any product, even those that have premarket testing and review, once the product gets onto the market,

it is exposed to many more people, many different kinds of people,

people that are taking different kinds of medications, have different

medical conditions, and any premarket system is not going to be

able to pick up rare events, interactions or other things that control

trials cannot do.

When you have a system such as here, where there is no premarket, that is even more important because that is the way that

we can pick up signals that there may be a problem with the product. And so we need it as a critical feature to signal us, hey, there

may be a problem with this product; FDA, you need to look into

it; you need to work with the company and say maybe we need to

do something to improve things.

Mr. WAXMAN. If a drug is on the market, and it has already gone

through an approval process where FDA assures the safety and efficacy of that drug, is the manufacturer of the drug required to report adverse impacts from the use of the drug?

Mr. LEVITT. In the context of prescription drugs, yes, manufacturers are required to report to FDA all adverse events that they

receive associated with their product. They have to report on a

more urgent basis those that are serious and unexpected, meaning

not on the product label; and later on, more routine reports. But,

yes, they are required to submit those.

Mr. WAXMAN. How about medical devices such as x-ray machines

or artificial joints; does the law require the manufacturer of medical devices to report adverse events?

Mr. LEVITT. Yes. Medical device manufacturers are required to

report. The definitions are a little different, but by and large, it is

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an attempt to require the submission of important serious adverse

events to the FDA.

Mr. WAXMAN. Now dietary supplements, however, are governed

under different rules. Can you tell us whether manufacturers are

required to inform FDA if they learn about an adverse event report?

Mr. LEVITT. There is no requirement that manufacturers make

those submissions to us.

Mr. WAXMAN. This, as you pointed out, is like a double whammy.

With other products, you have to assure the safety and in many

cases the efficacy before the product can be sold. Dietary supplements can go right on the market without any scrutiny by FDA in

advance. But even manufacturers of those products that had to be

preapproved before they could be marketed are required to report

when there is an adverse event. But dietary supplement manufacturers are not required to report an adverse event to you. They are,

however, encouraged to do it voluntarily; isn’t that true?

Mr. LEVITT. That is correct, as are health professionals. We probably need to strengthen our outreach there to get as many highquality significant reports as health professionals are coming

across, as well as to the industry.

Mr. WAXMAN. Well, it seems to me this puts a good manufacturer

at a disadvantage because it makes it impossible for a consumer

to know which products have been manufactured responsibly and

which products have not. Would you agree?

Mr. LEVITT. That is correct.

Mr. WAXMAN. Now, under the Dietary Supplement Health and

Education Act, we have a voluntary system of reporting adverse

events. This means that if a dietary supplement manufacturer

learns of a problem associated with its product, there is no obligation to report the problem to the FDA. Are you aware of any situations of manufacturers not reporting problems about its product to

the FDA?

Mr. LEVITT. We don’t have direct evidence, information, on that

one way or the other. Also, unlike the other systems, manufacturers are not required to register with the FDA.

Mr. WAXMAN. If they don’t tell you, you don’t know?

Mr. LEVITT. That’s correct.

Mr. WAXMAN. Well, let me tell you and everybody else here that

my staff is doing some research on this issue, and they talked to

the people in the State of Texas where they found that there were

manufacturers and distributors who had received a large number

of complaints about their products.

In fact, I have for the record a list of some of these adverse impacts from the use of the products. One company received over 150

complaints of side effects, including complaints of high blood pressure, kidney problems, difficulty in breathing. Another company received complaints that their product had been linked to at least one

heart attack and one case of seizures. Many of these complaints

even came directly from doctors’ offices, where the doctor learned

about what was happening to the patient and called the manufacturer and said, ‘‘You better know that your product is causing these

distressing events.’’

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While many of these complaints went to the manufacturer, we

found out from the Texas Department of Health that the companies

didn’t share these complaints with the public or the Texas Department of Health until they were compelled to do so by a court.

And I would like to ask unanimous consent to put in the record

at least a summary of some of these complaints I doubt you ever

heard about these complaints unless you found out about them

after the court case. But the manufacturers weren’t rushing to report voluntarily what they, in my view, should have been required

to report under the law, if the law had been drafted the way it

should have been.

Mr. BURTON. Would the gentleman allow us to put a sampling

of those along with the number that you have?

Mr. WAXMAN. Mr. Chairman, I ask unanimous consent that they

be put in the record at the discretion of the chairman. You can go

through them and determine whatever is appropriate to get the

point across.

Mr. BURTON. Very well.

[The information referred to follows:]

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Mr. WAXMAN. One of the arguments we sometimes hear is adverse event reporting is not needed because dietary supplements

are always safe. I want to ask you about that. FDA has received

about 1,000 adverse event reports relating to ephedra. About how

many of those reports are classified as serious?

Mr. LEVITT. Of the—we have received overall about, I believe the

number is about 1,000 reports altogether. The number, total number that is serious, I am going—I am going to give an estimate and

then provide for the record something that is more detailed. But

my impression, it is in the vicinity of 30 to 40 percent. I could be

wrong on that but that is the impression I have from talking—it

is a large enough number that it is—that it is of concern to us. It

is not by any means all of the reports.

Mr. WAXMAN. My last question to you is: Is it not correct that

of those reports, 45 were of deaths?

Mr. LEVITT. There are a number of reports of deaths in there. I

don’t know if that is the exact number but we could certainly check

on that, too.

Mr. WAXMAN. Thank you very much.

Thank you, Mr. Chairman.

Mr. BURTON. I think that we might ask Dr. Henney at some

point to sit down with us and discuss some of the issues that have

been raised by Mr. Waxman after this meeting to see if something

can’t be done to clarify some of these issues.

We would certainly like to look into that and talk to her about

that.

Mr. LEVITT. I think—I don’t know what the right process is but

I would hope there is also a process for FDA to obtain access to

the adverse event reports if there are safety issues there that we

need to know about.

Mr. BURTON. There is a definition of serious side effects for prescription drugs, is there not?

Mr. LEVITT. Yes.

Mr. BURTON. Did you have questions? I am sorry. Ms.

Schakowsky.

Ms. SCHAKOWSKY. Yes.

Mr. BURTON. Let me yield to Ms. Schakowsky and I will get back

to my questions in just a moment. I am sorry.

Ms. SCHAKOWSKY. Thank you, Mr. Chairman. I don’t mind waiting for you.

I wanted to continue the line of questioning that Mr. Waxman

was beginning.

You had said that there were 30 to 40 percent that were serious.

Actually, we heard—and we also heard that there were about 45

deaths. But what is considered serious? Could you tell us what

kind of events are considered serious?

Mr. LEVITT. Yes. The general issues that we would consider serious are as follows, and I think I will just read them to be sure that

I get this exactly right.

No. 1 is when the outcome is death, is life-threatening, it requires hospitalization or prolongs hospitalization, causes disability,

congenital abnormality or requires intervention to prevent permanent impairment or damage. Those are the general criteria under

the MedWatch program.

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In addition, within our program, we would add on the following,

which says that other medical events that may not be immediately

life-threatening but which require intervention to prevent one of

the serious medical conditions, meaning one of the MedWatch outcomes I just said, would also be considered medically serious.

So it would—both something where we have reached the outcome

as well as something that could lead to it. And we consider all of

those to be serious under, if you will, the general categorization of

dangerous, critical or alarming.

Coming back just to a point earlier, this is not something that

we have been as transparent to the outside world as we should be,

and that is something that we will be addressing so that it is clear

to everybody. It also is worth noting that in the recently revised

regulations for prescription drugs, the definitions are very consistent.

Ms. SCHAKOWSKY. Just to clarify, then, in my own mind, you are

saying that while these serious event—these reports are not required—that of the thousand reports, you think probably about 30

to 40 percent are serious. You have read what serious is. I think

anyone listening to that would agree that’s very serious; and it

seems to me that your expression of concern is certainly warranted

and that is shared by members of this committee as well and may

require some further action. I think it almost certainly would.

FDA has issued warnings to consumers about a number of other

supplements besides ephedra, and I want to mention a couple of

those. The FDA recently issued a warning about products containing GBL and asked companies to recall the product. According

to the FDA press release, GBL is related to 55 adverse events. Can

you talk a little bit about what those adverse events were and how

serious they were?

Mr. LEVITT. Yes. Well, the GBL is a product that converts itself

in the body to a drug referred to as GHB, which is a well-known

sedative and not an approved product on the marketplace.

We had, of those 55 events, they all were consistent with each

other as being quick after taking the product. About 20 of those

were associated with somebody who actually was unconscious,

sometimes into a coma. There was also one event that was reported

in the context of a death.

In that setting, it was clear, I think, that—to everybody looking

at it, we had a clear pattern.

Going back, Mr. Chairman, to your question about causality or

attribution, we had a very strong association; we had a known

product; we had exactly the same kind of result that would be anticipated from what we know of that product, and we said that

product needs to come off the market.

Ms. SCHAKOWSKY. In this instance, it was one death?

Mr. LEVITT. One death reported. One report was based on a

death, yes.

Ms. SCHAKOWSKY. In 1998, the FDA issued a warning about 5

HTP, which is found in supplements promoted to treat insomnia,

depression, obesity, and for children with attention deficit disorder.

According to the FDA press release, 5 HTP contained impurities

that are similar to the impurities that were found in L-tryptophan,

which was banned because it was so dangerous.

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Do you remember how many adverse events were associated with

L-tryptophan?

Mr. LEVITT. I am going to ask Dr. Yetley to see how her memory

is since that’s prior to my involvement.

Dr. YETLEY. That particular issue was one that was related to a

report that came out of the Mayo Clinic in which they had analyzed those products on the marketplace and had found the presence of an impurity. As soon as they had raised that issue to our

attention, we had our chemist work with the Mayo chemist. They

developed a method, they developed a standard method, for it. We

met with the industry, shared our information on how to test their

products for this particular contaminant.

It is my understanding that the industry has worked hard to

look at their products and to assess them. So that was not particularly an issue that came up from the adverse event system but was

one in which we were trying to prevent adverse events because we

had information about a contaminant.

Mr. LEVITT. If I could just add, I am not sure Dr. Yetley heard

the question properly. She reacted to something that happened

within the last year or so. If you are reacting—questioning about

L-tryptophan which was in the late eighties, there were a number

of reports associated with that.

Do you recall the number?

Dr. YETLEY. L-tryptophan is a related but somewhat different

product than the 5-hydroxy L-tryptophan.

This was a concern that was raised through the reports of adverse events. We had a number of serious injuries and illnesses.

We worked with the manufacturers. They did voluntarily recall

those products from the marketplace. We did issue warnings, and

there was some research done and we have never clearly resolved

whether or not those injuries were due to a contaminant, were due

to the product itself or to some interaction within the product, but

there was a fairly quick action on the part of the agency and a response by the industry in response to those adverse events.

Mr. LEVITT. Right. There was a sizable number, were there not?

Dr. YETLEY. It was a sizable number. I don’t remember the exact

number.

Ms. SCHAKOWSKY. If I could just make one more comment. It

seems to me then, given these examples, that adverse event reporting can help to resolve these dangers and that we have some good

examples of that being the case?

Mr. LEVITT. Yes, absolutely. And that was one of the points I

tried to highlight earlier, but thank you for reinforcing that.

Mr. BURTON. Before I yield to Mr. Horn, let me just say that it

is my understanding that L-tryptophan, it was because of an adulteration of the product that you had a problem; it was not the Ltryptophan itself?

Dr. YETLEY. It is not clear. The research that was done did not

clarify that completely.

Mr. BURTON. But once you worked with the industry and they

cleaned up the L-tryptophan to take out the other adulterated

products, was it no longer a problem?

Dr. YETLEY. I believe the marketing of that particular product

was pretty much limited or restricted to a great degree.

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Mr. BURTON. Well, it is still being marketed and used, though,

is it not?

Dr. YETLEY. I don’t know the current use, but it was not used

for quite a long time after that particular period.

Mr. BURTON. It was my understanding that it was because of the

adulteration, but we will look into that.

Mr. Horn.

Mr. HORN. Thank you very much, Mr. Chairman. I am sorry I

have missed some of the previous presentation.

Let me give you an example apparently that occurred on the

website. The FDA reported that a 27-year-old female had nausea,

passed out, suffered liver damage as a result of taking Slim NRG

Plus, a product containing ephedra. However, the woman had also

taken Nyquil and two glasses of wine. A drug screening showed she

had also consumed acetaminophen, nicotine and three other drugs.

I guess the question is: What does the FDA do to make sure that

the adverse events that it is reporting on its website are actually

related to the dietary supplement being listed on the website?

Mr. LEVITT. OK. Thank you for raising that. I got to address only

part of that point earlier in response to the chairman’s question.

Let us take a moment on the website itself, because I think the

website is misunderstood for what it is intended to be. Maybe

based on what it is, we need to make changes also, but the website

is nothing more than a table of contents of reports submitted to

FDA.

We got all of these reports. We need to kind of keep track of

them, and a system was worked out with just a minimal amount

of information which basically is the product, the company, the nature of the reaction reported, and I guess the ingredient. It is just

a line listing, and when you see it it is just one line across the

page. That is taken verbatim from the report that comes in, even

before there is an evaluation done.

That originally, as I have come to understand it, was the center’s

way, if you will, of cataloging what came in and then following

through and doing a more detailed review.

What has happened over time is there were so many requests for

that information, and actually under the revised FOI statute for

electronic availability we are actually charged with putting up on

the web frequently requested documents, and people are asking for

this all the time so it was put up on the web.

From FDA’s point of view, it was always understood to simply be

a table of contents of what was submitted. The problem, I believe,

that we have come up to is not so much that, although maybe there

are some issues there, too, but the juxtaposition of what the chairman raised about putting that up now and not being able to make

the underlying report available to the manufacturer for very long

periods of time. So that is the only thing that is up there.

What is done in other centers is that the initial line listing is up

there; but the report is up there, too. And so the manufacturer has

access to everything and you have, if you will, a full record.

As I testified earlier, and maybe before you were able to be here,

we are seriously behind in our purging, what is called purging, or

making those documents publicly available because we have to go

through each one and take out any identifying information.

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I have authorized funds for a contract to bring us up to speed;

but the way it ought to be running, which is the way we will try,

resources permitting, to do, is we have got to get all the information available to the manufacturers and up there so that there is

a complete and full record and people are not misunderstanding,

misusing or hurt by what was originally a table of contents of

something that comes in.

Mr. HORN. Well, shouldn’t FDA have a disclaimer as to the possible inaccuracies? For example, when they put it up here and say

the Slim NRG Plus bit and the fact is they didn’t know the woman

had taken Nyquil and the two glasses of wine and the five additional drugs—and it seems to me somewhere either the authors are

at fault in some medical journal and they should have noted that

and have a drug screen and so forth, or at least a patient history.

And it seems to me when somebody tunes in to a governmentsponsored website they think this is certainly truth, except for the

IRS. But actually I would think the FDA, with its scientific reputation, would want to put a disclaimer on any case it puts up there,

that you don’t know what else this person had that led to the particular conclusion of that little point in time of a case.

Mr. LEVITT. You are right. In fact, that is at least one thing that

we have been doing. It appears at the beginning of the website. I

have heard a recent suggestion that maybe somehow it ought to

appear——

Mr. HORN. On every case.

Mr. LEVITT [continuing]. On every page, but here there is half a

dozen disclaimers. But the one that you are referring to says

‘‘There is no certainty that a reported adverse event can be attributed to a particular product or ingredient.’’ The available information may not be complete enough to make this determination. So

we have tried to make that disclaimer, and maybe we need to tie

it closer to the other information so there is no confusion.

Mr. HORN. If a person is taking numerous drugs and supplements and possibly even alcohol, isn’t it reasonable to assume that

the medical condition could have been caused by any of those

things?

Mr. LEVITT. Yes.

Mr. HORN. One last question here. If a person takes two different

dietary supplements and has a serious problem and the FDA only

reports that the problem was related to one of those supplements,

couldn’t the FDA wind up banning or regulating the wrong substance?

Mr. LEVITT. Again, that report you are referring to is simply the

ingredient listed by the person sending in the report. It does not

reflect FDA’s judgment in any manner about whether it is serious,

whether it is actually attributed to that ingredient or not.

As I said, it is a line listing of everything that has come in.

That’s why I said it needs to be joined with the fuller document so

that all that information is clearly available and people are not

misled that just because somebody reported it, it is necessarily associated and or serious.

At the same time, a lot of them are and it would be of benefit

to have the information out there.

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Mr. HORN. If there are two different supplements, as we postulated there, it seems as though FDA doesn’t try to narrow down the

cause of the illness; and the end result of that not being done is

that the FDA could wind up banning one substance and it is the

wrong substance.

Which would really be the most dangerous, to leave that on or

to test it or what, as to which substance might really have been

the problem?

Mr. LEVITT. Again, it would be—let me take a moment on this.

It would be very unusual for us to make a conclusion about whether a product, say, ought to be on the market or not based on a single report. What we are trying to do is actually quite the opposite.

Each report needs to be looked at and followed up on, but then we

need to be looking at the reports in the aggregate to say, No. 1,

is there a pattern here? Is there a consistency?

So I think the system does have that correction already within

it, subject, as I said, we need better transparency if that’s not well

understood.

Mr. HORN. Thank you.

Thank you, Mr. Chairman.

Mr. BURTON. Thank you, Mr. Horn.

Ms. Norton, did you have any questions?

Ms. NORTON. No questions.

Mr. BURTON. Let me ask just a couple of questions.

Go ahead, Henry, and I will finish up. I will yield to you now.

Mr. WAXMAN. Mr. Levitt, if I could—just so I understand this

problem of what is on the website, what do you put on the website,

a complaint from a consumer that you haven’t checked out? Is that

it?

Mr. LEVITT. Every report that comes in, the first step is to simply

make a line entry into, if you will, the inbox that says, all right,

this is a report. We will assign it a number. We will put on that

listing whatever the report says.

Mr. WAXMAN. I think it is a valid complaint if a consumer reports a problem with a product, and it turns out that it may not

have been that product at all that caused the problem, but the

FDA has posted the complaint on the website.

On the other hand, I think people who have a problem with a

product and they are sophisticated enough to go to the website and

pull down the information that is there should have some information, even though you may not have reached a complete conclusion.

Now, I gather you have a problem in cleaning up your website

because you don’t have the resources to do it. How about putting

a disclaimer that these are reports that FDA has received but cannot verify? After all, you know, the manufacturers for dietary supplements have a disclaimer on their products saying they make the

following claim, but FDA has not approved this claim and so there

is a disclaimer that the claim may not be true.

That could be a subject for further discussion, but there is a disclaimer. Why can’t you make a disclaimer and continue to post reports so people can get that information?

Mr. LEVITT. We do have that disclaimer.

Mr. WAXMAN. You do have that disclaimer?

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Mr. LEVITT. That’s up there. The question that has been raised

is whether or not that—that disclaimer automatically comes up

when consumers, you know, go into the data base or it is somehow

at the beginning somehow, so we can look at that. But the disclaimer is there.

Mr. WAXMAN. Does the disclaimer say something like there is no

certainty that a reported adverse event can be attributed to a particular product or ingredient? The available information may not be

complete enough to make this determination?

Mr. LEVITT. Yes, that’s correct.

Mr. WAXMAN. That’s your disclaimer?

Mr. LEVITT. Right. And that’s up there and that’s available, and

there are a half dozen other disclaimers along with it.

Mr. WAXMAN. Look, in the ideal world we want you to get to the

bottom of the information, put on the website information that’s

useful for consumers to know but that’s accurate. I think that’s

asking a lot of you because you don’t have the staff resources—I

know from my experience when I was chairman of the Health and

Environment Subcommittee that oversaw legislatively and otherwise FDA. But maybe we should talk further about this issue because it seems to me again that we want the information, even if

it is not complete and accurate and full information, to be available

to people. We want full disclaimers of that information.

We want you to clean up that website as quickly as possible, and

if we are going to ask you to do that then we ought to provide you

the funds to do it, among all the other things we want you to do.

Mr. LEVITT. Thank you for recognizing that.

Mr. BURTON. You will find this interesting, but Henry and I

agree on this.

Let me just say that it seems to me that it would not be a great

deal of additional work, for instance on the Slim Fast issue, which

I used earlier. You have got four pages of allegations related to

Slim Fast that scared me to death when I read it. I thought, my

gosh, I must be missing something because I haven’t had any migraines or kidney infections or gall stones or dizziness. So if you

could just put out at the side of each one of these allegations, or

whatever you want to call them, please see disclaimer, please see

explanation at the beginning of the website or something so that

people can realize that this might be an isolated case that might

be related to something else that they were taking at the same

time, I think that would really be helpful.

It shouldn’t take a lot of additional work just to put that asterisk

out there or some kind of a notation to see the disclaimer.

Mr. LEVITT. We will look into that straightaway.

Mr. BURTON. OK. I want to get back to the issue of companies

that are listed on your website as having an adverse event. A lot

of times those reports come from doctors, as I understand it.

Mr. LEVITT. Uh-huh.

Mr. BURTON. The companies that may be the subject of the criticism, or adverse event, don’t even know about them. They file a

Freedom of Information Act request after they find out about them,

and they have to wait for a year many times before they really

know what the problem is; and that can cause, as I said before, a

lot of economic problems as well as other problems.

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They have complained to us about that because they have to wait

because of the Freedom of Information Act requirements.

Now, did I understand you to say that you have an avenue, other

than the Freedom of Information Act, to get that information to

these companies so that they can work with you to clear up a problem if it does exist?

Mr. LEVITT. No. I was—you did not understand exactly what I

meant to say anyway. What I meant to say was what we need to

do—and I said I have allocated some funds to get this done but we

are still behind, so that those reports, when they come in are

promptly made so they can be made publicly available to the public

at large but also certainly to the manufacturer. It is the same preparation process we have to go through, because somebody has to go

through every page of the records and be sure that any individual

names are not on there.

Mr. BURTON. No, I understand that. But a number of the companies that have contacted us have said, yes, we would like to work

with the FDA if these kinds of complaints are made.

Mr. LEVITT. Right.

Mr. BURTON. We would like to get on with it as quickly as possible and clear it up if there is a problem, but because of the Freedom of Information Act and because it takes so long we can’t and

it does cause problems.

So if there is some way to streamline that, I think it would be

helpful to the companies and make people look with a different attitude toward you and the FDA.

Mr. LEVITT. OK. Well, thank you. What we tried to do was to

have people on staff do it ‘‘when they had time.’’ And what happened was they never had time. So we did take that suggestion and

said, all right, we will hire an outside contractor.

We are in the process of training that contractor and being sure

that there is somebody dedicated to that task. As I said, it will take

us some time to catch up; but, you know, we need to find and have

the resources so that is available, because, I mean, the industry

complaints, as Mr. Waxman said on this, are correct. They need to

have the information, too, and they need to be part of the solution

here.

Mr. BURTON. If you could give us some kind of a report after you

get this contractor trained and up to speed on how long a company

can anticipate having to wait, it would be helpful to just give a general idea, we would sure appreciate that.

Mr. LEVITT. OK. We would be happy to do that.

Mr. BURTON. We discussed the fact that there were some fly-bynight companies making some dangerous products containing

ephedra. The number of milligrams that were in the product were

excessive, and I think we are going to probably hear from one of

the parents who lost their son or daughter because of that.

What did the FDA do when they found out about that?

Mr. LEVITT. Well, I mean, FDA had a really massive effort trying

to deal with all of the reports and questions that came in about

ephedra.

Mr. BURTON. OK. But when you found out that there was a company that was loading up products with ephedra so that kids could

get an artificial high or whatever, it happened to be way above the

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norm, did you move and were you successful in getting those products off the market?

Mr. LEVITT. That was a little before my time so I am going to

let Dr. Yetley try to answer that question.

Mr. BURTON. Did you get them off the market?

Dr. YETLEY. I assume you are referring to the so-called street

drug alternatives.

We did indicate—we put out warning, first of all, so there was

public warning, and then we transferred authority—or responsibility for those to our drug center, and they have dealt with those

as unauthorized drugs and taken appropriate compliance action.

Mr. BURTON. And they have been removed?

Dr. YETLEY. Yes.

Mr. BURTON. OK. Let me ask you two more quick questions here;

and then I would like to, unless another Member has additional

questions, hear from the second panel and get back to you.

Mr. WAXMAN. Mr. Chairman.

Mr. BURTON. I am just about finished.

Mr. WAXMAN. Go ahead and finish. I was just going to ask for

a unanimous consent.

Mr. BURTON. Sure. Did the legitimate companies that make products, including ephedra, work with you to solve that problem?

Mr. LEVITT. My understanding is there were a number of meetings with representatives from the supplement industry in an effort

to try and figure out what can we do to fix this problem. Again,

since Dr. Yetley was there, I will let her elaborate if we can.

Mr. BURTON. Can you tell us about the cooperation you received

from these companies? Were they cooperative? Were they trying to

help to make sure that illegitimate users of ephedra were getting

those products off the market?

Dr. YETLEY. We did get good support from the major trade associations, and they did publicly support the agency for dealing with

these as drugs.

Mr. BURTON. Did you get that kind of support from the supplement industry as well?

Dr. YETLEY. That’s the industry I am referring to, yes.

Mr. BURTON. Thank you very much. I don’t have any other questions.

Mr. WAXMAN. Mr. Chairman, is it true that some of these products are still being sold over the Internet? I have one product called

X tablets, an herbal Ecstasy alternative. Do you know, in fact,

whether some of these products are still available for sale over the

Internet?

Mr. LEVITT. Given that, under law, companies make market

products without telling the FDA, that is entirely possible. I don’t

personally have information on it one way or the other. I will ask

if anybody else does.

Mr. WAXMAN. I gather there’s another place where you are shortchanged in resources and that’s the enforcement area.

Mr. LEVITT. Yes.

Mr. WAXMAN. So I shouldn’t be surprised if there are products

that are being sold?

Mr. LEVITT. It would be entirely possible.

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Mr. WAXMAN. I would hope that you would be able to respond to

further questions we might have in writing for the record.

Mr. LEVITT. We would be more than happy to.

Mr. WAXMAN. I will ask the chairman for a unanimous consent

at the appropriate time so that we can include those in the record.

Mr. HORN [presiding]. Well, without objection.

Mr. WAXMAN. You are the chairman?

Mr. HORN. I am the chairman.

Mr. WAXMAN. Thank you, Mr. Chairman.

Mr. HORN. Without objection, they will be put at this point in the

record. Go ahead if you would like to continue questioning.

Mr. WAXMAN. No, no. I want the ability to ask them questions

to respond for the record after the hearing.

Mr. HORN. Right. If you want some more time, why, take it.

Mr. WAXMAN. No.

Mr. HORN. Let me ask just a few closing questions here. In reviewing the adverse events website for dietary supplement, it appears that there hasn’t been an update since October 1998. Now,

that’s 7 to 8 months ago. I am just curious, how frequently is the

website updated?

Mr. LEVITT. OK. Again, this really is a resource-dependent issue,

and what we have tried to do is to focus our attention first on, if

you will, the substantive review of the reports and to do the public

availability afterwards. In retrospect, we may have gone too far in

one direction on that.

We update it, I think, as available. Is there a specific—— Mr. HORN. Why don’t you speak in the microphone.

Mr. LEVITT. OK. The goal had been to update it every quarter,

quarterly, but we have not been able to keep up with that.

Mr. HORN. Suppose there is a change in that particular item you

picked 2 or 3 months before and there is a correction somewhere

in a journal or whatever it is, do you try to include those updates?

Mr. LEVITT. OK. Again, the website, as I tried to explain before,

I think, is, greatly misunderstood. It is a line listing of reports submitted to the agency, nothing more.

Mr. HORN. Now those reports come from various doctors?

Mr. LEVITT. They come from doctors. They could come from consumers. They come from companies. They come from poison control

centers, from States, from whatever source we receive from anyone.

Mr. HORN. So there is no peer review on this?

Mr. LEVITT. No. These are with any spontaneous reporting system. The idea is that if you, whoever you are, a doctor or consumer,

feel that you have seen a problem with something, there should be

a place that you can send that to; and then it is the responsibility

of the recipients, in this case FDA, to go through and do a more

detailed analysis of what that entails.

That goes to a lot of the issues we have talked about earlier; but

I guess I just want to repeat it again, the website has a whole series of disclaimers. It is not intended to provide an FDA analysis

or validation of the information that was reported. It is simply a

line listing. It is like a table of contents, of reports, that have been

submitted. So somebody looking at it could get an idea of what

kinds of products people are writing in about, the kinds of things

they are raising, but by no means would it be proper to reach any

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conclusions from that website on, ah, there is a problem with this

product. That would be grossly incorrect.

Mr. HORN. One last question. How many adverse effects would

you estimate have been filed on dietary supplements in the last 7

months? Do you have any feel for those data?

Mr. LEVITT. It has been running about 500 per year.

Mr. HORN. I see. OK. Thank you very much, Mr. Chairman.

Mr. LEVITT. Thank you.

Mr. BURTON [presiding]. I want to thank you, Mr. Levitt.

Let me say this about that. 500 complaints per year? Do you

know how many millions of people take these dietary supplements?

I think I take a million myself.

Let me thank you. I really appreciate your testimony. Please

stick around for a little bit because we might have another question or two for you. I really appreciate your cooperation. Thank

you.

We would like to now hear from a public panel. Dr. William

Soller of Consumer Health Care Products Association will discuss

elements and effective adverse events monitoring system. Dr.

Soller has extensive experience with nonprescription drugs and dietary supplements and will offer viable solutions for the problems

that have been identified today.

Dr. Theodore Farber is a pharmacologist and a board-certified

toxicologist with FDA and EPA experience. He will review the

FDA’s handling of ephedra adverse events. He conducted an extensive evaluation of the published adverse events on ephedra.

And Dr. Daniel Mowrey is the president of the American

Phytotherapy Research Laboratory. He will present testimony on

the use of ephedra throughout its history. He will also discuss the

level of scientific research in ephedra and what we know through

scientific evaluation on usage, serving size, side effects, and adverse events.

Also Dr. Annette Dickinson of the Council of Responsible Nutrition is joining us again to offer advice on how to develop a good

monitoring system.

Mrs. Karen Schlendorf is the mother of a young man who, while

on spring break in 1996, took Ultimate Xphoria and died.

Ms. Barbara Michal is the founder of H.E.A.T., Halt Ephedrine

Abuse Today, a nonprofit organization whose mission is to increase

public awareness about the dangers of ephedrine and its related

drugs, and to promote the prevention of abuse of ephedrine and its

related drugs.

And Dr. Raymond Woosley, a professor of pharmacology and

medicine at Georgetown University, will testify about the importance of good adverse events monitoring.

So let me just ask Dr. Soller, Dr. Farber, Dr. Mowrey, Dr. Dickinson, Mrs. Schlendorf, Mrs. Michal, and Dr. Woosley to please

stand because this is important. Please raise your right hands.

[Witnesses sworn.]

Mr. BURTON. Let me start with Dr. Soller, and if you could give

us an opening statement we would like to, if it is possible, restrict

your opening statements to 5 minutes, and then we will get into

questions.

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I want to apologize for not having more of our members here, but

as I expressed before we started, we had some problems here at the

beginning of the day and some of the Members are still in that conference and others probably have departed. Please proceed.

STATEMENTS OF R. WILLIAM SOLLER, PH.D., SENIOR VICE

PRESIDENT AND DIRECTOR OF SCIENTIFIC AND TECHNICAL

AFFAIRS, CONSUMER HEALTH CARE PRODUCTS ASSOCIATION; THEODORE M. FARBER, PH.D., PRINCIPAL,

TOXACHEMICA, INTERNATIONAL; DANIEL B. MOWREY, PH.D.,

PRESIDENT, AMERICAN PHYTOTHERAPY RESEARCH LABORATORY; ANNETTE DICKINSON, PH.D., VICE PRESIDENT

FOR SCIENTIFIC AND REGULATORY AFFAIRS, COUNCIL FOR

RESPONSIBLE NUTRITION; KAREN SCHLENDORF; BARBARA

MICHAL, H.E.A.T.; AND RAYMOND WOOSLEY, PH.D., PROFESSOR OF PHARMACOLOGY AND MEDICINE, GEORGETOWN

UNIVERSITY

Mr. SOLLER. Thank you. Good afternoon. I am Dr. Bill Soller,

senior vice president and director of science and technology for the

Consumer Health Care Products Association [CHPA].

Thank you, Mr. Chairman, members of the committee, for the opportunity to address you on a matter of fundamental importance to

the dietary supplement industry, adverse experience reporting.

Founded in 1881, CHPA represents producers of quality nonprescription medicines and dietary supplements, including over 200

member companies across the manufacturing, distribution, supply

and service sectors of the self-care industry.

I have had 20 years’ experience in the self-care industry, having

held scientific regulatory and product development executive positions in consumer health care product companies manufacturing

both OTC medicines and dietary supplements and have been with

the association since 1985, holding similar responsibilities.

On many occasions in my career, I have personally compiled,

analyzed, and reported AERs to FDA on self-care products.

By way of background, let’s keep in mind that the vast majority

of dietary supplements have a very wide margin of safety. Let’s

also not forget that there is general agreement that the current

sourcing mechanisms for AERs, FDA’s MedWatch, SN/AEMS, the

consumer hotlines, as well as mechanisms that are maintained by

the Consumer Product Safety Commission, U.S. Pharmacopeia, the

American Association of Poison Control Centers, the National Institute of Drug Abuse and Centers for Disease Control are adequate

signal generators of potential problems with consumer products,

though systems integration is needed.

And let’s not also forget the bigger picture. Ephedra may be the

example today, but we must all take a direct interest in ensuring

that in the future the right infrastructure and policies are in place

at CFSAN to enable it to handle efficiently, expeditiously, and fairly any and all AERs on dietary supplements.

Therefore, we recommend the following.

As part of Dr. Jane Henney’s initial directives as FDA Commissioner, FDA studied prescription drug approvals pre- and postPDUFA, issuing a report just this month, which calls for an overhaul of the prescription drug AER program, including adoption of

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a systems approach to FDA’s management of AERs. We support

this total quality management approach for CFSAN as well.

Second, we support renewed emphasis within CFSAN on FDA’s

long-standing overarching safety policy. The policy states for warnings that they must be scientifically documented, clinically significant, and important to the safe and effective use of the product by

the consumer. And the significant importance of this policy is that

it focuses us on scientific documentation.

Without rigorous critical evaluation of how AER data are collected, analyzed and reported, it is literally impossible to determine

their significance.

Third, the controversy surrounding ephedra is clouded by the nature of the data collection and analysis by the agency. This is not

unexpected, especially where AERs may be difficult to interpret

due to their nature, severity, source, and affected organ systems.

In controversial situations, a refined, integrated system with documented policies and procedures is vital to help ensure that the details of such situations are as accurately documented and professionally handled as possible.

Therefore, we could then concentrate on the science, not the administration, of the process.

In summary then, we recommend that CFSAN prepare a written

plan for and adopt a systems approach to managing AERs on dietary supplements, grounded in its current safety policy.

CFSAN should keep current written protocols for CFSAN personnel handling AERs to expedite accurate data collection, including a detailed decision tree for use by those whose responsibility it

is to filter serious and nonserious reports and route those reports

for expeditious followup.

Third, CFSAN needs a policy and procedures for timely sharing

of serious AERs with affected companies in order to help facilitate

adequate followup and so address incompleteness and inaccuracies

in AER reports. Affected companies are inherently motivated to ensure complete, accurate information on AERs.

Four, specific CFSAN training manuals and procedures should be

established to ensure quality collection, analysis, and reporting of

AERs.

Five, CFSAN should undertake a review of the core competency

of the personnel who would operate different facets of an adequate

AER system on dietary supplements.

Six, a reengineering of the public process to AER reports for dietary supplements is needed. AERs should be available to the public

in a timely fashion when, A, FDA has communicated with the affected company identified in the AER and; B, is prepared to provide

publicly a complete file of the report omitting confidential information, not just a table of contents.

Seven, public input is needed in the development of policies and

procedures to be used in CFSAN’s systems approach to AER management.

And the time is right for these steps. We want consumers to use

safe and beneficial dietary supplements for health promotion and

health maintenance. Consumer confidence in these products is essential to their usage, and recognizing that the vast majority of dietary supplements are safe and beneficial, a strong systems apVerDate 11-MAY-2000 11:31 May 24, 2001 Jkt 010199 PO 00000 Frm 00087 Fmt 6633 Sfmt 6602 E:\HEARINGS\61435 pfrm09 PsN: 61435
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proach to AER management for dietary supplements is nevertheless needed to ensure that those few dietary supplements that may

have safety questions are fairly and expeditiously addressed in

order to help maintain consumer confidence.

Hence, we urge this committee to take an interest in the recommendations we have set forth concerning CFSAN’s management

of AERs for dietary supplements. We are pleased to hear that Mr. Levitt would use the $2.5 million budget request to upgrade CFSAN’s AER system. However, we

recommend that the committee consider a specific inquiry to FDA

asking for a detailed resource allocation plan for adopting a documented systems approach to AER management.

Thank you, Mr. Chairman, members of the committee.

Mr. BURTON. We would like to have your requests and recommendations in writing, if you have those, and we will look at

them ourselves and also submit them to Mr. Levitt and to FDA.

Mr. SOLLER. Yes, sir. We provided them prior to the meeting to

counsel.

Mr. BURTON. OK. Fine. Thank you. I haven’t had a chance to

read them yet, but I will.

[The prepared statement of Mr. Soller follows:]

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Mr. BURTON. Dr. Farber.

Mr. FARBER. Thank you, Mr. Chairman.

I am Dr. Theodore Farber. I am—— Mr. BURTON. Can we get you to pull the mic a little closer?

Mr. FARBER. Sure.

Mr. BURTON. Thank you.

Mr. FARBER. I am Dr. Theodore Farber. I am president of

ToxaChemica, International, which is a consulting toxicology firm

located in Rockville, MD.

Before founding this company, I was in government service at

the Food and Drug Administration for over 19 years, serving in

many senior science positions.

I then served 4 additional years at the Environmental Protection

Agency, as a member of the Senior Executive Service. I was director of the health effects division in the pesticide program at EPA

and supervised and developed the science policy for the largest

group of regulatory toxicologists in the world.

I am board certified in toxicology for the last 20 years, and I believe I enjoy an international reputation in my discipline.

Mr. Chairman, if there is only one thing that I could say to the

committee, it would be that I have looked at every report in the

Food and Drug’s AER reporting system in the docket, and I can

confirm my belief that dietary supplements containing ephedra,

when used according to the label, are safe and effective and have

been used for millions of people here in America.

Food and Drug’s current system does not provide valid information to the FDA, the public, and the industry about safety of dietary supplements. Instead, because of the way in which AERs are

currently handled at Food and Drug, the AER lacks standardized

methodology, and this leads to inconsistent applied science from

one case to the other.

It causes public confusion over whether an adverse effect was

professionally assessed and actually connected with the product

mentioned and whether it is simply mentioned as one of the many

potential causes, including preexisting conditions and natural

causes in other products that may have caused or produced a negative reaction; and it is wasteful of the agency’s resources to pursue

whole categories of products, branding them as unsafe when the

agency might better focus its attention on specific products that are

irresponsibly manufactured and marketed.

This is a summary of how Food and Drug’s AER system works.

Reports from any source concerning the dietary supplement product are received by Food and Drug. They are collected and filed

within this AER system. The vast majority of reports, particularly

for any product that is the subject of an FDA press release, comes

to Food and Drug through a hotline, a number that Food and Drug

publicizes. These reports are, almost without exception, anecdotal

reports from lay persons who heard about or allege to have had an

experience, an adverse effect.

These reports are useless from a scientific perspective, as they

typically lack one or more pieces of information critical to scientific

analysis, including product identity and ingredients, product dose,

frequency and duration, and medical records describing the adverse

effects in accurate medical terms.

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FDA’s system does not take into account whether or how publicity affects the reporting rate and I have with me—and it is in

my written testimony—charts showing that most of the reports

FDA has received were as a result of FDA press releases and followup TV programs stating that ephedrine products are dangerous

and have killed people. These press releases and TV shows encourage the public to call an FDA hotline to report any problems.

I would like to make one final point. The AER files supporting

this proposed rule were in such a disarray when the rule was first

published that Food and Drug was required to take unprecedented

steps of closing the rulemaking to fix the AER files. Even after this

process was completed, I found that the vast majority of AERs for

these products, almost 85 percent of these events FDA had publicized as associated with ephedra products, were informationally

worthless.

Further, FDA has placed in the docket for that proposed rule a

clear statement of its policy on AERs, which acknowledges the scientific fact that unevaluated AERs are inherently unreliable and,

therefore, should not be used to establish product risk.

Nonetheless, as Food and Drug has implicitly stated in black and

white in the proposed rule, FDA relied on just 13 AERs to establish

proposed serving limits for these products, which conservative estimates show that there have been billions of these servings sold

that have been consumed by millions of consumers.

FDA even admitted in writing in the proposed rule that the

agency had not scientifically evaluated these 13 AERs to determine

whether there was any connection to product consumption in the

13 reported events. In fact, the treating physician in 1 of the 13

cases stated that there was no such connection.

Therefore, Food and Drug was almost forced to admit in writing

in the proposed rule that the agency’s proposed serving limits may

have no public health benefit.

Mr. Chairman and members of the committee, I thank you for

the opportunity to address you today, and I would be more than

happy to answer any questions.

Mr. BURTON. Thank you, Dr. Farber.

[The prepared statement of Mr. Farber follows:]

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Mr. BURTON. Dr. Mowrey.

Dr. MOWREY. Mr. Chairman, members of the committee, thank

you for inviting me here today.

My name is Dr. Daniel Mowrey. I own a company called American Phytotherapy Research Laboratory near Salt Lake City, UT,

where our main activity is to investigate the medicinal properties

of plant materials, their safety and efficacy.

For the past several years, I have been involved in the investigation of ma huang, its perhaps medicinal properties, its health benefits, its historical uses and so forth.

I have authored a book on the subject called Thermogenesis: Fat

Management Related. I think you have a copy there. It deals with

the historical background relating the advent, if you will, of ma

huang and ephedrine into the weight loss category and what scientific support there is for that. I think I list about 1,400 references in there to detail how that has all come about.

I was asked to testify today about the historical use of ephedrine

on ma huang. In doing that, I thought it was fairly impossible to

know how long people have benefited from ma huang. However,

some time ago I read where ephedra plants were found in a grave

alongside the remains of a Neanderthal man dating back about

20,000 years.

This seemed like a good starting point to begin a historical discussion of ma huang, but I must admit to some degree of hesitation

in citing this ancient case. It might just wind up in some AER. I

can see the headlines now, Killer Herb Has Been Killing People for

20,000 Years.

Anyway, back to my point. This case of, this Neanderthal case,

I think demonstrates mankind’s long association with ma huang.

Chinese and other Asian texts show that ma huang has been traditionally used in herbal medicine for at least 5,000 years.

Now, in traditional Chinese medicine, the twigs of this rather

scraggly looking ma huang plant were broken up or pulverized and

brewed up as a tea. They didn’t have capsules in those days, in the

ancient days, but they did have a lot of teas.

Several ounces could be used in one serving, and a serving could

be taken several times a day. It was served as a tonic; or it was

concentrated to be used in the treatment of colds, fevers, and other

debilitating conditions.

All in all, I think it was a highly prized herb, used throughout

Asia; and it still is to this day, for these traditional systems have

not changed much in the way that they use medicinal plants.

By the way, seldom was ma huang used by itself. It was most

often combined with a variety of other plants that moderated its

effectiveness and its action in the body; and I think that that particular property of ma huang is evident in the way that it is used

in modern therapy in weight loss.

Now, although ephedra is normally associated with traditional

Chinese medicine, it does grow in the United States, at least related species can be found here. As a matter of fact, early American

settlers in Utah, where I reside, brewed up a beverage known as

Mormon tea or Brigham tea. It was a favorite beverage and it was

used by pioneers to combat exhaustion and fatigue, and often as a

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primary source of energy or food, since the conditions in the early

pioneer days in Utah were not very good.

Brigham Young was said to enjoy an occasional cup of this namesake tea, although I don’t think we have any evidence that any of

his 20-some-odd wives did that.

The point to all of this is to show that throughout recorded history, in cultures around the world, ephedra has been considered

just another herb to be routinely used by human beings. It was

never singled out as an exception to standard herbal lore, but fit

quite naturally in the traditional medical and nutritional systems.

While great reservations are found in traditional medicine about

the use of plants, such as magic mushrooms, mandrake, jimpson

weed, foxglove, rawolfia and other pyschoactive and cardiovascular

plants, no record exists anywhere to suggest that similar concerns

were ever directed toward ephedra.

So in recent years, ephedra has become a favorite herb of millions of Americans as a tool for safe and effective weight management. We have identified the active constituents, synthesized them,

and these products, or the ephedra-related products, have been

widely used throughout modern countries, civilized countries, if you

will, not just Third World countries, but actually throughout Europe.

In fact, ephedrine-based weight loss products are the most popular weight management product in Europe and is rapidly becoming so in America.

Given the fact that obesity itself is more prevalent than ever before and that more people are dying of obesity-related disorders

than ever before, the notorious syndrome X, the use of ephedra as

a dietary supplement may be just the thing that we have been

looking for.

Given its centuries-long reputation as a perfectly safe and useful

herb, we have to ask the question, why all of a sudden is there this

concern over ephedra’s safety?

I can see two reasons for that. One is just flat out abuse. The

second, I think, is an AER system that has failed us by creating

misinformation rather than giving us the truth. The two reasons

are intertwined.

The AER thing has been addressed. I just would like to say

something about the area of abuse. While I sympathize with people

who have lost members of their family to taking substances containing ma huang, whether that was the active constituent or not,

I think that we are in a situation where we need better labeling

for these things.

I don’t think we are in a position where we should get rid of

the—throw the baby out with the bath water, as it were.

We need to use the tool the way that it can be used safely, to

help the millions who need it, at the same time devising labeling

requirements and other regulations that reduce the risk of abuse.

I thank you very much for allowing me to speak today.

Mr. BURTON. Thank you very much, Dr. Mowrey.

[The prepared statement of Dr. Mowrey follows:]

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Mr. BURTON. Dr. Dickinson, it is nice seeing you again.

Dr. DICKINSON. Thank you very much, Mr. Chairman.

The Council for Responsible Nutrition is a trade association of dietary supplement manufacturers representing some hundred member companies who are deeply committed to producing safe and

quality products.

We are proud of the safety record of dietary supplement products

overall, but we recognize that there is a need for an adverse reaction reporting system because any product, including preapproved

products, can result in unexpected effects when taken by millions

of people in the general population.

Therefore, the adverse reaction reporting system is a very important signal to us where there may be some errors in product manufacture or some other issues that are causing consumers to be

harmed, and it is a valuable indication of that need for action.

We share the concerns expressed by the chairman in your opening remarks regarding the need for FDA resources to handle these

systems appropriately, the need for prompt reporting of adverse reactions on the public system.

We question the appropriateness of listing the company name

and the product name as part of the table of contents. Mr. Levitt

was referring to the publicly available website. The AER system is

a table of contents of the system, and I would like to suggest an

alternative to the kind of listing that we see on the current system.

We also share the chairman’s concern about the need to correct

errors that may creep into initial listings; and, actually, our new

proposal may address some of that concern.

There is an overwhelming need to evaluate the strength of the

association, both in terms of the seriousness of the reactions and

the nature of the causality of the product taken and the effects

seen.

I would like to spend just a couple of minutes describing what

may be a very useful new way of approaching the development of

this system.

In our statement that we submitted prior to this hearing, we

suggested that there might be a three-step system that could be

adopted for making these reports publicly available.

First of all, as soon as FDA receives the report, we believe it

should immediately become available on the public system, that is,

on the website. We would suggest, however, that that initial posting perhaps should only include a description of the generic nature

of the product involved and a description of the ingredients of that

product, if that is available, and the nature of the symptoms that

are observed in the adverse reaction.

We see no reason, no compelling reason, why the name of the

company and the name of the product should be part of this very

first initial product listing which is only an indication that a report

has been received and has not been at this point evaluated in any

way.

Therefore, we would suggest that FDA consider having a separate part of its reporting system that is reserved for the initial reports where there would only be generic information about the reaction.

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We agree with Mr. Levitt that the priority is that as soon as

FDA receives these reports, they should immediately purge them

of personal information that is not releasable, so they may be released in a very prompt fashion.

We also believe that the FDA should immediately share those reports with the manufacturer or, in the case where the manufacturer has not been identified, with trade associations representing

the industry so they may work with FDA to provide more complete

information about the nature of the product, about the nature of

its expected effects, and also assist in investigating the particular

adverse reaction report.

Therefore, we would suggest that as soon as FDA has conducted

the second phase of the investigation, that is, has shared the report

with the manufacturer and has done some analysis of the likely

causality involved in the report, that it be moved from this initial

report section, which is a summary form into one of two more permanent report sections.

One of those two sections would be reserved for adverse reactions

that the FDA has, in fact, determined are likely to be related to

the product itself. And in that case it may be appropriate to include

in that listing the name of the product and the name of the company after the company has been notified of that.

We think that there should be a third section of these reports

which will be reserved for reports which are determined definitely

not to be related to the product taken or about which there is insufficient information available to make a determination.

Therefore, we would end up with a three-part reporting system,

an initial part which is a summary, a second part which is essentially the ones that are either not related to the product or about

which there is not sufficient information, and then a third part

which would really be the core of the permanent record and would

be the basis for FDA’s future analysis of any action to be taken

which would be limited to those reports that have been evaluated

and where there is sufficient evidence to believe that the report,

the adverse event is, in fact, related to the product.

We think that this would improve the ability of FDA and the industry and other health professionals to use these adverse event

reports in a productive way to address questions that need addressing as promptly as possible.

Thank you very much.

Mr. BURTON. Thank you, Dr. Dickinson.

[The prepared statement of Dr. Dickinson follows:]

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Mr. BURTON. Ms. Schlendorf, we appreciate you being here, both

you and Ms. Michal; and we are very sorry about the experiences

you have had.

Ms. SCHLENDORF. Thank you.

Mr. Chairman, members of the committee, my name is Karen

Schlendorf. To me Peter Schlendorf is not an adverse event but my

youngest child who, like too many others, suffered from the fatal

effect of a herbal supplement which contained ephedrine.

I believe that I am speaking for so many people who can no

longer speak for themselves, Kristopher Michal, Rosanna Porras, to

mention a few; but let me tell you about Pete Schlendorf.

As a mother, it is very difficult to put into words the depth of

my feelings for my youngest son. Pete was the joy of my life. From

the day he was born, Pete was someone very special. He made me

smile every day, and I thanked God that I had been blessed with

such a wonderful gift.

My three children meant the world to me; and as a full-time

mother, I enjoyed every minute that I spent with them. On the day

that I began my job as a high school guidance counselor, Pete, who

was then 10, picked a bouquet of flowers from our garden for me.

I had always given the children a small gift on the first day of

school and told them how proud of them I was, and now he was

doing the same thing for me. He was always a kind and thoughtful

person who made people glad that they knew him. He brightened

a room every time he entered it.

He was always the center of attention, not because he asked for

it, but because it seemed to come to him naturally. Pete was bright

and funny, athletic and talented and a leader among his peers. I

was proud of his accomplishments and prouder still of the man he

was becoming.

Then one day the unthinkable happened. He died. Pete had gone

to Florida on spring break with some of his friends. On a cold and

overcast day, they decided to explore some of the shops along the

beach. All week they had seen ads and banners promoting herbal

supplements of all kinds. They went into one of the shops and decided to try one.

It is all natural, safe, harmless. The store clerk said that she and

her friends took 10, 12 of them all the time, made them feel great

and gave them lots of energy. So the boys tried them.

Pete took somewhere between four and eight pills and almost immediately began to feel strange. His heart rate was faster, he felt

tingly, hot all over and had a pounding headache. He took a shower, but it didn’t help.

He told the other boys to go out, and he would lie down for a

while; and when he felt better, he would join them later. The last

time his friends saw him alive, he was sitting on the edge of a bed

reading the label on the box. What had he taken? What was

wrong? What should he do? There was no help on that box.

It took weeks, months for us to understand what happened to

our beautiful, wonderful, healthy son. At least now we know the

facts. But I don’t know that we will ever really understand. Pete

died because a company cared much more about profits than about

lives. Pete died because he had an unfortunate chance encounter

with Ultimate Xphoria.

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The manufacturers of this product have admitted to us their irresponsibility and their callousness. They have admitted that they

are not sure how many or which additional herbs were in each

batch.

They claim not to know where the ma huang came from, which

part of the plant was used, the time of year it was harvested, or

how strong the concentration was. They didn’t know, or perhaps

they didn’t care; but my son died because Ultimate Xphoria was

improperly manufactured and irresponsibly marketed toward

young people.

A number of ingredients in this product posed a risk to Pete or

any other healthy individual. Combined, they caused an insurmountable risk of harm. I know that there is a great deal of information in publications and on the Internet that disputes these

truths. I have read them myself. But this is the truth.

I have a copy of Pete’s autopsy, something no mother should ever

have to see; and it shows beyond a shadow of the doubt that the

only thing in Pete’s system was the ingredient in this product. He

had been on spring break with his friends, but there was no evidence of any drug or alcohol or anything else except the lethal

herbal supplement that he bought over the counter in a little shop

on the beach.

Ephedrine is a drug. It has been known as a drug for over 5,000

years. No amount of legislation will make it a food. Proponents of

ephedrine-containing supplements like to say that the Chinese

have used it for centuries. They have, through practitioners who

prescribe it as part of their traditional medicine, not for weight

loss, not for energy boosts.

Scientists have agreed on what ephedrine does. It dilates bronchial muscles, contracts nasal mucosa, raises blood pressure, acts

as a cardiac stimulator. Although there may be some disagreement

as to a safe limit of ephedrine, I do not dispute that in proper

hands, ephedra can be appropriate and safe.

However, the Dietary Supplement Health and Education Act of

1994 has allowed irresponsible persons to contaminate the marketplace with false claims and dangerous marketing. I doubt that it

was the intention of this governmental body to allow people like

those who caused my son’s death to get rich at the expense of

America’s youth.

I fully understand that there are many people and certainly

many manufacturers making millions of dollars from these products who don’t want to hear any of this, but I would hope that my

government would want to hear this.

Filing an adverse event report was our vehicle to the truth, and

I did this in honor of my son, Peter Charles Schlendorf.

Mr. BURTON. Thank you very much. That was a very touching

statement.

[The prepared statement of Ms. Schlendorf follows:]

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Mr. BURTON. Ms. Michal.

Ms. MICHAL. Mr. Chairman and members of the committee, my

name is Barbara Michal of Novi, MI, founder of the nonprofit National Coalition Halt Ephedrine Abuse Today. I am here today at

my own personal expense, and I am deeply grateful for you allowing me to testify today.

My keen interest in the ephedrine regulation issue came about

through a parent’s deepest terror, the death of a child. On March

14, 1997, ephedrine killed my 24-year-old son Kristopher.

Since that time, I have been researching ephedrine; and I am appalled at how much information is available as to the serious dangers of this powerful cardiovascular and central nervous system

stimulant and equally appalled at the lack of strict regulation of

this drug.

Some members of the dietary supplement industry with their

huge profits and their powerful lobbyists have mounted a concerted

campaign to discredit the work of the FDA in gathering adverse

event reports and in promulgating proposed ephedrine controls

rules. Their motivation is to protect their profits, not the safety of

the citizens of the United States.

Mainstream drug companies not only welcome adverse event reports, they have physicians and pharmacologists on staff to review

and evaluate each adverse event report. With prescription and

mainstream over-the-counter drugs, physicians and other healthcare practitioners know to report adverse events to the FDA.

However, the unregulated dietary supplement industry is another story all together. There is no industry-wide adverse event

reporting procedure. Product labels generally do not carry 800

numbers for consumer use in reporting adverse events.

In general, the public is unaware that the FDA wants to receive

adverse event reports on dietary supplements, and I strongly doubt

that the dietary supplement manufacturers have physicians and

pharmacologists on staff to evaluate what adverse event reports

they do receive.

The industry disputes the validity of the data base of the FDA,

yet they are not required to submit reports to it. Now they come

to you complaining that the FDA adverse event reporting system

is seriously deficient, the data base is suspect and the FDA has not

used sound scientific studies upon which to base their proposed

ephedrine control rules.

I respectfully ask whether the dietary supplement industry has

submitted even one peer-reviewed, sound scientific study to prove

the safety of their ephedrine-laced products in humans. They are

bashing the science and data of the FDA because they have nothing of substance to support their position.

They also use the Chicken Little argument, the sky is falling.

They claim that strict regulation of ephedrine will destroy the dietary supplement industry. This argument is preposterous on its

face. Some dietary supplement manufacturers have recognized the

serious dangers and potential liability of this amphetamine analog

and have already removed it from their products; and those products are selling quite well, thank you.

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My organization, Halt Ephedrine Abuse Today, is conducting a

survey of ephedrine use on the Internet. As of April 30, 1999, with

227 people reporting, 48 percent report addiction.

Of those reporting using dietary supplement products as opposed

to synthetic ephedrine products, 28 percent, over one-fourth report

addiction. Among other adverse reactions, we have had reports of

psychosis, stroke, cardiac arrythmia, kidney damage, nerve damage, heart attack, and death.

Contrary to the staffing problems with the FDA not being able

to followup on these reports, I have spoken personally with many

of these people after they have contacted me through the Internet.

We have received an additional 85 responses since the end of April.

They have not yet been collated.

This report is not scientific. It has not been reviewed by a licensed medical professional. It is purely the voices of American citizens detailing the adverse event reactions and injuries they have

experienced. And this is just the tip of the iceberg.

My organization is hearing only from people with Internet access

and who are actively seeking information on ephedrine; and of

those, very few have reported their experiences to the FDA, and

some even say, I didn’t know I should.

Comparatively, the FDA already has in place a centralized reporting system where both private citizens and health-care professionals can report adverse reactions. If the industry has a problem

with the reporting system and data collected, they should be working directly with the FDA to suggest improvements, which I have

heard today they are doing, which I am very pleased with.

They should not be bringing their crusade to Congress in an effort to tar and feather the FDA without being sure that they provide constructive input as to how to fix the alleged deficiencies.

Regarding the industry’s argument that the FDA has no legitimate science upon which to base their proposed ephedrine control

rules, I respectfully refer the committee to the bibliography at the

end of the June 2, 1997, proposed rules as published in the Federal

Register.

Along with my written statement that I submitted, I included a

bibliography of medical journal articles that I have collected. The

proof is out there. The fire storm the industry is trying to ignite

against the FDA serves only as smoke and mirrors to divert the

focus from the real issue: Is ephedrine a threat to the health of the

citizens of the United States? Yes.

Is the industry taking responsibility for seeking out and collecting adverse event reports to learn the truth? No. Does ephedrine need to be strictly regulated? Yes.

I sincerely thank you for this opportunity to be heard. The playing field in this controversy is far from level. We ephedrine victims

and our families don’t have millions of dollars in corporate profits

to spend. We don’t have powerful lobbyists with political connections. We don’t have paid professionals whose job it is to be aware

of and attend every hearing and committee meeting.

We are members of the general public; and we have a voice, too.

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Thank you, Mr. Chairman and members of the committee, for hearing that voice.

Mr. BURTON. Well, thank you, Ms. Michal. We appreciate your

comments.

[The prepared statement of Ms. Michal follows:]

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Mr. BURTON. Mr. Woosley.

Dr. WOOSLEY. Good afternoon, Chairman Burton and members of

the committee. I am actually a physician; I am a pharmacologist

and physician.

Mr. BURTON. Excuse me, Dr. Woosley.

Dr. WOOSLEY. No problem. It gave me a chance to emphasize the

fact that I am a physician.

I have to say I am moved and even shaken to follow the previous

two witnesses. I reviewed the FDA reports of their children’s

deaths, and I have to tell you it was difficult then, and it is more

difficult now. I read those cases of—as they described, young children unknowingly taking poisons.

I have helped the FDA analyze these cases, and that is one of

the reasons that I am here today. I have helped them analyze these

and many other cases, and I would like to tell you that there is

nothing wrong with that process. It can be made better, but it

doesn’t make mistakes.

Since 1977, I have conducted clinical research and basic research

on the mechanisms of the adverse effects of drugs in humans. In

over 250 scientific publications, I have examined the toxic effects

of prescription and nonprescription drugs, mainly on the heart.

My research has identified the mechanisms responsible for the

potentially lethal cardiotoxic effects of several drugs, including

Seldane, a widely prescribed antihistamine recently removed from

the market.

I mention my background because it is this experience upon

which I base my conclusions and the recommendations to you

today. You have asked this panel to address a very serious question, and I don’t appreciate the levity that some have introduced;

it really seems inappropriate.

This question has major consequences for the health and welfare

of many citizens in our Nation. You have heard testimony from

others that there are major weaknesses in the FDA’s voluntary reporting system; and I also have criticized it in the past, but usually

for what it has not done, not for what it has done. Some have tried

to cast doubt on the data that comes from the FDA’s surveillance

system. Please don’t allow them to confuse you on this issue.

In 1994, I was asked by the attorney general of the State of

Texas and the Center for Food Safety and Applied Nutrition at the

FDA to review 88, and later another 147, cases. These were cases

of suspected toxic reactions of ephedrine-containing products. I

have enclosed a copy of my initial report to the FDA for the record.

As you will see, in 1994 I concluded that there were reports of

chest pain, heart attack, stroke, seizures, cardiac arrest, sudden

death, two that we have heard today, some of these people in the

prime of their lives. I concluded that these reactions are perfectly

consistent with what one would expect to see from excessive dosage

or extreme sensitivity to ephedrine.

In August 1996, I served as a member of the FDA Food Advisory

Committee to review all of the scientific evidence that had been accumulated by the FDA. The FDA has done due diligence. They

have had a process—perhaps it hasn’t been made known to everyone, but they have seriously investigated this issue. There was full

agreement by this committee that the 800 cases submitted to the

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FDA were absolute proof of the harm associated with dietary supplements containing ephedra.

I and others have constructively proposed improvements to the

FDA’s current voluntary reporting system because it has inadequate staff. It often requires months to years before identifying an

adverse event associated with a drug or a devise. The system is

plagued by underreporting, incomplete reports, and inadequate

staff for analysis of those reports. However, no credible argument

has ever been made that the system makes errors in detection. It

is a blunt instrument, but an essential one, that is capable of identifying frequent, serious problems, especially when they are closely

associated with exposure to a product, as in this case.

In 4 years, over 800 reports of adverse events associated with

over 100 different ephedrine-containing products were received at

the FDA, 100 different, not just a few rebel products, 100 different

products. The FDA has estimated that less than 1 percent of serious adverse drug reactions ever get reported. Therefore, the actual

number of reactions to ephedra is far greater than the number that

they have on record.

I have absolutely no doubt of the validity of the harm detected

by the FDA scientists. In the past, the adverse drug reactions detected by the systems have been routinely confirmed by regulatory

scientists in other countries that have used a wide range of different methodologies. An important part of the FDA system is the

confirmatory process applied in the analysis of these, often less

than adequate, reports. For example, because we know that ephedrine increases the blood pressure and heart rate in animals and in

people, the profile of adverse events that you would predict to occur

would be arrhythmias, stroke, cardiac arrest, and sudden death.

These are exactly the kind of reactions I reviewed in those reports.

Additional confirmation is obtained by comparing the patterns of

reactions to those seen with drugs that have similar pharmacologic

action, such as amphetamine and methamphetamine. These have

been the exact same kind of events reported with ephedrine.

Additional evidence for the reliability of the association is seen

in the fact that 26 percent of the 800 reports included documentation that the adverse events subsided when the product was withdrawn. Further, in 4 percent of the cases, the exact same symptoms recurred when they reinstituted the therapy or the drug was

again administered.

In summary, the FDA’s spontaneous reporting system accurately

detected and confirmed the harm that results from compounds containing ephedra. The public must be protected from the proven

harm of these products.

Because of the biologic variability in the way people respond to

these products and the fact that many people don’t know that they

have conditions which predispose them to the products harmful effects, such as coronary artery disease, it is impossible to identify

a safe dose of these products.

I sincerely request that you give your strong support to the

FDA’s efforts and affirm their authority to take even stronger action and remove every one of these products from the marketplace.

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When my 7-year-old son grows up and goes to Florida on spring

break, don’t let these products kill him.

Mr. BURTON. Thank you, Dr. Woosley.

[The prepared statement of Dr. Woosley follows:]

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Mr. BURTON. I have a granddaughter and a grandson, and I

share your concern about their exposure to things that could harm

them.

Let me ask you a question. You reviewed the reports on the two

young people who died. By any chance in those reports did you notice how much ephedra they had taken?

Dr. WOOSLEY. We tried to estimate that based on their labelled

content, but in the FDA hearings it became very clear that you

can’t. FDA scientists collected those products that were being marketed then and measured their ephedra content. The content of

ephedra and ephedrine-like alkaloids varied from 1 milligram to

100 milligrams, even though they were labeled to contain on average about 12 milligrams. We have no way of knowing how much

these two young people took. The other aspect of it is it really

doesn’t matter how much it was, any amount could have been lethal.

Mr. BURTON. It is of concern. I take Sudafed and my wife takes

a product that she uses for her asthma.

Dr. WOOSLEY. But that is not ephedrine. That is Sudafed. That

is a much weaker compound. It is a totally different drug.

Mr. BURTON. All right. We will get back to that. That may be a

layman’s understanding.

Dr. WOOSLEY. This is a potent, toxic drug.

Mr. BURTON. What I would like to understand, when your son

was in Florida and he took this, as I understand it, that particular

product was advertised as giving people some kind of a feeling of

euphoria?

Ms. SCHLENDORF. Yes, a feeling of euphoria or an energy boost

or 100 other things.

Mr. BURTON. Right.

Ms. SCHLENDORF. It was also stressed that it was perfectly safe

and harmless. Pete took at least four pills, could have taken as

many as eight. His friends said they thought he took four. We were

trying to account for all of them, so there could have been a couple

more than four, but they didn’t think that they were taking anything dangerous.

And what came out in our investigation of the pills and of the

company, the company didn’t know how much ephedra was in the

product; and one box could have varied greatly to the next. We

don’t know how much he took.

Mr. BURTON. And I don’t like to get into too much of the detail

because it is not comfortable for everybody, but the autopsy that

was performed, I presume, did it indicate in any way how much of

this product or this substance was in his system?

Dr. WOOSLEY. I don’t remember in this specific case, but I recall

in several of the cases there was analytical data indicating the

quantity in the body.

The problem with all of that is, it doesn’t really matter how

much is in the body or even in the pills. There are people who are

exquisitely sensitive. He may have been such a person.

In the hearings, I argued long and hard but failed to win the argument that there is no safe dose of ephedrine as a dietary supplement because there is no way you can give it to a large number

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of people without hurting an exquisitely sensitive person, for example someone who didn’t know that they have high blood pressure.

Mr. BURTON. There are some products that I might buy over the

counter which are perfectly legal and very safe for healthy people

to take that might cause hives or severe problems for other people

in my family, so that may not be unique to ephedrine.

Let me ask Dr. Farber about this. Doctor, Dr. Woosley has indicated that there is no safe amount of ephedra that can be taken,

and you seem to have some expertise in this area. Can I have your

opinion on that.

Mr. FARBER. Yes. I can’t agree with Dr. Woosley. It is almost contrary to what every pharmacologist or toxicologist knows. Over 400

years ago, the father of modern toxicology said that the poisoning

is in the dose and so forth.

And for a pharmacologist to say that there is no level of a material that is safe is mind boggling to me. There is a safe level of

ephedra alkaloids; and the products of the responsible companies

in this industry which do have proper labeling presents a product

to millions of individuals that can be taken safely every day, and,

in fact, billions of servings have been taken by people over the

years.

This would, indeed, make this product safer than peanuts and

shellfish and chocolate and strawberries and aspirin and wine; and

I could go on and on and on in regards to products that we all use

with the concept that we are using it safely, that, in fact, has produced a higher incidence of reactions in the public than these products.

Mr. BURTON. Do you have a comment, Dr. Mowrey?

Dr. MOWREY. In the ephedrine hearings that took place in 1995

and 1996, I believe those were the years that Dr. Woosley was a

part of, questions came up about what is the history of toxicology

with ephedrine hydrochloride prescribed at a dose of 150 milligrams per day, which is over twice as much as what we are saying

is—is established in the research on ephedrine or ma huang currently in use.

Somebody said there isn’t any. I can’t remember who that individual was, but the point was that with all of the millions and millions of doses of that ephedrine hydrochloride that have been administered, such as in Primatine, which does contain ephedrine,

there is virtually a total lack of this kind of toxicology that we are

discussing here today.

And so the idea of a disconnect was suggested. There is some

kind of a difference between the alkaloids present in ma huang and

those in ephedrine; and it was an open question at that time.

Since then there has been research published to demonstrate the

pharmacokinetics of ephedrine in ma huang is virtually identical to

the pharmacokinetics of ephedrine hydrochloride. I think we have

settled that issue at least temporarily in view of maybe we need

more research along those lines, but I think that question has been

addressed and the initial response is that they are fairly identical

in their reactions in the body.

Mr. FARBER. Mr. Burton, could I make another comment?

Mr. BURTON. Sure. Go ahead.

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Mr. FARBER. Dr. Mowrey brings up an important point in regards

to Primatine and some of the products that are offered to millions

of Americans in over-the-counter preparations. Primatine contains

ephedrine, and the labeling allows for a dose level as high as 150

milligrams a day.

With the dietary supplements that we are talking about right

now put out by responsible companies, the labeling suggests that

there be no more than an exposure of 100 milligrams of ephedrine

alkaloids, not necessarily ephedrine, but ephedra alkaloids; and

some of those alkaloids are weaker, in fact, than ephedrine.

But it is interesting to note that people out there are taking

Primatine at 150 milligrams a day—and at one time several years

ago it was as high as 300—taking 150 milligrams a day and having

ubiquitous contact with caffeine in coffee, in tea, in chocolate, in

cola beverages; and there are no significant number of AERs being

reported or in the files of the Food & Drug Administration. Doesn’t

that raise some questions? Thank you.

Mr. BURTON. Dr. Soller, has there ever been any analysis as to

what is a safe amount of ephedrine and what is an excessive

amount of ephedrine? Obviously Ms. Schlendorf’s and Ms. Michal’s

sons took amounts that were excessive and did end up in their demise.

How do we know what is a safe amount, and what do we tell the

American people?

Mr. SOLLER. Thank you. It is always difficult to try and be objective when you are—and deal with the science when you are dealing

with tragic stories; and of course, we very much reach out to the

parents, knowing that we have children as well.

And so with that and attempting now to step back and think objectively and what we know about the science, there has been a review of ephedrine through the OTC review that began in 1972 and

subsequent reviews as well; and as a bronchodilator, ephedrine is

used both as an inhalation form and an oral tablet.

Inhalation it will be about 5.5 milligrams per inhalation and

then wait about 5 minutes and take another dose. And for the tablet, a total of a 25 milligram dose taken on a 4-hourly basis.

Now, information that has been sent in to FDA in reviewing this

particular issue looked at the drug abuse warning network and

found that ephedrine is fairly low on the list in terms of potential

for abuse, that is, reports of an abuse situation to an emergency

room setting.

And that is not particularly unusual in the OTC field because it

is at the issue of a low potential for abuse, not absence of abuse.

But what was backed up in that particular data-set for ephedrine

was a 15-year cohort of AERs reported to companies finding that

in a period where about a billion OTC tablets were sold, there were

171 adverse experiences and 3 of those were serious reports. There

were no deaths.

So there appears to be a different situation on that OTC side

than on this other side, and I would just like to make one or two

more comments that kind of rounds out a view in terms of what

I have heard here.

That is that the main issue here is for CFSAN to focus in on the

safety of dietary supplements, and I would agree with Dr. Woosley

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that we have basically a system in effect at FDA which can be refined.

And even on the drug side, Jane Henney knows that there needs

to be refinement by CDER, and we would suggest that same systems approach be put through all centers, including CFSAN, and

that we do not get into the kinds of situations where we are arguing the administration of AERs but we are looking at the science

and carefully documenting. That is very important to do.

The other aspect is that GMPs are very important to the industry, and we have commented to FDA and urged that GMPs be

adopted into regulation that would be somewhat different than food

GMPs, not quite as high as drug GMPs for appropriate technical

reasons we need not get into.

But that is very important because it would raise the issue of

identity and concentration within the particular dietary supplement and would very much help, as you would get reports from the

field that would talk about unknown amounts.

And if a company doesn’t know what is in their particular product from an identity standpoint, it is our belief that raising the

level of awareness on GMPs, allowing FDA to have that standard

of inspection, would help the field and some of the occurrences that

we have heard about today.

Mr. BURTON. Thank you. Ms. Schakowsky.

Ms. SCHAKOWSKY. Thank you, Mr. Chairman. Since we are talking today about accurate reporting, I just wanted to elaborate a bit.

We are talking about 500 voluntarily made adverse event reports

on dietary supplements. That was Mr. Levitt’s comment.

But I asked him later privately, and he said that is a tiny number of adverse events, that is how many were reported under this

voluntary system, that is all there were. When I said 1 percent, he

seemed to indicate that was more like it.

So I think it would be a mistake for us to conclude that there

are not any adverse events larger than 500. But I wanted to also

ask Dr. Farber in the interest of accurate reporting, Dr. Farber, do

you have or have you had any kind of a financial relationship with

a dietary supplement manufacturer of an ephedra product?

Mr. FARBER. I have been retained by the law firm of Hyman,

Phelps & McNamara that represents several diverse companies in

the dietary supplement industry.

Ms. SCHAKOWSKY. And you said that AERs are useless. That was

your testimony.

Mr. FARBER. No, I really didn’t.

Ms. SCHAKOWSKY. No, I wrote that down. You said AERs are

useless.

Mr. FARBER. In this particular instance, they are close to worthless. I could show you some further information in regards my

analysis on these AERs. I have personally spent, and my associate,

over 700 hours examining every one of the AERs in the public

docket. If you are interested, I can show you the analysis.

Ms. SCHAKOWSKY. What I am interested in is the AERs that

were filed by Ms. Schlendorf regarding her son Peter. Is that

worthless?

Mr. FARBER. No. No. I didn’t say that. I said that when you look

at the whole situation, there is very little that is—that you are able

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to interpret. Now, I have looked at the Schlendorf file, and I have

looked at the autopsy report. I feel very sad for Mrs. Schlendorf in

regards to this situation, but regrettably this young man took an

illicit street drug, masquerading, perhaps, as a dietary supplement,

and regrettably lost his life.

I don’t condone the marketing of this product. Neither do the

people that I have been working with or the industry that I have

been trying to help. They are appalled that these products have

been allowed to remain in the marketplace.

The Food & Drug Administration, indeed, had the powers under

DSHEA to remove these products before Peter bought the product.

They did not take the action that they were permitted by DSHEA

to take against these things.

Ms. SCHAKOWSKY. I thought that you testified that it is safer

than peanuts.

Mr. FARBER. I said when the products of the responsible industry

companies are taken according to the labeled instruction on the

product that they are safe and they are effective. That is not to

say—I am not saying that abuse potential doesn’t exist with

ephedra. It does.

But I know—and it has been recently established—I think you

are familiar with the Physicians’ Desk Reference. I think almost

every American has looked at this book to check on side effects of

drugs. There is a new PDR on herbal remedies. That PDR says

that ephedra is safe at levels up to 300 milligrams a day.

Now, the responsible members of this industry are recommending that their labeling state not to take any more than 100

milligrams a day.

Ms. SCHAKOWSKY. Thank you, Doctor. I would like to let Dr.

Woosley respond to a number of things that were said here today.

Go ahead, Dr. Woosley.

Dr. WOOSLEY. Thank you for that opportunity. I think it is very

important to point out that the PDR and the PDR for herbals is

simply a compilation of materials submitted by manufacturers. It

has absolutely no other special credibility.

I would also defend myself as a pharmacologist in my statement

that ephedrine has no safe effective dose as a dietary supplement.

You can give 25 milligrams, 50 milligrams, 75 milligrams of ephedrine to everybody in this room and no one will ever feel anything

more than a rapid heart rate and a headache and maybe trivial

side effects.

But if you give it to millions the way that it is happening today,

you get hundreds, or tens at least, of people dying like the ones

that we heard about today, even at the low dose that is currently

being recommended with no, absolutely no, proven benefit other

than a high.

Do we want to recommend products be out there that can kill

when there is no proven benefit?

Ms. SCHAKOWSKY. Could I go on for a minute. Just to underscore

that, I am looking at some of the marketing of this product on the

Internet.

Psychedelic Shrooms. Take a psychedelic magic carpet ride with

the greatest pill on earth. Contains ephedra, sinac, whatever that

is.

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Then we have got each capsule contains 800 milligrams of ma

huang extract; dosage orally, one to two capsules on an empty

stomach 30 to 40 minutes before activity. Do not exceed recommended dosage.

We have got Midnight Ecstacy, Herbal Coke, Turbo Charge, all

being advertised right now on the Internet.

Dr. Tim Johnson said on the tape this morning that he felt that

ephedra should be acknowledged as a drug and therefore should be

regulated as a drug, and I would like to hear the doctors’ comments

on whether or not they agree with that.

Mr. FARBER. Clearly the products that you have discussed—and

I can go on and name many, many more like Brain Wash, Cloud

9, Ultimate Xphoria, Love Potion 69 and so on and so forth—they

have all been taken out of the market at least by action of the Food

& Drug Administration.

These products are winding up on the Internet, and the Food &

Drug Administration has to work out some game plan to take action against these products. They are illicit street drugs; they are

not dietary supplements.

Ms. SCHAKOWSKY. Should ephedra be regulated, as Dr. Tim

Johnson said, as a drug?

Mr. FARBER. No, I don’t believe so. If these dietary supplements

are used according to the label—and the labeling on these products

are almost identical to the labeling on Primatine—they can be used

safely and effectively by the public without having to turn them

into prescription items.

Ms. SCHAKOWSKY. And what is a safe dose?

Mr. FARBER. A safe dose would be 25 milligrams a day four times

a day, not exceeding more than a 100 milligrams per day of

ephedra alkaloids. The literature indicates that 25 milligrams per

kilo four times a day is a safe dose even in the presence of caffeine.

And you can go back into the literature.

Ephedrine had been derived from ephedra 75 years ago by K.K.

Chen who became the scientific director of the Eli Lilly Laboratories. It has been extensively studied. We do know its pharmacology and what its side effects and toxicity is.

It is not a substitute for methamphetamine. For somebody to say

it has the potency of methamphetamine and it has the capability

of producing highs like amphetamine is wrong.

The DEA has acknowledged that it is not a substitute methamphetamine, and the United Nations has indicated that this material is not a drug or a substance that has any particular high

level of drug abuse potential, and that has been as late as March

of this year.

In fact, there is a letter to Congressman Farr from the State Department declaring that ephedra is considered by the United Nations to be not a significant drug of abuse.

Ms. SCHAKOWSKY. Mr. Chairman, I wanted to ask that the accompanying materials to Ms. Michal’s statement also be put into

the record; and she seems really anxious, so say something.

Mr. BURTON. Without objection. Ms. Michal.

Ms. MICHAL. Thank you very much.

As far as the addiction and abuse and the effect of ephedrine

mimicking amphetamine, it is an amphetamine analog. It is molecVerDate 11-MAY-2000 11:31 May 24, 2001 Jkt 010199 PO 00000 Frm 00196 Fmt 6633 Sfmt 6602 E:\HEARINGS\61435 pfrm09 PsN: 61435
193

ularly similar to amphetamine. It has been proven in studies by

Dr. Paul Wellman at the head of the department of psychology at

Texas A&M University that it affects dopamine in the brain exactly

the same way cocaine and amphetamine do.

I mentioned that I was getting these reports from people over the

Internet. I have just two comments that I would like to share with

you as far as ephedra not mimicking amphetamine or giving them

the same feeling.

I have a 40-year-old female from California reported that she

was addicted to speed. She is a recovering drug addict. She took

a product called Power Trim, two pills as per the label, took it once

and she said, I knew right away it is the same stuff that I took

when I was addicted to methamphetamine.

I have another one that basically said the same kind of thing.

She was a former drug addict addicted to meth—a female, 24 from

Oklahoma, and she took two pills, took it once of Advantage A.M.

300, and it was the same reaction: this is the same stuff that I was

addicted to before, and I can’t take it again.

Ephedrine is an amphetamine analog. I have a 48 percent addiction report rate, dosage run-ups to incredible levels.

Ms. SCHAKOWSKY. Mr. Levitt, is it true that those are illegal on

the Internet? Are those drugs that I was referring to that are being

marketed on the Internet, are they, in fact, illegal according to the

FDA, which is what Dr. Farber said that those are illegal?

Mr. BURTON. We might ask him to return to the table after we

conclude with this panel.

Ms. SCHAKOWSKY. I’m sorry.

Mr. BURTON. That is fine.

Let me just end up by asking one or two more questions. I want

to make a comment. Dr. Woosley, you said that the food supplement industry did that PDR, but as I understand it from my staff,

that PDR is based on the German government’s commission and

monograph. Is that correct?

Dr. WOOSLEY. There is something called the German Commission

Monographs that is a translation of the monographs on herbal

preparations.

Mr. BURTON. Is that the one to which you were referring?

Dr. WOOSLEY. No, that is a different document. The PDR for dietary supplements is a separate book and it is—Medical Economics

markets these products.

Mr. BURTON. As I understand it, the industry took their PDR

from the German government’s?

Dr. WOOSLEY. They may have taken parts of it, but it is a form

of advertising. It is not a scientifically rigorous document.

Mr. FARBER. Mr. Chairman, if I could make a comment.

Mr. BURTON. Dr. Farber.

Mr. FARBER. I have extensively used the German Commission E

monograph, not AufDeutsch, but the English translation, and clearly ephedrine is recognized as a useful herb and recognized to be

safe at dose levels considerably higher than 100 milligrams per

day. The West German government has set up this commission,

and it is heavily dependent upon the opinions found in these monographs.

194

Mr. BURTON. Let me ask Dr. Mowrey one more question. Dr.

Dickinson, because we have not asked you a whole bunch of questions does not mean that we don’t value your contribution.

Dr. Mowrey, can you give us any information about ephedra and

how it works on fat metabolism?

Dr. MOWREY. This is a fairly new application for ma huang. It

has its historical roots in the science of thermogenesis, and in particular in the discovery that brown adipose tissue in human beings

is truly capable of significant thermogenesis in terms of its ability

to help the body in its efforts to control weight.

Ephedrine turns out to be the only safe and effective molecule

that we know of today to really activate this process in the body

via sympathetic mediation. The process is under the control of the

sympathetic nervous system, and we stimulate that with ephedrine.

There is plenty of research to support the contention that it is

a safe and effective treatment for obesity in human beings. Like I

say, it is the most popular treatment throughout Europe. Ephedrine/caffeine combinations there account for 80 percent of the

weight loss market, and considerable research has been generated

by Arn Astrup and a group in Denmark to demonstrate the efficacy

and safety of this particular combination.

Granted, there are mild adverse events that occur, as we have

been mentioning here, but serious adverse events are not seen in

that research. That research, the subjects of course are screened so

they don’t have cardiovascular complications coming into the research. Labels are designed to help screen out people from taking

the product that might be susceptible to that kind of an accident.

In the United States the Harvard group led by Patty Dailey with

Lawrence Lanceburg on the team established the safety and efficacy of long-term treatment of human beings with an ephedrine,

caffeine, and aspirin combination. That was published in the International Journal of Obesity in 1993.

Since the publication of that document, there has been a dramatic increase in interest in this particular mechanism for weight

control. I think that it represents right now perhaps the boldest

and the best program that we have for controlling weight because

it seems to address the underlying physiology of the problem.

In fact, most of the genetic research going on right now with

leptin and other genetic mutations all seem to have as a common

pathway metabolism in adipose tissue, in particular brown adipose

tissue.

So it’s a very strong thrust for the medical profession right now

to be involved in doing this, and it is, I suppose, what has led the

dietary supplement industry into producing products that contain

those substances.

Mr. BURTON. OK. Well, let me just say to all of you how much

I appreciate your time and your patience.

Once again, our condolences to both of you. We will certainly

take into consideration everything that you two have said, as well

as Dr. Woosley. We sure have heard a diverse group of opinions

here. So thank you very much.

195

We would like to have Mr. Levitt return to the table just for a

couple of seconds. Mr. Levitt, thank you for being patient and sticking with us for a little bit here.

I think what I would do is I will initially yield to Ms.

Schakowsky, and then I just have a couple of questions for you, Mr.

Levitt, esquire.

Ms. SCHAKOWSKY. Thank you so much, Mr. Chairman. I really

appreciate this opportunity.

Let me ask you directly then what I had mentioned before. The

500 voluntarily made adverse events reports represent, in your

view, what percent or how much of the total adverse events that

occur with dietary supplements?

Mr. LEVITT. Well, we believe with all regulated products that the

reports that get submitted is a tiny percentage of what is really out

there, because people don’t necessarily either make the connection

themselves or even if they make the connection think that either— either don’t know where to report it to or don’t know how to or

aren’t sure what is going to become of it.

So we estimate, even in the pharmaceutical area, that reporting

is in the neighborhood of 1 percent of what really is out there.

Ms. SCHAKOWSKY. So would it be accurate then to conclude, because there are so few reported cases then, that there are, therefore, so few problems out there?

Mr. LEVITT. Well, I think it is hard to say that. What I think it

is important to say is that the point of the adverse event reporting

system, and I appreciate the chance to emphasize this, is to signal

a potential problem. And even with under reporting, which is accepted in all of these systems, the chances are high that somebody

is going to report it and then FDA has a chance to see it and check

other data bases, other existing information, check the literature

and, see, yes, do we think this signal is right.

So there is definitely under reporting, as there are with all of

those. What we hope is reported is, if you will, an illustrative example and we can pick from even under reported important signals

that can identify safety problems.

Ms. SCHAKOWSKY. Thank you so much for that.

I also wanted to clarify whether or not these drugs that contain

ephedra, that are advertised over the Internet, are they—is that illegal to purchase them and to offer them for sale?

Mr. LEVITT. OK. The rule on that is that if these products are—

contain what we would consider a drug claim, that makes them

subject to the drug rules. Now what you have there is we have had

to go back and say are there—by the kind of title that they give

the product, by the kind of statements, if they are really essentially

marketing it as an alternative to street drugs, that we will consider

that a drug and in this case, since we know they don’t have premarket approval as an approved drug, then they would be illegal.

But the fact that they are illegal doesn’t mean that it is easy to

chase down. Things market over the Internet. FDA can try to do

something. It is very simple for somebody to change their website,

alter their name a little bit, and it is very much a difficult process

to chase these people down.

Ms. SCHAKOWSKY. So it is a subjective conclusion on what they

are claiming to be? I mean, energetic sensations, waves of sensual

196

pleasure, gentle tingling sensations, states of nirvana, is this illegal?

Mr. LEVITT. The actual analysis of those is done by a different

part of the FDA so I am not expert in the specifics, but that is the

general point. The general point is how—if in the jargon that is

used, if what they are really saying is that this is an alternative

street drug, it is used for recreational purposes, it is not identified

for weight loss or for something that is a normal mainstream use,

then that would make it a drug claim and not lawfully marketable.

Ms. SCHAKOWSKY. Thank you.

Mr. BURTON. Thank you, Ms. Schakowsky.

Mrs. Schlendorf’s and Ms. Michal’s children lost their lives because of the over use or over—excessive consumption of these pills.

They have been taken off the market by the FDA, have they not?

Mr. LEVITT. You mean those particular ones?

Mr. BURTON. Yes.

Mr. LEVITT. My staff are telling me yes.

Mr. BURTON. What I would like to know, and followup to what

Ms. Schakowsky just asked, is were the advertisements fairly consistent with what she just read for these other things that are on

the Internet?

Mr. LEVITT. I—you don’t know? Are they fairly consistent with

what—— Mrs. SCHLENDORF. Yes, they are, and I also know that the exact

product Ultimate Xphoria that my son took, it was recommended

to take four and he only took four to maybe eight. That particular

product is no longer manufactured. The company is still in business

and they are manufacturing other similar things.

Mr. BURTON. OK.

Mrs. SCHLENDORF. There are lots of other things on the Internet

very similar that any 10-year-old can buy. Those have not been

taken off the market.

Mr. BURTON. OK. Thank you.

I would like to ask, Mr. Levitt, can’t the Federal Trade Commission work with you to get these products that are being advertised

on the Internet, that are using similar advertising techniques, can’t

they followup and try to run these people down?

I know that there are some ‘‘Internet police’’ now that are out

there trying to get unscrupulous people off the Internet. It seems

to me that the same thing could be done for these products that

are endangering young people with excessive amounts of ephedrine.

Mr. LEVITT. Well, there are mechanisms that we are using.

Mr. BURTON. OK.

Mr. LEVITT. And shall continue to use for those.

But may I just say I think it is a mistake, and at least a number

of the testimony in the previous panel suggested that the evidence

and the adverse events that we have found are not limited to those

that are viewed as ‘‘high abuse levels.’’ The questions that were basically asked were five.

No. 1, are there consistent patterns of signs and symptoms associated with the use of these different ephedra alkaloid containing

products? And the answer to that was yes.

Two was, are the patterns consistent with the available scientific

evidence and known physiologic and pharmacologic effects of

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ephedrine alkaloids? The answer was yes. The answer I am giving

here was the answer from our Foods Advisory Committee.

Three, does exposure occur temporarily before the onset of the

observed scientific symptoms, meaning did they take the product

first? The answer was yes.

Is there other evidence of causality, meaning dechallenge, rechallenge? Dr. Woosley referred to that also, and the answer was yes.

And then the question was, considering the totality of the available information, is there a biologically plausible explanation for

the adverse events? And the committee concluded, I believe unanimously, that the answer was so.

Mr. BURTON. Was there any indication from that about the

amount?

Mr. LEVITT. There was a number of views expressed about the

amount. Some expressed Dr. Woosley’s view that it would not be

possible to establish a safe amount. Others on the committee suggested that FDA try and establish a safe level. That’s what FDA

tried to do in the proposed rule and so forth.

If I may, just one other point that is related to this. Appended

to my written testimony is a chart that I would just like to put up

briefly because it was—so much of this was addressed by the previous panel, because I think, again, a point that is often misunderstood. There are a lot of adverse events, some of them more serious

than others, some less serious, obviously, than others, and we have

talked about that. But what FDA did, and what is important to understand about the system in general, is that the point of those reports is not to give you a definitive answer. The point of those reports is to signal, is there a potential problem here? If they do,

what else can we look at?

And the chart here shows, you start really at the bottom. What

is in the literature that we know about it? Are there any controlled

clinical trials? In this case, there were some trials dealing with

weight loss. What do we know about the OTC drug experience?

What do the experts say?

We take all of that together and say, is this supporting a global

finding that there is a public health problem with these products?

And they unanimously said, yes.

And so I was appreciative of some of the prior testimony about

the FDA process. Before, we talked mostly about the process in

general, but this is a case where the system did identify a real public health issue.

People are struggling on exactly what is the right remedy. You

referenced that. Is there a safe dose or not a safe dose? How many

different products are out there? Is it some products and not other

products?

There is a lot of complexities to the issue, but I think that should

not take away from the underlying finding. And the Timothy Johnson segments, I think, underscored that, that there is something

going on here that we need to try and remedy and do the right

thing about that.

We are trying to do that, but I think, as you have also seen, it

is a challenging labyrinth to get all the way through.

Mr. BURTON. Obviously there are some strong differences of opinion.

198

Mr. LEVITT. Right.

Mr. BURTON. The thing on the Internet, though, and we are

going to review all of this information that has been submitted by

everybody, the thing on the Internet is really important and you

are going to put these disclaimers on there, you say, to try to make

sure that people don’t—— Mr. LEVITT. Yes. You mean the webpage, yes.

Mr. BURTON. On the webpage, right.

I would like to ask Dr. Yetley one last question. Is she still here?

This is on a different subject, but since we have you here I would

like to ask you about it. We have received hundreds of letters from

the public regarding the Codex Committee on Nutrition and Food

for Special Dietary Use. There are a lot of consumers that are concerned that through an international governing body, upper limits

will be set on the dosage of their vitamins.

Can you give me an outline of what the controversy is on that

real quickly?

Mr. LEVITT. Could I just say, thank you for asking that question

because again there is a lot of misinformation out there about that.

I am sure Dr. Yetley can explain.

Mr. BURTON. Thank you for prefacing her comment with that. I

appreciate that.

Ms. YETLEY. Thank you. The Codex Committee is an international standard setting committee. It is part of the WTO agreements, or at least it feeds into those.

There is a proposal on the table that was forwarded by the German government, which is proposing to set standards for vitamin

and mineral supplements that would include both minimum and

maximum levels.

First of all, let me make it very clear that even if the Codex

Committee were to adopt these standards, it would not affect the

products in the United States. The products under DSHEA would

still have jurisdiction here. So it would not affect availability of

these products in the United States.

This issue has come up before the Codex Committee on Nutrition

and Foods for Special Dietary Use for the last two meetings. The

U.S. position has been to oppose this particular standard because

it is not consistent with our laws. However, the rest of the delegates have, as a majority, wanted to move forward.

We are now in the process of offering to work with other governments to write a background paper that would lay out the pros and

cons of the various perspectives of different governments and different delegations. So it will give us a chance to lay forth our philosophies and concerns as well as other governments’.

Mr. BURTON. We would like to, if it would be possible, Doctor, to

have you meet with our staff for a full briefing.

Ms. YETLEY. I would be glad to.

Mr. BURTON. We would really appreciate it.

Mr. LEVITT. I think that it is just indicative of the fact that these

products are regulated differently in different countries, and when

you get into different international fora, everybody tries to move it.

Mr. BURTON. Sure. We would like to have a briefing just so we

can understand that better.

Mr. LEVITT. Sure.

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Mr. BURTON. Mr. Levitt, thank you very much. Doctor, thank you

very much.

We I want to thank all of our witnesses. It has been a long day.

We really appreciate it, and we hope this has shed some light on

this whole problem. The meeting stands adjourned.

[Whereupon, at 4:45 p.m., the committee was adjourned.]

[Additional information submitted for the hearing record follows:]

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