PUBLIC MEETING ON THE SAFETY OF DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS VOLUME II of II [DHHS Office on Women's Health does

not guarantee the accuracy of this transcript.]

Wednesday, August 9, 2000 U.S. Public Health Service Cohen Building Auditorium Washington, D.C.

MOFFITT REPORTING ASSOCIATES (301) 390-5150

The meeting in the above-entitled matter was convened, pursuant to notice, at 9:00 a.m.

MOFFITT REPORTING ASSOCIATES (301) 390-5150

A G E N D A Public Meeting: Safety of Dietary Supplements Containing Ephedrine Alkaloids Wednesday, August 9, 2000 9:00 a.m. OPENING REMARKS Wanda K. Jones, DrPH, Director Office of Women's Health 9:05 a.m. 9:10 9:13 9:16 9:19 9:22 9:25 9:28 9:31 9:34 9:37 9:40 9:43 9:46 9:49 9:52 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Public Comment Session B Robin Willis, Private Citizen Betty Lou T. O'Day, Private Citizen Marilyn H. Gunn, Private Citizen Lisa F. Wilkins, Private Citizen Eric D. Gordon, Private Citizen Cynthia Wotring, Private Citizen Angela Stanek, Private Citizen Allison R. Blevins, Private Citizen Margaret A. Love, Private Citizen Lyn Ailstock, Private Citizen Therese Heard, Private Citizen Anna C. Callahan, Private Citizen Belinda G. Ivey, Private Citizen Tracey Schiavello, Private Citizen Bernadette Hunter, Private Citizen MOFFITT REPORTING ASSOCIATES (301) 390-5150

9:55 9:58 10:01 10:04 10:10 a.m. 10:25 a.m. 10:25 10:40 10:45 11:00 11:05 11:20 11:25 11:40

21. 22. 23. 24.

Karl Hasik, MD, Private Citizen Arthur M. Schyler, MD, Private Citizen Marion L. Banks, Private Citizen Jerry McLaughlin, Private Citizen BREAK Abstract Session 2

Robert M. Hackman, PhD University of California, Davis Q&A Kathy Fomus Council for Responsible Nutrition Q&A John Hathcock, PhD Council for Responsible Nutrition Q&A Mark Blumenthal, American Botanical Council Q&A

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Public Meeting: Safety of Dietary Supplements Containing Ephedrine Alkaloids 11:45 11:50 12:05 12:10 12:25 12:30 1:30p.m. Paul J. Rubin, JD, Patton Boggs (Introduction) Carol N. Boozer, Dsc, Columbia University Q&A Patricia Ann Daly, MD, York Hospital (PA) Q&A LUNCH (On your own) Abstract Session 3 George A. Bray, MD, Louisiana State University Medical School 1:45 1:50 2:05 VA 2:20 2:25 2:40 Q&A Charles H. Hennekens, MD, University of Miami, School of Medicine Q&A Q&A Arne V. Astrup, MD, PhD, Denmark (by videotape) Graham A. Patrick, PhD, RPh, Medical College of

MOFFITT REPORTING ASSOCIATES (301) 390-5150

2:45 3:00 3:05 3:20 3:25 3:28 3:31 3:34 p.m. 3:45 3:45 3:55 3:58 4:01 4:07 4:10 4:13 4:16 4:19

R. William Soller, PhD, Consumer Healthcare Products Association Q&A Gary L. Huer, MD, Texas Nutrition Institute Q&A Comments by patients of Dr. Huber: John Martin, Private Citizen Darynda Crocker, Private Citizen Molly Mason, Private Citizen BREAK Public Comment Session C 26. 27. 28. 29. 30. 31. 32. 33. 34. Roy Brabham, MD, Baton Rouge Gayla Heflin, Private Citizen Kimberly Jerrow, Private Citizen Carolyn Sciuto, Private Citizen Margo Ellis, Private Citizen Lynn McAfee, Private Citizen Fatima Ellis, Private Citizen James Sands, Private Citizen Debra Cohen, Private Citizen MOFFITT REPORTING ASSOCIATES (301) 390-5150

Public Meeting: Safety of Dietary Supplements Containing Ephedrine Alkaloids

4:22 4:25 4:28 4:46 p.m.

36. 36. 37.

Lori L. Piazza, Private Citizen Sandra Lynn O'Brien, Private Citizen

CLOSING REMARKS Wanda K. Jones, DrPH, Director Office of Women's Health

5:00 p.m.

Adjourn

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LISTENING PANEL Chair: Wanda Jones, Dr. P. H.

Deputy Assistant Secretary for Health (Women's Health) Director of the Office of Women's Health U.S. Department of Health and Human Services Aaron H. Burnstein, PharmD Clinical Pharmacokinetics Research Laboratory Clinical Center Pharmacy Department Building 10, Room IN-257 Bethesda, MD Paul Coates, PhD Director Office of Dietary Supplements NIH Harris Lieberman, PhD Supervisor Research Psychologist US Army Research Institute of Environment Medicine 42 Kansas Street Natik, MA 01760-5007 Rossanne M. Philen, M.D., MS MOFFITT REPORTING ASSOCIATES (301) 390-5150

Health Studies Branch National Center for Environmental Health Centers for Disease Control and Prevention 1600 Clifton Road, NE Mailstop E-23 Atlanta, GA 30333 Mary Ann Richardson, Dr.P.H. Program Officer National Center for Complementary and Alternative Medicine National Institutes of Health Marcel Salive, MD, MPH Prevention Scientific Research Group Division of Epidemiology and Clinical Applications National Heart, Lung and Blood Institute National Institutes of Health Berne Schwetz, DVM, PhD Acting Deputy Commission for Food and Drugs Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857

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P R O C E E D I N G S [Time noted: DR. JONES: Good morning, everyone. 9:00 a.m.] My

borrowed watch shows that it's a little after nine, so let's get started. Sorry. We have a little bit different setup

up here on the stage so it takes us a few minutes to reorient. At any rate, good morning, again. For those

of you who weren't here yesterday, I am Wanda Jones and for those of you who were, I'm still Wanda Jones, Deputy Assistant Secretary for Health and Director of the Office on Women's Health located in the U.S. Public Health Service. I welcome you to day two of

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our public meeting on The Safety of Dietary Supplements Containing Ephedrine Alkaloids. For those of you who weren't here yesterday, I want to briefly summarize the purpose of the meeting and then for all of you go over the day's logistics because we have had a few changes. The Office on Women's Health called this meeting to discuss the available scientific information on the safety of dietary supplements containing ephedrine alkaloids. During the course of

this two-day presentation, yesterday and today, we hope to have four specific questions addressed by the many individuals and organizations who have come to provide information at the meeting. I will recap the

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questions. First, what positive and adverse physiologic actions would be expected of ephedra based on its known constituents? Does the available information

show an association between the use of dietary supplements containing ephedrine alkaloids and adverse events, for example, cardiovascular, central nervous system, psychotropic events, et cetera, when used as directed? Second, are there any circumstances for which there are well-established indications for the use of dietary supplements containing ephedrine alkaloids; what does and duration of use are needed for those indications; and what is the quality of any MOFFITT REPORTING ASSOCIATES (301) 390-5150

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data to support such use? Third, how would one characterize the seriousness and/or severity of the risks of ephedrine alkaloids labeled for weight loss and exercise enhancement taking into account issues such as user demographics, age, sex, or race ethnicity, the amount consumed across the population, use with other natural or synthetic stimulates such as caffeine, synephrine, or yohimbine and the added stress of exercise as well as individual sensitivity to these types of products. Fourth, are the outcomes associated with the use of these products affected by dosage, user characteristics such as age, predisposing health conditions, or their behavior such as combining use MOFFITT REPORTING ASSOCIATES (301) 390-5150

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with other stimulants or other compounds.

Are they

affected by the duration of the exposure or by other means? And those are our questions. Let me remind you further that the information and data gathered in this meeting will help the Food and Drug Administration in it's ongoing assessment of ephedra so we will be depositing a record of this meeting in the FDA docket. Now, let me turn to format and logistics. First of all, once again we have our sign language interpreters for the deaf who are with us today. Lisa

Beth who is here in front of me and Yvonne who will be taking turns back and forth. If you have need to be

able to see them, please move toward the front of the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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room where you can clearly see their signing. This morning we opened with public comment. The persons who have registered for comment and whose names appear in this morning's list should be prepared to approach the microphone as their scheduled time approaches. Now, I understand that they have

requested that their time which was originally allocated to be three minutes, and the microphone will be here, and we will ask you to come to the podium actually. We had allotted three minutes, but I

understand that you all have requested that you would reduce your time. floor mikes? Oh, you're going to do it from the Okay.

Cool.

You're going to reduce your time to provide MOFFITT REPORTING ASSOCIATES (301) 390-5150

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time to two additional speakers, or two speakers who are on the agenda. And if I understand the request One

clearly, you will each speak for one minute? minute? Okay.

So watch for the red light and I will It

turn it on as the end of that minute approaches. goes very fast.

If that time is insufficient, you are

welcome to deliver the full text of your remarks to the folks out in the registration area where there is a box in which we are collecting copies of slides, printed remarks, and so forth, for the record of this meeting. AUDIENCE PARTICIPANT: everyone will take one minute. allotted three. [Off mic.] Not

Some will take the

I think as they come up, if they MOFFITT REPORTING ASSOCIATES (301) 390-5150

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announce to you what their plans are, would that be helpful? DR. JONES: Okay. Yes, that would be helpful then.

Thank you for the clarification. So they had three minutes allotted, those of

you who are in need of less time, then just let me know. But we will time you anyway, that's what we are

set up for. After the break, we will proceed to an abstract session wherein speakers will have 15 minutes followed by five minutes of question. Then after

lunch another abstract session follows and then the meeting concludes with a public comment session and closing remarks. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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It is my goal to start and end the meeting and all presentations including public comment as scheduled. We want to be sure everyone who is

registered for time to speak has that time available to present his or her views. All speakers shown in

the agenda and those who come to the microphone with questions, during the Q&A sessions, should state for the record, their name and their affiliation. And

speakers presenting to us, on the agenda, should also state the source of funding for their activities and the source of funding for their travel here. In addition to the box in the registration area, once you go home today you might want to still make comments. So I remind you that FDA has opened MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the public docket as of August 10th, 2000 through September 30, 2000, and they would welcome your written comments to the docket. This docket will

display all of the information that the Agency has received, including the information presented at this meeting. This meeting is being transcribed and the transcript will be made available in the docket as quickly as possible, we expect within 15 working days. And, again, information on how to access the public docket and submit your comments is included with registration materials. One other brief note on housekeeping. food or beverages are allowed in the auditorium. MOFFITT REPORTING ASSOCIATES (301) 390-5150 No You

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heard that bad news yesterday, but if you are here this morning with us the first time, it's no easier to tell you today either. The restrooms are in the long corridors. you exit the auditorium and turn right, you will see signs at that major intersection there, either right or left, directing you to restrooms. And there are If

maps available at the registration desk of places that are quick, close by, for a quick bite for lunch. So with all that, let m note two additional scheduling changes. Loren Israelsen, who is listed as

the first public commenter, gave me a note yesterday, unable to stay. Some urgent business called. So, he

expressed his regrets.

He will not be with us this

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morning.

And then in the slot labeled No. 23 on your

agenda, at 10:01 a.m., Dr. Jerry McLaughlin of Spanish Fork, Utah will be speaking. So, without further adieu, Ms. Willis. MS. O'DAY: Good morning. My name is Betty

Lou O'Day from Booth Wynn, Pennsylvania, I am a Starlight International Independent Distributor. I am

not being compensated to be here today, but Starlight is paying my expenses. pounds until my mid-30s. My average weight was 112 At age 38 I tried Diet I

Doctors with shots and pills thinking it was safe.

also tried starvation programs, fad diets, and weight loss centers. Some took the pounds off, but I could

not maintain the weight loss. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I enrolled in a medical program which included an exercise trainer, nutritionalist, and medical monitoring. This was an agonizing challenge

that led to a disaster in my overall health, metabolism, and additional back problems. At age 44 and at 175 pounds, a new challenge -- cancer. I became a cancer survivor but a weightAt age 56 I was told I needed an knee I could not walk without a cane as my

loss failure. replacement.

weight had climbed to 220 pounds, and it was difficult to breath, causing extreme fatigue. Starlight International's NatruralTrim, an ephedra-based product was the answer to my prayer. Within three months I lost 30 pounds, 36 inches, and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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as an additional bonus my knees improved and I no longer needed the knee replacement surgery. My health continues to improve. have lost 71 pounds and 50 inches overall. product helped me gain control of my life. To date I This This is

the first time I have had no adverse events in my health. I looked for pictures, but when you become uncontrollably obese you avoid having the camera take your picture. I did bring a pair of slacks which were snug at the time, and I defer any left over time to the physicians. [Presenting slacks.]

And I outgrew these. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES: Ms. Gunn. MS. GUNN:

Thank you, Ms. O'Day.

Hello, my name is Marilyn Gunn.

I am a pre-school teacher in the Richmond, Virginia area. I am also an independent distributor for Starlight International. I am not being paid for my

testimony today, but Starlight is paying my expenses while here. For 16 years I have struggled with my weight. I also take medications for high blood I knew how crucial

pressure and Type II diabetes.

weight loss was to my health, but no matter what diet or exercise program I tried, nothing seemed to work for me. I was so desperate two years ago that I took MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the entire summer off from my job to work with a couple of diabetes specialists in order to get my condition under control; all that hard work, but still no weight loss. At the end of that frustrating summer my friend recommended NaturalTrim. I took it but was so

scared of a reaction that I monitored my blood pressure and my blood sugar hourly for the first two days. When I saw no change and everything remained

normal, I had hope for the first time in many years. I went on to lose 22 pounds, 25 inches, and two dress sizes. For the last year and a half I have maintained that weight loss and my blood sugar MOFFITT REPORTING ASSOCIATES (301) 390-5150

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readings have been at or below what is considered normal or non-diabetic. I feel so much better now.

My health is back and I am living life to its fullest. I defer my remaining time to the doctors. DR. JONES: Ms. Wilkins. MS. WILKINS: name is Lisa Wilkins. Thank you. Good morning, my Thank you, Ms. Gunn.

I'm a substitute teacher and an

independent Starlight distributor from Newport News, Virginia. I am not being compensated for my time, but

my expenses are being taken care of by Starlight International. Over the past ten years or so I have tried various weight loss methods from extensive exercise, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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protein shakes, even to the point of vitamin B12 shots in my arms. I've lost some pounds, but I've always

gained them back. I was introduced to an ephedra-based product called NaturalTrim by my physician and lost over 17 pounds. In addition, while I was taking the

NaturalTrim the allergies and sinus problems I had been plagued with for years, melted away along with the extra pounds. This was very important to a person

like me who lives in the middle of a pecan grove. NaturalTrim gave me back my energy, my self control, and has been the only weight loss product that I've had enough confidence to recommend without hesitation to anyone. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Any time that I have remaining, I do defer to our physicians. DR. JONES: Mr. Gordon. MR. GORDON: Good morning. My name is Eric I'm not Thank you, Ms. Wilkins.

Gordon, I come from Nazareth, Pennsylvania.

being compensated for my time, but my expenses are being reimbursed by Starlight International whom I happen to be a distributor for. On December 3rd, 1999, in a public restaurant I happened to stand up at the table and open my pants so that I could -- undo the top of my pants so that I could put more food in my stomach. And my wife preceded to humiliate me in front of the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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entire restaurant and pulled out this pill box and said to me, "You'll start taking these products tomorrow morning." On December 4th, I started on NaturalTrim, I weighed 242 pounds, I wore a size 44 pants. Could not

exercise because I'm a severe asthmatic, and my asthma was only exacerbated by my overweight. I started in the NaturalTrim, I tried to exercise, two days after I started, I was able to do a half a mile on a treadmill. Couldn't continue, so I

stopped and waited until I would see if I lost some weight. By February 1st I had lost 25 pounds, I went

back to exercising, was able to do two and a half miles. By May 30th I had reached my goal, I lost 62 MOFFITT REPORTING ASSOCIATES (301) 390-5150

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pounds -- 60 pounds, excuse me. Today I presently weigh 182 pounds. I wear

a size 36 pants; I run six miles a day, five days a week; my asthma is completely under control; and I no longer run for distance, I'm running for time. right now about an 8.9 minute mile. I run

I'm healthier

today than I have been in 20 years and all due to NaturalTrim. I do have a picture here I would like to show you. 1999. This picture was taken on December 1st,

I would be the person in the center, and if you

take a look at that picture you can see what this product has done and I will defer the rest of my time to the physicians. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES: Ms. Wotring. MS. WOTRING: Cynthia Wotring. Pennsylvania.

Thank you, Mr. Gordon.

Good morning.

My name is

I am a dental hygienists from MAS,

I am not being paid for my time here

today, but my expenses are being covered by Starlight International and I am a proud independent distributor of Starlight International products. In March of 1998 I was unhealthy, overweight, and tired. I have dieted all my life, I could always lose the And so at age 42

since junior high school.

weight, but I always gained it back.

I found myself resigned to the fact that I was going to live with middle-aged spread; and it wasn't a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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pleasant outlook. Thank goodness a friend introduced me to an ephedra-based product called NaturalTrim. I knew this

product was different as soon as I took the first dose. I remember clearly because it was Easter weekend, and I didn't want to eat my children's chocolate Easter bunnies. For the first time in my I had renewed energy

life my food cravings were gone.

and I didn't feel the need for a nap in the afternoon. Within the first week of taking NaturalTrim my clothing was getting looser. After two weeks, I had

lost six pounds simply by swallowing NaturalTrim. I was able to achieve with NaturalTrim a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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weight loss that I had previously been unable to manage. I lost over 20 pounds in three-months' time

and even more importantly, I have been able to maintain that weight loss for over two years. During that time I did not experience one single adverse effect from the use of the ephedrabased product. lifechanging. I have shrunk from a size 14 to a size 9 petite. In addition to the weight loss, I have But the benefits have been

tremendous energy, productivity, improved health, and as a result a better quality of life. I defer all my remaining time to the physicians. Thank you. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES: Ms. Stanek. MS. STANEK:

Thank you, Ms. Wotring.

Thank you.

My name is Angela I am not

Stanek and I'm from Allentown, Pennsylvania. being compensated for being here today, but my expenses are being paid for by Starlight International.

I am also a proud distributor of

Starlight percents. My personal testimony is this: year-old mother of two. over 23 years. I am a 38-

I have battled my weight for

I found NaturalTrim and with it I I am free to make my own

finally have found freedom.

food choices, I no longer obsess about what to eat and when to eat it, and I have control of my appetite for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the first time in my life. As a result of using NaturalTrim I have successfully lost 42 pounds over 40 inches, and four dress sizes in clothing. This is what I wore for

Christmas three months before I began NaturalTrim. [Presenting dress.] With using this product, I have total confidence in its safety, in its effectiveness; I have total confidence in recommending this product to anyone that is interested in losing five pounds or more. I personally have had no adverse effects from using NaturalTrim, nor do I know of anyone that has had any problems or adverse effects. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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NaturalTrim's has helped me to take control of my eating and my life. It's helped me to make I

better choices with my everyday meal decisions.

felt comfortable instead of forced into making my meal choices which has made for a much easier transition into healthier eating every day. These changes I can

live with for the rest of my life instead of trying to live for the life of the diet of the day. I know I could not have done this with my weight and inches without using this NaturalTrim product. This is the most successful tool I have ever

used to lose weight where I need to and to keep it off. I thank you for your serious consideration MOFFITT REPORTING ASSOCIATES (301) 390-5150

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for this most effective supplement. time to the physicians. DR. JONES: Ms. Blevins. MS. BLEVINS: Thank you.

And I defer my

Thank you, Ms. Stanek.

Good morning.

My

name is Allison Blevins from Newport News, Virginia. I am a stay-at-home mother. I have two children. I

am also an independent distributor of Starlight International. I am not being compensated to be here

today, but my expenses are being paid by Starlight International. I started taking NaturalTrim a little over two years ago at the age of 25 to lose weight after the birth of my daughter. In only four months I had

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lost 27 pounds and 21 inches.

I never felt deprived

or hungry and I also had plenty of energy to keep up with my toddler. I must have enjoyed being skinny a lot, because I got pregnant again with my son. finished nursing him, I started back on the NaturalTrim. In five months I have lost 25 pounds, 18 After I

inches, and I'm getting skinny again. I have had no adverse effects of the NaturalTrim and have recommended it to several people. I defer my time to the physicians. DR. JONES: Ms. Love? MS. LOVE: Hi, my name is Margaret Love. I Thank you, Ms. Blevins.

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am 38, and I own a trucking company with my husband in Matthews, Virginia. I am not being compensated for

today, but my expenses are paid by Starlight International. I have been overweight for 13 years. After

a long struggle with Lupus and daily steroid use, I tried exercise and a lot of different diets, you name it, I've tried it; not one of them was successful. When my friend shared her success on NaturalTrim I had hope. In just days I started to lose weight. In

eight weeks I lost 24 pounds, 29 and a half inches, and am still losing. 16 within that time. I have gone from a size 20 to a I now also have more energy and I even

I not crave that nightly bowl of ice cream. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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have the desire to drink water for the first time. And most of all, I have not had any adverse effect to NaturalTrim. For once in my life I have also found a

weight management program that actually works for me. Thank you. DR. JONES: Thank you, Ms. Love.

Ms. Ailstock. MS. AILSTOCK: Good morning. Hello, my name I am

is Lyn Ailstock from Mechanicsville, Virginia. an independent distributor for Starlight International.

I am not being compensated for my

testimony, Starlight is paying for my travel expenses. I am a stay-at-home mom of three and I had battled being overweight my whole life; trying one MOFFITT REPORTING ASSOCIATES (301) 390-5150

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diet after another.

The problem has always been, as

soon as I went off the diet, I would regain what I had lost plus more. I was introduced to NaturalTrim last

year and successfully lost 35 pounds over about five months. I lost the weight without the torture I normally experienced during dieting and have been able to maintain the loss over the last year. I had more

energy and did not experience the depression that I had always suffered with my previous weight loss. Plus, when I went for my yearly physical, I was told I was in terrific health. And as an added bonus my

husband also lost 46 pounds and has successfully kept his off also. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Thank you. DR. JONES: Ms. Heard. MS. HEARD:

And I defer to the physician. Thank you, Ms. Ailstock.

Good morning.

My name is

Therese Heard and I'm an independent distributor with Starlight International. Virginia. I live in Mechanicsville,

I am not being paid for my testimony today,

however, I am being reimbursed for travel expenses. I have worked in the health care insurance industry for the past 16 years. overweight for ten years. I have been grossly

For 19 years I have

suffered with chronic pain and a total loss of strength and energy due to fibromyalgia and chronic fatigue syndrome. Needing to lose 70 pounds, and I

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have a picture of what I used to look like, is what prompted me to try an ephedra-based product called NaturalTrim. I have lost 25 pounds and two dress sizes in five months. I am still losing. I now have the And

energy to exercise using weights and a treadmill. I finally have the strength to walk up and down the

stairs without using the railing which is something I could not do before. the physicians. DR. JONES: Thank you, Ms. Heard. And I defer any extra time to

Ms. Callahan. MS. CALLAHAN: Hi. I am Anna Callahan from

Newport News, Virginia where I work for a property MOFFITT REPORTING ASSOCIATES (301) 390-5150

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management company. distributor.

I am a Starlight independent

I am not being paid for my testimony

today, but Starlight International is covering my expenses. I needed to lose weight badly, but when a friend introduced me to NaturalTrim I was very skeptical. You see, I have suffered from chronic

asthma for six years and have taken an arsenal of prescription drugs and regular breathing treatments. So I didn't think NaturalTrim would be safe or effective with the drugs I was taking. I was wrong. I am 35 pounds lighter, I am skinnier, and I can breath on my own. I have control of my life, and I was so glad

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of my health, for the first time in a very long time. Thank you. physicians. DR. JONES: Ms. Ivey. MS. IVEY: Hi. My name is Belinda Ivey. I Thank you, Ms. Callahan. And I defer my time to the

am a 34-year-old wife and mother of two.

I am also an

independent distributor with Starlight International. I am not being compensated for my testimony, today, however, Starlight international is paying for my travel expenses. I work as an administrator in the Richmond, Virginia area. I have tried many diets in the past, I After

could lose weight, but I couldn't keep it off. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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only three months on a product called NaturalTrim I've lost 31 pounds, lots of inches, and four dress sizes. I have the energy now that I had lost. feel healthier than I have ever felt before. And, I

finally, I'm keeping the weight off and I love it. And I would like to defer the rest of my time to the physicians. DR. JONES: Thank you, Ms. Ivey.

Ms. Schiavello. MS. SCHIAVELLO: My name is Tracey

Shiavello. I am an independent distributor with Starlight International. I am not being paid for my

time here today, but I am being reimbursed my travel expenses. I would like any additional time to be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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deferred to the physicians. As a past marathon runner and certified aerobics instructor I was a skeptic when it came to herbal supplements. My training had always been eat

right and exercise to stay fit and maintain healthy weight. NaturalTrim changed my thinking. To date I have lost 25 pounds on NaturalTrim. three months. Three years ago I lost 15 pounds in And one and a half years ago I used

NaturalTrim again and lost an additional 10 pounds in three months. As well as maintaining the weight loss, my body composition and proportions have dramatically changed. I eat more and exercise less. For me,

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NaturalTrim took away my cravings for high carbohydrates, high sugar, and high fat foods. found myself eating lean protein, fruits, and vegetables. lifestyle. It was easy to incorporate into my I had more energy throughout the day and I I

never felt drugged. Obesity is a growing epidemic. In all of

the years I taught aerobics I was never able to help people take control of their weight the way I know can sharing NaturalTrim. Since my success with NaturalTrim I continue to educate myself on the effectiveness of herbal supplements. I am passionate about Starlight

International and the impact responsibly made herbal MOFFITT REPORTING ASSOCIATES (301) 390-5150

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products will have on America's preventive health care and chronic health issues. Thank you. DR. JONES: Ms. Hunter. MS. HUNTER: Bernadette Hunter. Good morning. My name is Thank you, Ms. Schiavello.

After my incredible success with

NaturalTrim I became an independent distributor for Starlight International. I am not being paid for my

time here today, but my expenses are being paid for by Starlight. I too would like to defer any extra time I

have at the end to Dr. Hasik and Dr. Schyler. I am a 38-year-old stay-at-home mom with four small children. I have been active in sports my

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whole life and I've always considered myself a health conscious individual and was fairly knowledge in regards to fitness and nutrition. After the birth of

my fourth child, my tried-and-true regime of diet and exercise did nothing to budge the extra 20 pounds I still had to lose. Unfortunately this was the fashion [Presenting shorts.]

statement of the day for me. The size is daunting.

After 15 frustrating months of trying, I was introduced to NaturalTrim. In just three short months

with my normal exercise routine, and eating what the rest of my family was eating, I was able to lose 21 pounds and over 21 inches. As NaturalTrim curbed my

appetite and reset my metabolism, I experienced no MOFFITT REPORTING ASSOCIATES (301) 390-5150

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adverse side effects whatsoever. felt better than I had in years.

On the contrary, I

Because NaturalTrim is an all-natural, herbal product I was confident to recommend it to all my friends who were eager to know what had finally helped me keep the weight off. I have easily

maintained the weight loss for almost a year now and have recommended this product to many, many people who have done the same without any adverse reactions. Thank you. DR. JONES: Thank you, Ms. Hunter.

Now, I presume you're Dr. Hasik? DR. HASIK: DR. JONES: Yes, ma'am. And you have a lady behind you

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and then I presume the other doctor is -DR. HASIK: DR. JONES: now? Dr. Schyler. Yes. What will your process be

The three of you are going to -DR. HASIK: I would like to speak for Marion L. Banks

approximately three to four minutes.

who is with me will also speak for a very brief period of time and then Dr. Schyler will speak. DR. JONES: DR. HASIK: DR. JONES: DR. HASIK: Okay. Thank you. Thank you. My name is Dr. Karl Hasik, from

Tuscaloosa, Alabama, and I am a distributor of Nutrisutical products. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I am here with Marion L. Banks, from Jasper, Alabama, who is not a distributor. Our expenses have

been paid by Starlight International, but we are not being compensated for our time. I am a Board Certified, obstetrician gynecologist and I have worked in private practice, as an employed physician, and in academic medicine over the last 17 years. I practice medicine and distribute

nutrisuticals concurrently as part of my medical practice. I derive financial benefit from both my

practice of medicine by doing surgery and giving consultations as well as offering supplements to my patients as an option. I offer options to help improve my patients' MOFFITT REPORTING ASSOCIATES (301) 390-5150

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health.

I would never recommend any option that would

not help someone improve their health even if I stood to gain financially from such a recommendation. I have used ephedra-containing products in my practice and personally to visible beneficial effect. Ephedra product assist in weight loss by

providing appetite suppression and increasing an individual's energy level. If you are not hungry and

if you increase your activity due to your increased energy level, it is much easier to lose weight. has been my and my patients' experience. I can relate one different experience in the last two years of one individual who was prone to anxiety. She took one sample containing ephedra and MOFFITT REPORTING ASSOCIATES (301) 390-5150 This

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experienced a rapid heart rate which cleared spontaneously within one hour. I would expect this

person would have had the same type of reaction to caffeine. There have been no other such occurrences

in my experience with ephedra-containing products. Indeed, the amount of ephedra in our products used is no more than that contained in common cold formulas and preparations and those are not under investigation. The indications for use of ephedracontaining supplements may be multiple; but clearly seem to answer our populations' need to lose weight, and obtain and maintain optimal health. Being overweight blocks many of our paths to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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wellness, both physiologically and psychologically. We have heard that being overweight increases our physiologic challenges with such ailments as Type II diabetes melitis, hypertension, heart disease, as well as aggravating joint disease. something to drink. Excuse me. I wish we could have

Ephedra-containing products help promote weight loss which will improve and alleviate many of these physiologic conditions. Other modalities used

to promote weight loss are very difficult, very artificial, very dangerous, or very unsuccessful. Psychologically those of us who experience the overweight state, and don't want to, tend to possess an impaired self concept. We are frequently

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looked upon as weak of will or character.

We are

reminded on a daily basis in the print and television media of the fact that we are not normal because normal is that svelte model. This cognitive Weight loss

dissonance cannot build self-esteem. does.

Ephedra-containing products help people toward that goal of weight loss. pounds using these product. I have lost 15

I have experienced no

difficult interaction while taking these products and performing strenuous exercise. Nor have I had any

difficult interaction using ephedra-containing products while taking other herbal energy products including the use of caffeine. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Mine and my patients' experiences have shown that a set dosage recommended by the manufacture has been very effective in assisting toward weight loss. The amount of ephedra alkaloids in the products we have used is no more than that found in common cold formulas which are considered safe with ephedra as we should now consider our product safe with ephedra. I do not recommend ephedra products for pregnant women. Other than that, I have personally But I

seen no one who could not take these products.

am aware of the recommendations and contraindications on our packaging which I feel provides sufficient protection. I have taken these products on two

occasions for five months and I know of others who MOFFITT REPORTING ASSOCIATES (301) 390-5150

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have taken them much longer with only continued improvement in their wellness as a result. Let me introduce Marion L. Banks who has traveled with me today to briefly tell you about her experience. And I thank you very much for your time And even though

and letting me share my experiences.

I am part of the public comment section of this event, I would be glad to answer any questions that you might have after we are finished. Thank you very much. DR. JONES: Ms. Banks. MS. BANKS: I am Marion L. Banks, a 45-yearI am proof Thank you, Dr. Hasik.

old school teacher from Jasper, Alabama.

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that ephedra-based products are indeed a safe, simple, and reliable program for losing and maintaining weight loss. I am not a distributor of ephedra products,

just a consumer. After struggling with weight gain while in graduate school in the early years of my teaching career, and adding more and more excess weight over the past 23 years, I unsuccessfully tried to resign myself to being fat. My various attempts to exercise,

follow diet programs, and to use diet products have been discouraging. It is simply unacceptable to me to remain fat the rest of my life. For my physical and

emotional health's sake, I am taking NaturalTrim an MOFFITT REPORTING ASSOCIATES (301) 390-5150

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ephedra-based product and I am following the suggestions by the program concerning diet and exercise. In four months I am thrilled to be 30 pounds lighter. effects. I have not experienced any negative side This has just been a wonderful and positive I feel certain that I will continue to

experience.

lose weight until I reach my goal and then maintain it with this weight management system. Thank you. DR. JONES: Dr. Schyler. DR. SCHYLER: Schyler. Good morning. I am Dr. Arthur Thank you, Ms. Banks.

I am not being compensated for my time MOFFITT REPORTING ASSOCIATES (301) 390-5150

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today, but my expenses are being paid by Starlight International. I am here today not as a proponent of any company, vitamin, herb, or chemical entity. simply as an advocate for my patients. I am here

I graduated

from the University of Kansas, School of Medicine, in June of 1980. I did a three-year residency at I've been

University of Kansas, Mokeyhill Clinic. practicing medicine for 17 years.

I am Board

Certified by the American Association of Family Practice. My practice focuses primarily in cardiovascular, endocrine, and lipid disorders. The

majority of my patients are adults, the elderly, and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the frail elderly.

I became a distributor of dietary

supplements to help my patients obtain herbal products. As I am doing here today, I always disclose to my patients my involvement as a distributor of these products. Working with patients to develop a

weight loss program encompasses many aspects that need to be addressed. First, there are no magic bullets, there are no miracles in a bottle, but I have seen how ephedra products enhance my patients' weight loss efforts. Patients need to stay with a program and focus on the goal of weight loss. To help them with that goal, I

have used ephedra products in my practice for the last MOFFITT REPORTING ASSOCIATES (301) 390-5150

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three years.

I discovered their benefit when

attempting to find a safe, effective alternative to the Fen-Phen clinic in our town. Approximately 500 of

my patients have used ephedra products during that time. I have been impressed with the success they

have achieved. Patient SG is a 48-year-old white female who started on the product to help her control her exogenous obesity. She lost 33 pounds of body weight Her initial blood pressure of

over four months time.

160 over 104 while on medication dropped down to 118 over 76. tears. In my office on hearing this she broke into I asked her what was wrong; she told me that

she had been praying for the past ten years to find MOFFITT REPORTING ASSOCIATES (301) 390-5150

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some wy to get off of her blood pressure medication because her entire family had been hypertensive and obese. By losing this body weight, feeling better, and being able to exercise, she saw that her life was going to change for the better. Patient KG is a 346-pound, 42-year-old African-American male. In two months he has dropped He

22 pounds by using an ephedra-containing product.

has noted an increase in his mobility, an increase in his endurance, and a significant decrease in his chronic low back and hip pain. I am excited about his

great decrease and the risk from Syndrome X which is an exceedingly prevalent in the African-American MOFFITT REPORTING ASSOCIATES (301) 390-5150

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patient population. Syndrome X is defined as a combination of hypertension, diabetes melitis Type II, hypercholesterol, and obesity. All of the research

currently being done on Syndrome X includes specific attention to excess body fat. Patient JB is a 72-year-old male with significant cardiovascular disease including CHF, peripheral vascular disease, diabetes, and unstable angina with claudication. I started this patient on a

ephedra-containing product in 1998 which allowed the patient to lose approximately 10 pounds of body fat. This 10-pound drop in his body weight allowed him to control his diabetes with oral medication avoiding the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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use of insulin. It also allowed him to increase his exercise, tolerance, and endurance. He is now working

out at the gym on a regular basis, walking on the treadmill four to five mornings a week for 30 minutes and using weight machines. Patient WW presented to my office in midApril of this year at 331 pounds. He was

significantly debilitated, short of breath and only 28 years of age. In two and a half months he has dropped Now he

32 pounds using an ephedra-containing product. sees a bright future with increased mobility and increased activity.

His blood pressure has dropped 18

points systolic and 14 points diastolic with the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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simple weight loss program that he has followed. I have also been impressed with the paucity of side effects from these ephedra products limited entirely to nervousness or sleep disturbance. Obesity was once thought to be a matter of aesthetics, but now we realize that excess body fat is the cause of many of our most serious and devastating diseases. It is the cause of hypertension in many

people and by simply reducing excess body fat, many people's blood pressure returns to normal. Obesity by itself is now defined as a separate reversible cardiovascular risk factor. It is

second only to tobacco use as a preventative health risk. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Let me make a few observations on medical history. We told depressed people to just cheer up

until we discovered neurotransmitters and found compounds that would correct their depression. We told people with high blood pressure to just relax. Until we found compounds that would

dilate blood vessels, decrease fluid load and correct their hypertension. We told diabetics to just stop

eating sugar until we found compounds to correct their diabetes. Yet, we still tell the overweight to just My clinical experience

stop eating and exercise more.

tells me that this does not work for the vast majority of people. My experience has demonstrated to me that MOFFITT REPORTING ASSOCIATES (301) 390-5150

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these products are safe when used appropriately. While I used them in my practice, I am comfortable with people using them on their own just as I am comfortable with people taking Sudafed on their own. I am quite disturbed by the mischaracterization in the media about the safety issues regarding the appropriate use of ephedra products. This media frenzy may prevent people who

need to lose weight from trying this viable alternative. I also address the issue of safety when I counsel my patients. I tell them that in my clinical

training we are in charge of emergency departments at local hospitals. Some of our most severe cases were MOFFITT REPORTING ASSOCIATES (301) 390-5150

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overdoses we triaged through the poison control center. DR. JONES: Hasik, please. You have about 30 seconds, Dr.

Or Dr. Schyler, I'm sorry. Young children who ingested

DR. SCHYLER:

too many vitamins, depressed patients overdosing on tylenol, all life threatening situations that too often end in tragedy, but certainly not because of dangerous drugs, but beginning of the misuse of common substances which are safe to consume. One always need to weigh the risk benefit ratio of anything with patients. I think the risk

benefit ratio of ephedra is dramatically in the favor of benefit. I do not know how I could ethically not MOFFITT REPORTING ASSOCIATES (301) 390-5150

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recommend them as safer, less expensive, and more effective alternatives. I am a clinician and I know that this is the public portion of the presentation, but if you have any questions, I would be more than happy to answer them for you. Thank you. Thank you, Dr. Schyler. I hope I'm I do

DR. JONES:

And now, Dr. Jerry McLaughlin.

not butchering names too badly this morning. apologize if I am. DR. McLAUGHLIN: slide, please. Where did the slide guy go? on him, he is supposed to be there. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I just checked

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DR. JONES:

Okay.

We've got some slides. I might add that my I

DR. McLAUGHLIN: abstract was lost.

So I didn't have a slot.

thought it was part of this vast conspiracy in Washington Hillary talks about. [Laughter.] DR. JONES: And this doesn't help when your

slides aren't ready; right? DR. McLAUGHLIN: [Laughter.] DR. McLAUGHLIN: DR. JONES: Yes. Slide guy? There we go. Since we Now this is happening.

And you had requested six minutes? are accommodating and giving -MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. McLAUGHLIN: so.

I had it timed for seven, But it should

And originally I had 15 possible.

take me around seven minutes. DR. JONES: Seven. Okay, thank you.

DR. McLAUGHLIN: thing to mash here. DR. JONES:

I don't have the little

Step on up to the podium, that

will facilitate your advancing the slides as you need to since it's wired there. DR. McLAUGHLIN: Thank you. Okay. I come from Nature I have a

Sunshine Products in Spanish Fork, Utah. Ph.D. in pharmacognosies. medicinal products.

It's the study of natural I

I am a registered pharmacist.

have 34 years of experience in teaching and research MOFFITT REPORTING ASSOCIATES (301) 390-5150

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in various pharmacy schools in the United States. last 28 years at Purdue University.

The

I have over 330

publications dealing with isolation identification of natural medicinal materials. This we are already familiar with, but I point out that the structures of the ephedrines are similar to the structure of arcatacolamine compounds, norepi and epi. action. This slide we have already seen parts of, but I like to use it because it represents the different pharmacological things that happen with the ephedra products. They can work on the heart and This increases the blood And this then gives them their

increase the heart rate.

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pressure and it can work on the GI tract. cause nausea and vomiting.

This will

They can work on the beta

receptors or the alpha receptors in the blood vessels causing basal constriction that will increase our blood pressure. It will also cause decreased nasal

secretion and this causes a rebound phenomenon which we don't really like. Let me see if I can focus that a little bit. One thing that isn't considered a lot is that the ephedra products will hit the sphincter muscles and the urinary bladder and this will impede urine flow, and this should be contraindicated then in people with prostate problems for example. And up

here stimulation of the central nervous system giving MOFFITT REPORTING ASSOCIATES (301) 390-5150

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us nervousness and all those things and anorexia comes along with this and this is the use. Other major use

of it is in bronchial dilation and the treatment of asthma. Okay. Our company puts out about 600 We have gross

different natural supplement products. sales of about $300 million a year. products contain ephedra.

Ten of our

In 1998, which is the last

year for complete records, we have sold over 600,000 units of our ephedra products and these represented pretty close to 30 million ephedra doses. Most of

them were for weight loss, but some of them were for asthma. This is an example of our product. MOFFITT REPORTING ASSOCIATES (301) 390-5150 Several

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of our products deal with Chinese concoctions and this "chi" means that this is a weight loss -- Chinese weight loss product, one of our better selling ephedra products. Okay. We have records that we actually

maintain at the company of complaints and also records of praise for our products. I didn't bother

tabulating those, but I just went back to our records to see what kind of complaints we had had. And our

customer service people take in about 30,000 calls a month. Now, this is dealing with questions about the But

products and sales and price and everything else. they do log any complaints that come in.

And in the

first six months of this year we received only four MOFFITT REPORTING ASSOCIATES (301) 390-5150

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complaints about those products.

Remember, there is

probably dealing then with 300,000 units sold. In addition we have a second team that I'm in control of as vice president for research and development and quality assurance and research and development. This team is made up of two pharmacists And they log So I went back

and a very well-trained nutritionist. about 500 technical questions a month.

and asked them, you know, what kind of complaints have you guys received? These are all in the computer and

I can make them available if you want. From the last year and a half that crew had received nine complaints. I should have listed out

what the complaints were, but five of them concerned MOFFITT REPORTING ASSOCIATES (301) 390-5150

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heart palpitations, and the other ones were, as usual, as you might anticipate, jitteriness and things like that. Okay. So then I went to the web site that

the FDA has accumulated and we had records there from '93 to '98 which are about a six-year period. Our

company's products had been complained about 11 times; 11 adverse affects and two were for hypertension, three for headache, one for nausea and three for nervousness and two for heart palpitations. Considering all the millions of doses, or servings, I should say, of these products, I think that this is a pretty good record of safety. And I'll

point out we had not hospitalizations, no deaths from MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the use of our products. Okay. So how can we calculate or figure out

this good safety record and how can we attribute this? Well, I think number one our ephedra products contained ephedrines exactly as labeled. We have a

quality assurance department of 20 people, and these folks have GC mass specs, HPLC mass specs and we make sure that all of our products are just what they are supposed to be on the label. To evidence that Dr.

Gurley from the University of Arkansas recently reported in the American Journal of Health System Pharmacists an analysis of 20 of these ephedra products, ours was included. Ours was right on, 11.9

milligrams and we are supposed to have 12 per capsule. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Our labels explicitly warn of the cautions for our product and I will show you a copy of our label in a moment. Number three, caffeine and other We

stimulants are not included in our products. simply have ephedra in there with some other

combinations of, for example, Chinese herbs that are not stimulating. Caffeine exacerbates the effects of

ephedra and does many of the same things, CNS stimulation, bronchial dilation, and I don't think we really need this double whammy of CNS stimulation for weight loss. Our multi-level marketing method involves training people who then turn around and help other people. So we say people helping people. And I think

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multi-level marketing really involves that. and the label doesn't sell a product.

The box

The product is

sold by a person and they get good counsel and they get good advice about our products. Here is the caution label. This product

contains ephedra see your health care provider prior to use if pregnant or nursing, any medical condition exists, or taking any prescription drug. Discontinue

if nervousness, sleeplessness, loss of appetite, or nausea occur. And loss of appetite, we mean excessive

loss of appetite. Maximum ephedrine dose for healthy adults is 100 milligrams per 24-hour period for no longer than 12 weeks. Improper use of this product may be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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hazardous to your health.

Not intended for persons

under 18, not to be taken with any other ephedra or ephedrine-containing products. Okay. In all this hubbub the dangers of So I went back and checked In 1997 we found that 2.3 Out of these

obesity are being ignored. just some common records.

million Americans died of all causes.

people I looked at the records and 42 percent of these deaths were due to conditions that typically emanate from obesity. These conditions are heart disease, These conditions

hypertension, stroke, and diabetes. kill people.

If we can keep people from getting these conditions we are going to save lives. Unfortunately

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I can't quantitate that and I can't quantitate the benefit of saving lives that an herbal ephedra product has on inducing weight loss, but it is there. And you

would have to consider that if you would take this away, more people are going to die from the lack of it. So thus safe and effective ephedra products for

weight loss can actually save lives. Drugs approved by the Food and Drug Administration are dangerous. say. Oh, that's terrible to

But ephedra has a high benefit to risk ratio

contrasted to the drugs that have been blessed by the Food and Drug Administration and put out there for physician to prescribe. These drugs include, you

know, dexedrine, amphetamines, ritalin, the other MOFFITT REPORTING ASSOCIATES (301) 390-5150

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drugs which initially started out for weight loss or diet pills as you recall. Fen-phen, of course, with

its pulmonary hypertension and the problems that it causes with heart valve damage is certainly one of the things blessed by the FDA, but then it later approved to be a disaster. The Lazarou report, if you want to read that and go back and look at the JMA from 1998, about 7 percent of hospitalized patients have adverse drug reactions and about 106,000 people die per year from adverse drug reactions using FDA-approved drugs. DR. JONES: McLaughlin? DR. McLAUGHLIN: Okay. Can you please wrap up, Dr.

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DR. JONES:

You've used seven minutes. If we look at Tylenol, Would you say that That's not There

DR. McLAUGHLIN:

Tylenol kills 153 people a year.

ephedra is more dangerous than Tylenol?

true, Tylenol is more dangerous than ephedra.

is about 111,000 cases of Tylenol overdose per year. Why the great concern about ephedra? While

the FDA seeks to encumber our herbal products with their bureaucratic overregulations, and they're searching for a new horror case like the sulfanilamide elixir that brought about their existence in the late 1930s. And furthermore, the press and the news media need to feed something sensational every day to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the consuming public whether it's real, exaggerated, or concocted. And also remember that very little of

their advertising money is at jeopardy with the herbal versus the giant pharmaceutical industry. Every night

you will see ads for prescription drugs on television and they don't want to jeopardize that market. DR. JONES: Please wrap up, Dr. McLaughlin. Thank you. I am finished.

DR. McLAUGHLIN: DR. JONES:

Thank you very much.

Were there questions from the panel? Dr. Philen. DR. PHILEN: Thank you. You mentioned about How are

keeping track of complaints you receive.

these tracked, do you have a recordkeeping system and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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then what do you do with these complaints after you've tracked them? DR. McLAUGHLIN: Okay. There are two areas,

the customer service people record them according to stock number for the product and there is a summary statement that's typed in from the FDA's recordkeeping point of view, it's probably not perfect. You know,

I'm not sure if it's recorded as to age and weight and male or female, but, you know, we do record the complaints. Okay.

From the group under my control it's a little more detailed. And we have those records, and

I can make those records available if you guys want to see them; you know, they're there. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. PHILEN:

Do you pass them on to the FDA

or to any other organization? DR. McLAUGHLIN: on to the FDA. No, we've never passed them

It was my understanding that the web

site was for consumers and physicians. DR. PHILEN: What kind of training do the

customer service people have? DR. McLAUGHLIN: training. They have in-house

We have Dr. Siegleman who is our vice

president for Health Sciences and he and Clough Folse who is one of the managers that I have for health sciences, they train those sales people as they come in as to the adverse effects and how to record these complaints and things. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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They don't have scientific backgrounds.

But

our three people in our R&D group do have scientific backgrounds, I mean, the two pharmacists and a dietician. DR. PHILEN: Why don't you handle all the

complaints in one central area? DR. McLAUGHLIN: complaints. There are two tiers of

The major complaints are potentially They refer

coming into the customer service group.

things then to the R&D group if they consider them serious. And also the R&D group gets some direct

phone calls themselves too, especially from our managers and distributor that have learned their phone numbers. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES: questions.

Two other panelists have

Dr. Burstein. DR. BURSTEIN: Yes. Aaron Burstein, NIH. I

just happen to notice the discrepancy in terms of the reports of heart palpitations and from your previous comments it appears that you don't necessarily report those to the FDA; do you at least encourage your patients to report those? Because it appeared that

your division received five reports of heart palpitations, yet the data you present indicates that the FDA only had two cases in their database with your product? DR. McLAUGHLIN: Well, as I said, we don't We just

report the complaints that we get to the FDA. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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have our own records. DR. BURSTEIN: But at least in those cases

do you at least encourage the patients to report themselves, or does it just kind of end there with the reports coming in to you? DR. McLAUGHLIN: No. We have never It didn't occur

encouraged the patients to report it. to us to do that. want.

We can do that from now on if you

I can instruct people to do that. DR. JONES: Dr. Lieberman. Harris Lieberman, U.S. Army.

DR. LIEBERMAN:

My question has to do with your caution on your package to consume ephedrine-containing supplements for no more than 12 weeks. Can you explain the

MOFFITT REPORTING ASSOCIATES (301) 390-5150

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rationale for that? DR. McLAUGHLIN: Well, I think, you know,

everybody understands that these things could get to be habit-forming and that we don't want to be a part of that. The idea is for temporary induction of

weight loss in combination with diet and exercise. And anybody that would want to take it for longer than that runs the danger of getting hooked on it. DR. JONES: Dr. Richardson? Yes. Hi. I am sure you're

DR. RICHARDSON:

familiar with the work by the German Commission E monographs and that work. DR. McLAUGHLIN: DR. RICHARDSON: Yes. And I know one of the basic

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premises of that group is a rational approach to phytotherapies and the first central tenet is evidence of dose response relationship. And I just wondered if

you could tell us, has your group done any research on the actual dosing with these products and what is the rationale for the dose that you have included in your product? DR. McLAUGHLIN: Well, I wasn't there when

the doses were established, of course, but last night I was reading on this and there were a whole series of studies that have been done on weight loss induced by ephedrine itself. Now, as we know ephedrine is a

mixture, so it's really hard to say what ephedrines were there. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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But I was talking with Mark Blumenthal last night and there are four studies dealing with ephedra. Okay. The crude drug or extracts of ephedra dealing I think if we can base the

with weight loss.

ephedrine concentration or the total ephedrines -- and our company totals ephedrines, okay, for our ephedra label, okay, and equate that to ephedrine itself and then relate that to the previous weight loss studies, we come up with the dose. And I believe that the German Commission Edose is much higher than what the AH -- the American Herb Products Association is recommending. But I am

not sure about that because I am just second hand I'm telling you that. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES:

Panel, to be fair to Dr.

McLaughlin, we are really riding him with questions. Can we make your questions brief and allow questions from the floor? And let's move on. We are --

DR. RICHARDSON:

Yes, just one more

question, and it is much higher. Is your company doing any research at all? Are there any plans to do any research to evaluate the efficacy and the safety of these products? DR. McLAUGHLIN: products, no. With the safety of these

With other products, I mean, these We don't do continuing We do

products are established.

research on things that are already out there.

have research going on with new things that we are MOFFITT REPORTING ASSOCIATES (301) 390-5150

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developing. substantial.

And that research, I think will be very

DR. JONES:

One last question, Dr. Philen.

Did you have one last question, quickly? DR. PHILEN: Well, I was just concerned that

if they are getting complaints it appears that no health care provider is in a position to receive the complaint and advise the person whether they should seek medical care or whether their complaint has any relationship to the product they're taking. And

perhaps you should consider having a health care provider in charge of doing that? DR. McLAUGHLIN: as health care providers? Do you consider pharmacists And if you don't I'm going

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to be very disappointed. DR. PHILEN: So do they talk with a

pharmacist when they call? DR. McLAUGHLIN: Some of them do. If they

get referred by the customer service people, then they will talk to the pharmacist. defense, okay. DR. PHILEN: I have a great deal of That's our next line of

discomfort with someone with a health care problem calling and talking to a customer service representative based on just my general overview of how helpful customer service representatives are in the entire business. And, you know, although you may

train them, I still have a concern. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. McLAUGHLIN:

Well, what I am trying to I am telling you

do here is to tell you the truth.

that we have customer service representatives who receive complaints, they receive praise as well. record these. the recordings. DR. PHILEN: DR. JONES: floor? Dr. McLaughlin, while Ms. Michael is coming up, I will just note for the record, you named Tylenol, but your slide showed acetaminophen. And I Thank you. Are there questions from the They

I am telling you the records from all

am sure you did that for those in the audience who might not recognize the generic name of the drug. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. McLAUGHLIN:

The statistics I showed

were for acetaminophen products and not Tylenol specifically. DR. JONES: I just want to be sure that's

reflected in the record so that we don't act like we are talking about data on a named product. DR. McLAUGHLIN: DR. JONES: Ms. Michal. MS. MICHAL: Ephedrine Abuse Today. Barbara Michal with Halt Dr. McLaughlin, in the figures Right.

That you did not present.

that you gave on the adverse event reports that you have had reported to your company, you indicated only those that were indicated as a result of the ephedra. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Who made that determination? DR. McLAUGHLIN: MS. MICHAEL: I did. How many overall

You did.

complaints have you received? DR. McLAUGHLIN: complaints from all things? MS. MICHAEL: products. DR. McLAUGHLIN: MS. MICHAEL: Oh. Regarding all of your ephedra Regarding overall

Whether you have determined

that the adverse event was attributed to the ephedra or not. DR. McLAUGHLIN: Right. I think I said four

from customer service and actually there were eight. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I ruled out four because they didn't seem to have anything to do with any of my little diagrams. those was back pain which maybe should have been mentioned. MS. MICHAEL: involvement. DR. McLAUGHLIN: Yeah, skin rash. It's hard Possibly from kidney One of

to eliminate the other ingredients, of course, as being hypersensitive causing. MS. MICHAEL: Spotting.

Do your product labels have an

800 number for the company so that -DR. McLAUGHLIN: MS. MICHAEL: I didn't --

Does your product label

contain an 800 number for the customers to very easily MOFFITT REPORTING ASSOCIATES (301) 390-5150

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reach you to give you complaints? DR. McLAUGHLIN: that. Honestly, I don't know

But I know that our products are sold through

distributors and managers and people have people to contact and those people certainly know how to get ahold of our company and to do. DR. JONES: to move on please. MS. WOOD: Next question please. We need

Ms. Wood. Doctor, I am speaking for

personal experience, I know you have numerous people here today. When I took ephedra in 1995 I was the Like I said yesterday, I

epitome of good health.

never tasted a drop of alcohol, I was as healthy as can be, jogged five miles a day, and I would not take MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Tylenol or any kind of medicine for a headache. would get rid of it with yoga and meditation.

I But

when I started taking ephedra my entire life changed. DR. JONES: MS. WOOD: Your question please? My question to you is this, when

somebody starts taking ephedra how closely -- I mean some of them are your patients that there are thousands who go to health food stores and by the pills, how continue follow-up the side effects that it may have on certain people and obviously it has not had on all these wonderful people sitting over here, how can you trace the 100 and thousands and millions doses that have been sold all over the country and the side effects that are being suffered by those people MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that are not here today? DR. McLAUGHLIN: People can call us and

complain and I am telling you the number of complaints we have received. Incidentally, yesterday you said

you took ephedrine and not ephedra. MS. WOOD: here. Ephedra. I have my bottle in

Solera ephedra. DR. McLAUGHLIN: This was in 1975 I believe

yesterday. MS. WOOD: 1995. DR. McLAUGHLIN: MS. WOOD: repeat my question. '95, okay. Sorry I'm going to

So, my question.

You have 20, 30 people here but

you have sold millions all over the country; how can MOFFITT REPORTING ASSOCIATES (301) 390-5150

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you trace people like me who suffered miserably as a result because they were susceptible? Like we said yesterday, some people are susceptible to certain things. We went out and had

dinner in a restaurant, I suffered for the last two days because of MSG and my friends nothing happened to them. They ate the same food. I have suffered severe

headache for the last two days. DR. JONES: asked your question. Thank you, Ms. Wood, you have I am not sure -I will try to answer that.

DR. McLAUGHLIN:

I think probably in your case we have to answer that as physicians do with the word "idiosyncracy." idiosyncracy is a is a quantitatively abnormal MOFFITT REPORTING ASSOCIATES (301) 390-5150 An

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reaction to a product.

And I think that this happens

-- it is quantitatively different than other people. It is not a hypersensitivity. Hypersensitivity This is a

involves immunity in many cases.

idiosyncracy, it's an unpredictable type thing, and do we throw out all the good that a product does for millions of people because of a bad reaction for a few people? DR. JONES: move on. Next question please we need to

Please identify yourself. For the record the last speaker was Simieh

Wood. MS. PORTER: Library of Congress. I'm Donna Porter from the My question has to do with your

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comment that your ephedra products are not sold with caffeine or other stimulants. I have two questions

really; has that always been true of your products and if it is so why the decision was made to not combine them with other stimulants since so many of the other ephedra products are sold that way? DR. McLAUGHLIN: of our products. I am sure it is always true

Our company was formed in 1972 by They do not

people of the Latter-Day Saint faith. believe in caffeine. DR. JONES:

Thank you, Dr. McLaughlin. That ends our public comment

Thank you all. period.

We are about five minutes ahead of schedule

and, therefore, I would like to start the next session MOFFITT REPORTING ASSOCIATES (301) 390-5150

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at 10:20 a.m. and we will maybe allow the extra five minutes at lunch if we need to. much. [Brief recess at 10:20 a.m.] DR. JONES: Please find your seats. Thank you all very

At the break and I inherited a request from someone at the audience to clarify from yesterday's agenda why didn't the Ephedra Education Council have to divulge their affiliation and funding? They did. They indicated that the American

Herbal Products Association and industry trade groups -- I did not pull the entire record from yesterday, but each speaker also talked about background information; this meeting we have asked people in good MOFFITT REPORTING ASSOCIATES (301) 390-5150

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faith to divulge information and my recollection and my notes from what the council presented yesterday plus we have from their submission to us a statement. So there is sufficient information therefore us to go by. Who specifically paid for them, don't you want the panel to know? Again, you know, they stated that they were industry or trade. I think of our interests it is not

necessary to name names, which specific company, what have you for purposes of this public meeting. A Q&A with Ephedra Council from the audience we did in deed with our Q&A session we split the time approximately in half and there was time offered and I MOFFITT REPORTING ASSOCIATES (301) 390-5150

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saw no one rise to the microphone.

I turned and asked

twice to the audience and, you know, if no one comes to the microphone or indicates if they need assistance to ask a question, to raise their hand, we would get a microphone to you, so if that was a particular barrier I regret that we did not make clear that was available. And then why wasn't industry limited on time with their presentations? They were. They had the same time allotted

for the ephedra education panel, education council panel that was allotted to the earlier discussion of adverse events and reports and they were allowed the freedom to break that time up just as the FDA panel MOFFITT REPORTING ASSOCIATES (301) 390-5150

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had requested that they break that time up as they needed to, to get the information out. So both of those panels, while, yes, this speaker might have gotten 45 minutes, that speaker might have taken 35, that's how they requested their time be allocated and we respected that request. respected requests of that sort where we possibly could. Abstract sessions, per se, are being run much a scientific meeting abstract sessions are run; 15 minutes for presentation of data, five minutes for Q&A. So if there are further concerns from We

individuals late in the day today, we will have some time available in the agenda, you can either write MOFFITT REPORTING ASSOCIATES (301) 390-5150

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those comments out and put them in the record or be prepared to express them this afternoon. So let us proceed. We have had another

minor change in our abstract session this morning, one presenter substitution. We will be starting off with

an introduction -- I mean our first abstract session, Dr. Hackman, but the second abstract session, the presenter has changed to Dr. Kathy Fomus. introduce her at the time. Dr. Hackman, are you here and ready to go? Great, thank you very much. DR. HACKMAN: Good morning and thank you for My name is So we will

the opportunity to provide comments. Robert Hackman.

I have a Ph.D. in nutritional MOFFITT REPORTING ASSOCIATES (301) 390-5150

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biochemistry from the University of California Davis. I have been a professor for 19 years, 14 of which were at the University of Oregon and for the past five years at the University of California Davis were I am currently an associate research professor in the department of nutrition. For the first four half years of my involvement at UC Davis I was executive director of the office of alternative medicine funded research center and currently I am a research professor engaged in natural products research. For the past seven years I have been an industry consultant. I am currently chair of the

scientific and medical advisory board for Advocare MOFFITT REPORTING ASSOCIATES (301) 390-5150

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International, a nutritional supplement company out of Dallas, Texas. I am a paid consultant for Advocare

and they have provided funds for me to be here today. Other members of Advocare's scientific and medical advisory board and include Dr. Harry Pruce, M.D., professor of internal medicine at Georgetown University, School of Medicine; Steve Waterston, professional strength and conditioning coach for the professional football team in Tennessee and a licensed a lecturer for the Drug Enforcement Administration on hazards of substances in sports training; and Professor Sidney Stowes, professor of pharmacology and dean of the School of Pharmacy and Allied Health Sciences at Creighton University. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Advocare tries its best to follow the scientific literature and formulate responsible products that can benefit both personal and public health. As such, Advocare has formulated and sold for

the past seven years and ephedra-caffeine-containing product as part of a system that provides a multivitamin nutrient supplement with vitamins, minerals, omega-3 fatty acids as well as an ephedra-caffeine tablet. The tablet contains 20

milligrams of total ephedra alkaloids and 75 milligrams of caffeine; consumers are advised to take that goes before breakfast and again before lunch as part of a comprehensive, multinutrient, vitamins, mineral, herbal system. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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My comments today are not scientifically based. I am not here to give you new double-blind Simply I am here to offer my anecdotal

placebo data.

observations over the past seven years of watching these ephedra-based products that Advocare sells being sold in the market and listening to the comments of, well after hundred people that have benefitted, I have to admit I stopped keeping track. I recognize that my comments are not scientifically based but I do want to convey to you that the overwhelming number of people that I have talked with have incredibly positive experiences about using ephedra-caffeine as part of the overall system for losing weight and feeling better. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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If I were talk to one or two people, who knows what can happen, but after 10 or 20 or 30 or 40 or 100 people over seven years it makes me believe that is more than a placebo effect that is helping people shared the unwanted fat that they have. A few weeks ago I talked with maybe 10 people that have lost over 100 pounds on this. I

spoke with Linda, one of Advocare's distributors and customers who has lost 226 pounds, I spoke with Zenda, another Advocare distributor who was lost over 200 pounds, and Jim, a pediatric oncologist who between

he, his wife, and his son have lost over 225 pounds. But perhaps more importantly, I looked at Danny who lost 45 pounds and kept it off for the past five MOFFITT REPORTING ASSOCIATES (301) 390-5150

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years. Those are some numbers, but I think the biggest thing that I can contribute to this meeting is try to convey the look in people's eyes, the feeling in their heart when they tell me that they have tried everything and nothing worked until they started using this system. I must confess, I have had an enormous dry-cleaning bill over the years as people cry on my shoulder thanking me for helping to formulate these products, but that is a wonderful price to pay for the comments, some of which were represented earlier here today, of people saying that they have tried everything, they have no other options, they have MOFFITT REPORTING ASSOCIATES (301) 390-5150

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given up hope, and that with a responsibly formulated low dose ephedra-caffeine product as part of the overall system, they feel that they have gotten their life back. I have done a number of research studies in the area of weight management, published in peer review journals, and I observed over the years personally that most people know what to do when it comes to a diet and exercise. eat, we just do not. Most of us know what to

Most of us know we need to And so I searched for some

exercise, we just do not.

other way to motivate people and after the behavioral aspects were tried in my research programs we looked at the research out of Denmark on ephedra and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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ephedrine and caffeine, and that led me to help Advocare formulate the supplement that I speak about today. The product that Advocare makes it is clearly labeled as to the use of the product. It is

clearly labeled as to the content of ephedra and caffeine. It is clearly labeled as to the I advise anyone who talks with me

contraindications.

that tells me that they have trembling or jitteriness, so to speak, or sleeplessness to read the label and discontinue the use and I think that that is an appropriate way to handle adverse events. If people do not have ephedra and caffeine as one of their many options in losing weight and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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feeling better about themselves, both physically and emotionally, then I see that consumers have significantly limited options. I understand that it

is not the role this panel to make regulatory or advisory comments, but I would like to note that ephedra and caffeine does have a role in both personal health and public health and that clearly labeled products that are responsibly made in accordance with or less than the AHPA recommendations for ephedra have a huge impact on many people's lives and I can attest to that for the over 100 people that I have talked with. Thank you very much for your time and attention. I would be pleased to answer any MOFFITT REPORTING ASSOCIATES (301) 390-5150

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questions. DR. JONES: Thank you, Dr. Hackman. Dr.

Are there questions from the panel? Schwetz and then Dr. Coates. DR. SCHWETZ:

Berne Schwetz from the FDA.

If people take the product of the company that you work with, if they take the product as recommended, how much ephedra do they take? And do you recommend

no longer than X length of time and when you become aware of adverse events what do you do with that information what does the company do with that information? DR. HACKMAN: The total daily intake of

ephedra alkaloids from the formula that I referred to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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is 40 -- 4 0, 40 milligrams of total ephedra alkaloids divided into two,20 milligrams doses advised to be taken before breakfast and again before lunch. With

that there is a total of 150 milligrams of caffeine divided into two, 75 milligrams doses. Consumers are

advised to take the formulation no more than, what is it, 84 days or - 80 to 84 days and then we make a recommendation for consumers to discontinue use for a 10- to 12-day period allowing their system to recalibrate, in our opinion, and hopefully integrating the new behaviors as well as possibly the physiological benefits. As for the question of adverse effects reporting, I do not have the exact knowledge of how MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that is done. a consultant.

I am not an employee of Advocare, I am I believe that the reports are funneled

to the company's general counsel, but I do not know the internal operation system well enough to give you the definitive answer to your question. DR. JONES: DR. COATES: Dr. Coates. Paul Coates. If you do not

mind I will follow up about the adverse event business. Only because you talked a lot about the

people that come to you, with reports of positive benefits, and so my question is, would somebody come to if they did not have a positive results with this? You see what I mean? DR. HACKMAN: 0h, I know; I know exactly

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what you mean. DR. COATES: You have said that you are

receiving these remarks, would anybody have come to you with a negative remark? DR. HACKMAN: People do come to me with

concerns about sleeplessness and jitteriness primarily. I advise them the same thing that is on

the label, to discontinue use. The informal recordkeeping that I have as to how many negatives to positives, I would estimate to be maybe one to 10 negative or adverse events to positives. But I do not keep a written log of that,

so it is only my best estimate. DR. COATES: Thank you.

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DR. JONES: panel?

Further questions from the

[No response.] DR. JONES: Questions from the floor?

[No response.] DR. JONES: Hackman. Dr. Fomus from the Council for Responsible Nutrition. DR. FOMUS: Good morning Dr. Jones, My name is Being none, thank you, Dr.

distinguished panel, ladies and gentlemen.

Kathy Fomus from the Council for Responsible Nutrition and I am substituting for John Cordero. Mr. Cordero regrets that he cannot personally deliver these remarks, however,I am pleased MOFFITT REPORTING ASSOCIATES (301) 390-5150

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to be here in his place. The Council for Responsible Nutrition was founded in 1973 and represents more than 110 companies in the dietary supplement industry. CRN members

adhere to a strong code of ethics and comply with self-regulating dosage limits had label warnings. CRN's member companies manufacture dietary supplements to high-quality standards under CRN's good manufacturing practices which were adopted in the mid 1980s. CRN has been actively involved for about seven years with the Food and Drug Administration, other associations and the scientific community in the evaluation of the scientific evidence and policy MOFFITT REPORTING ASSOCIATES (301) 390-5150

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options for ephedra.

Over the last two years or so

efforts to resolve issues on safety, dose, and duration have bogged down. Coming to a head with a

General Accounting Office report criticizing FDA's procedures and evaluating ephedra. CRN which prides itself on adherence to scientific evidence took the GAO analysis very seriously and contracted with the prestigious and experienced CANTOX Health Science International to perform a quantitative risk assessment. In addition

to the CANTOX risk assessment there is a major new clinical trial by Columbia and Harvard Universities that is pending publication. In a letter to Mr. Joseph Levitt, Director MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of FDA's Center for Food Safety at Applied Nutrition CRN called FDA's attention to the Columbia/Harvard clinical trial as well as the CANTOX risk assessment. Noting that neither report would be available for detailed discussion today, CRN's letter urged a delay in policymaking until these studies could be carefully considered in a fully transparent matter. Given that these will be two of the most comprehensive studies of there types on ephedra, it would see that they are necessary for credible scientific conclusion on which policy might be based. Upon completion these reports should be subject to scrutiny in a public forum. FDA is urged

to convene a follow-up meeting to allow public MOFFITT REPORTING ASSOCIATES (301) 390-5150

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discourse on these studies before reaching any conclusions on ephedra. I would like to take a few moments to describe this emerging evidence. First, the clinical

trial conducted by Columbia and Harvard universities. This trial has been completed, the data are being analyzed, and tentative plans have been made to report to results at a conference at the end of October. This study is one of the largest and longest duration clinical trials conducted on ephedra. Additionally it examines the impact of ephedra on a large number of health indicators. A preliminary

trial has already been described in a published abstract. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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In a letter to FDA, Dr. Carol Boozer of Columbia University, and one of the principal give investigators, explained the status of this study and its importance in evaluating ephedra. Given the

quality, size, and duration of this clinical trial, it would be premature, unjustifiable, and a public disservice for FDA to reach conclusions on ephedra without waiting for the availability of this data. Second, as I mentioned earlier, CRN has contracted with CANTOX Health Sciences International for a formal risk assessment of ephedra as a dietary supplement. CRN has publicly presented the design and

methods of this assessment and has briefed FDA staff on it as well. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Following this presentation my colleague, Dr. John Hathcock, will describe the merits of a formal, structured, risk assessment, citing the uses and impacts of the different types of evidence available. CRN believes that FDA should carefully

examine the results of the CANTOX risk assessment before reaching scientific conclusions on the safety of ephedra. This will be the first risk assessment carried out completely in accordance with a set of procedures and guidelines identified in advance using the tolerable upper intake or UL protocol developed by the U.S. National Academy of Sciences. In contrast to

FDA's rush to judgment, CRN's evaluation of the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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science relevant to the safety of ephedra will embrace the totality of available evidence including the Columbia/Harvard data. As we all know, the scientific evaluation process that FDA used in an attempt to justify its 1997 proposed rule was strongly -- and I believe accurately -- criticized by GAO. These criticisms led CRN

FDA to withdraw most of that proposed rule.

strongly recommends that FDA not repeat the mistake of drawing premature and unjustified scientific conclusions as it did in developing its 1997 proposal. Instead CRN urges FDA to use a deliberate, careful, and fully transparent public procedure of scientific assessment so that its future policy MOFFITT REPORTING ASSOCIATES (301) 390-5150

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position on ephedra, if any, will be fully justified and defensible. Thank you for your attention. I defer the

remainder of my time to my colleague Dr. Hathcock who will speak next and questions will be addressed at the end of his presentation. DR. JONES: Thank you, Ms. Fomus. I am timing you for 15

Dr. Hathcock. minutes.

Just to be clear, I had not been given to

understand in advance there was any negotiation of time or anything. So 15 minutes. I believe I can accommodate

DR. HATHCOCK: that. DR. JONES:

Thank you.

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DR. HATHCOCK:

Thank you, Dr. Jones.

Good

morning to you and the panelists.

The title of my

presentation is, risk assessment, an application of criteria for causality to ephedra AERs. The risk

assessment is nothing more and absolutely nothing less than a systematic, quantitative evaluation of the potential for a substance to produce adverse effects. For risk assessment to be objective and avoid bias it is crucial that it be performed under an established model, a set of clearly identify procedures and criteria. It is equally important that the risk

assessment model to be used with its built-in objective procedures and criteria be selected in advance. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Unstructured reviews and evaluations are extremely subject to biases of the reviewer. me for a moment. The objective of a risk assessment reflects the policy intent behind the decision to use this procedure. Depending upon the scientific evidence Excuse

available, risk assessment can answer a range of questions. For example, questions which it may answer

are given in the following examples. Is this substance toxic at any dose? According to Paris Solis some 500 years ago that one is a foregone conclusion. Another question might be, does a specific daily does say 00 milligrams produce adverse effects? MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Another question might be, what is the highest dose that is unlikely to cause adverse effects? Clearly

that was the objective of our risk assessment as we will see. Also the appropriateness of our risk assessment model to deserves some clarification. assessment has been most commonly applied to environmental chemicals that include additives. example the acceptable daily intake or ADI method commonly applied to food additives uses large safety factors sometimes called uncertainty factor usually 10 or 100. EPA's reference dose model commonly applied For Risk

to environmental chemicals in pesticide residues in food, considers five types of uncertainty, with each MOFFITT REPORTING ASSOCIATES (301) 390-5150

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being assigned a standard default uncertainty factor of 10, 3, or 1. Thus the final composite uncertainty factor in the reference dose model can range from 100,000 down to 1. The most commonly selected composite

factors though, however, are 10, 30, 100, and 300. In recent years there is a strong movement in the science of quantitative toxicology toward risk assessment models that utilize uncertainty factors that are fully derived from the specific database, thereby avoiding all arbitrary default values. The U.S. National Academy of Sciences Food and Nutrition Board is a leader in this movement. Under financial sponsorship largely from FDA, a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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subcommittee of the Food and Nutrition Board developed and published its tolerable upper intake level or UL model for application to nutrients. The UL method was

a good idea because it is less objective and arbitrary than other methods. It uses better science than the

other methods is that it derives the uncertainty factors directly from the database. This approach was

necessary because the standard default uncertainty factors such as in the ADI and RFD methods often generate nonsensical answers when applied to nutrients. Illogical answers such as the safe intake being below the RDA often occur because the range between the intakes that are nutritionally useful and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the possibly adverse level are less than 10 for some nutrients and less than threefold for a few. In effect, the UL method recognizes that vitamins and minerals are deliberate, intentional, and desirable components of the human diet. CRN chose the UL risk assessment model for application to ephedra for several reasons. First,

the uncertainty factors are fully derived from the database. Second, it acknowledges that ephedra is a And,

deliberate ingredients of dietary supplements.

third, it addresses the totality of the scientific evidence -- all types of scientific evidence. CRN's objective in applying the risk assessment model was straightforward to identify the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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highest daily intake that is likely to posed no threat of adverse effects to almost all individuals in the healthy population. The U.S. National Academy of

Sciences UL model with all of its built-in definitions, procedures, and criteria, and obligations together with application by a neutral third party was selected to avoid bias. Perhaps that is enough on the

principles of risk assessment. Now I would like to address the AERs, what they are they are not; what they mean and what they do not mean; how they should be used to and how they should not be used. And, finally, how they fit into

risk assessment and how they do not fit in. To evaluate AERs all other types of data on MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the human health impacts of any substance it is useful to examine the criteria for causality originally developed in the context of environmental medicine but were recently adapted and incorporated into the U. S. NAS -- by the U. S. NAS model for risk assessment. The criteria include strength of the association, consistency of the association, specificity of association, the temporal relationship, the dose response relationship, biological plausibility, and overall coherence. A body of

evidence from several well-designed and conducted clinical trials can measure up strongly against most of these criteria because each factor can be controlled. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Epidemiological studies often prove weak against one or more of these criteria especially the strength, consistency, and specificity factors. Congruence of biological effects it epidemiological studies were those observed in animal studies and clinical trials can increase the confidence in the data. AERs must not be overinterpreted. Of course

there is a tendency to do this if the effects of biological are plausible and the relationship is temporally logical. Biological plausibility and

temporally correct relationships however can never prove causality. Some ephedra AERs passed these two criteria MOFFITT REPORTING ASSOCIATES (301) 390-5150

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but fail against others. is this:

An important consideration

there is no need to overinterpreted and

depend on AERs is to reach scientific conclusions when there is a sufficient body a evidence of a vastly superior type mainly clinical trial data. Indeed,

under these circumstances no decision should be made primarily or solely on the AERs. Instead the only

logical way to do a risk assessment on ephedra or any other substance for that matter is to consider the totality of publicly available scientific evidence. Here it is interesting to note that the Nutritional Label and Educational Act demands precisely that approach in deciding whether a health claim can be authorized by FDA. It demands

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consideration of the totality of the scientific evidence. Likewise, any risk assessment on any substance should consider the totality of the evidence. With regard to the scientific meaning of

AERs it is noteworthy that a disclaimer box appears on the screen whenever one searches the FDA's Center for Food Safety and Applied Nutrition web site for AER associated with any product. This disclaimer

acknowledges in slightly different words that AERs cannot demonstrate causality. includes the following points: There is no certainty that a reported adverse effect can be attributed to a particular MOFFITT REPORTING ASSOCIATES (301) 390-5150 The FDA disclaimer

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product or ingredient.

The total number of adverse

events cannot be used to estimate the rate of the adverse event to the population. A reporting of

adverse events may be affected by several factors including time in the market and publicity. acknowledged limitation on the meaning and significance of the AER it is surprising to see that most of FDA's actions on ephedra have been based primarily on the AERs. If the AERs are flawed what With this

information then can they provide and what information can they not provide? And, finally, what information

have they provided about ephedra? AERs are simply reports by persons who believe that an adverse event may have been caused by MOFFITT REPORTING ASSOCIATES (301) 390-5150

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a product.

The publicly available AERs on ephedra

range in size from less than one page to approximately 500 pages. It is easy but quite fallacious to assume

that an AER of hundreds of pages must provide convincing evidence that would pass the causality criteria. Clearly from my examination of them, most of the detailed AERs spend most of their attention in a very detailed characterization of the adverse events and in establishing the person actually took a product containing ephedra. The following false rationale

seems to be employed if a person took a product and had an adverse event that is plausible for ephedra, then ephedra is likely to have caused it. It seems to

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be that simple, but it is fallacious. If that line of thinking had any validity defensible scientific conclusions and policy decisions would have long since been reached and we would not be here today. Many of the AERs do not contain information that would shed any light on the specificity of the association. information. Many of the AERs do not contain product Many of the AERs that do contain some

product information are nevertheless hopelessly confounded by congruent consumption of other substances that carry equally convincing biological plausibility and with the same temporal relationship. For ephedra all other stimulants can MOFFITT REPORTING ASSOCIATES (301) 390-5150

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confound interpretation of an AER.

Examples of

confounding stimulants include the OTC drugs containing ephedrine, pseudoephedrine, and other similarly acting compounds, caffeine and other methylzanhthines from OTC drugs, nicotine and a wide variety of foods and beverages contain one or more of those ingredients. Also and AER can be confounded by pre-existing medical conditions that not only could help contribute to a reaction to ephedra, but also could have been the primary or perhaps the only cause of the event. One AER in particular provides an A middle-aged man somewhat

excellent example.

overweight drank coffee, took an ephedra supplement, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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what jogging, and died of a heart attack. heard this one discussed already.

We have

Post-mortem examination showed that his two largest coronary arteries were more than 75 percent closed by atherosclerotic plaque. contribute to the heart attack? cause or contribute to it? contribute? Did the jogging Did the caffeine

Did he ephedra clause or The only nobody

Would it have happened anyway?

scientifically defensible answer is this: knows. I wish we did, but we don't.

And there is no

way to analyze AERs to avoid such uncertainties because the best documented AERs simply do not provide all the needed information. If the individual AERs cannot support a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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cause and effect conclusion does the number or pattern of AERs on ephedra provide sufficient information? anyone might wish to that that were true, the answer is a firm no. Whether causally related or not, and As

nobody can tell, the number of AERs would be expected to increase with the length of time in the market and the number of people using the product. The number of ephedra AERs per year has varied with a much stronger temporal relationship to publicity from FDA than to increases in sales. If the

accumulated AERs nominally related to ephedra have no identifiable meaning, could well documented AERs show cause and effect? Unfortunately, the answer is no.

AERs alone can never answer this question; MOFFITT REPORTING ASSOCIATES (301) 390-5150

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what is the rate of identical adverse events in a similar population who did not consume the product? A large body of well-documented AERs adds up to not much. Precisely what it does add up to it is The controls are

one-half of a case controlled study. missing.

Even if the study were completed with inclusion of appropriate controls it would still be an epidemiological study and would pale in comparison with a greater meaning of controlled clinical trials. In summary, the criteria for causality adopted by the National Academy of Sciences demand that we pay a greater attention and depend primarily on clinical trial data instead of AERs and excessive MOFFITT REPORTING ASSOCIATES (301) 390-5150

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risk on ephedra.

The only time to AERs should

dominate the evaluation is when they are the only evidence available and when other evidence cannot be ethically obtained. In general, AERs should be used in as a flag to identify areas for additional research. To reiterate comments made by my colleague, Dr. Fomus, a few moments ago no scientific conclusions on ephedra should be reached until the data from the forthcoming Columbia/Harvard study -- clinical trial are available and can be evaluated through a public process. But with or without those new data any

safety evaluation of ephedra should depend strongly on the substantial available evidence from clinical MOFFITT REPORTING ASSOCIATES (301) 390-5150

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trials and not from the inherently insufficient AERs. Thank you for your attention, I look forward to questions. DR. JONES: Thank you, Dr. Hathcock.

I would presume you and Dr. Fomus would take questions together. time. I appreciate your combining your

Questions from the panel, Dr. Coates. DR. COATES: Dr. Hathcock and Dr. Fomus, I

will not ask you about the status of the clinical study to which you referred, I suspect we will get some more information about that from the principals. DR. HATHCOCK: DR. COATES: I hope so. But could I ask you what the

status is of the quantitative risk assessment that you MOFFITT REPORTING ASSOCIATES (301) 390-5150

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have done in collaboration with CANTOX and when approximately can one expect to see results? DR. HATHCOCK: preliminary draft. We have received a

We are not making the results of

that public because we believe that it would be an improper thing to do to issue even tentative conclusions in the face of the new major forthcoming evidence that might cause a major revision. We

believe that the impact of the Columbia/Harvard study will be to greatly increased the confidence that we have in the data that would either decrease the uncertainty factor or change the new observed adverse effect level. DR. COATES: Could I follow up? The

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quantitative risk assessment as you have described it is based on what you have said is the totality of evidence; does that include unpublished clinical trials and other clinical studies? Or does it -- is

it restricted to the published peer reviewed literature? And so I guess the question you can

anticipate is, if the Columbia/Harvard study is at a certain stage well then its publication dictates the publication release of the results of the Q&A? DR. HATHCOCK: We are including in the risk

assessment all data that are publicly available whether they are peer reviewed or not, and that is clearly identified whether they are or not and that can be taken into account and others judging the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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validity of the process.

But if and when the

appropriate data and details of methodology are released, whether or not it's in a peer reviewed paper, we will cite that source and acknowledge the status and proceed. DR. JONES: DR. PHILEN: Dr. Philen. My questions were primarily

about the study, so if perhaps somebody later on is going to be better prepared to answer it, I will just wait. DR. HATHCOCK: DR. JONES: About the clinical trials --

We do have a presentation. -- I understand that Dr.

DR. HATHCOCK:

Boozer is on the program and -MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES:

Yes, Drs. Boozer and Daly. -- I would not presume to

DR. HATHCOCK: preempt her. DR. JONES: DR. SALIVE:

Very good.

Dr. Salive. You have

Marcel Salive, NIH.

called into question any adverse event reports that are confounded by anything. question. I guess I have a

I mean, are you calling into question the

other ingredients in the product as a confounding issue? Because to me that is really begging the

question considerably if the products are not a pure synthetic product, there are going to be multiple ingredients like we heard yesterday and so they all have some effects all the body obviously. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. HATHCOCK:

What I am doing is saying

that when you look at a published case report or series of case reports, or clinical trial, or a pharmacokinetics study, or animal study, or whatever, you apply the criteria for causality. Going through

those then with AERs you are forced to apply those to one case at a time. Many of them are going to fall

out because, well, a temporally incorrect relationship in the reverse direction makes it nonsense of course. If there is a major confounding by pre-existing condition or concurrent consumption one has to take that into account in determining whether there is likely validity to the report. The overall analysis of AERs so depends on MOFFITT REPORTING ASSOCIATES (301) 390-5150

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doing all of those and then seeing what's left.

I am

not saying that we totally throw out anything that is even slightly confounded that one person drank one cup of coffee per day would that be considered confounded and likely not, but that is my judgment. DR. SALIVE: Okay. A follow-up question is

if that is, the case then you are saying also you would consider pre-existing conditions a confounding issue? My reading of the trials that have been done so far there are many exclusionary criteria for pre-existing conditions and so even the clinical trials do not provide any data on safe use of the product in people with pre-existing conditions of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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which there are a fairly large number in the country who may be interested in taking the product and want to know about the safety profile, you know, that might be relevant to them; how could that information be obtained? DR. HATHCOCK: Ultimately and under the

National Academy's UL model, they have provisions for evaluation of subpopulations. subpopulations is helpful. Good data on

It is necessary to really

make any judgments other than speculative judgments. If one concludes though that you want to remove any possibility of an adverse effect based on a pre-existing condition or a sensitivity that has not yet been documented there is no end to that. MOFFITT REPORTING ASSOCIATES (301) 390-5150 The only

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acceptable -- if the only acceptable risk is zero, then there is no way to go to any possible use of the product. I do not believe this is warranted and

certainly the National Academy model recognizes that certain subpopulations simply have to be removed from consideration such as they have not published on this yet, but I can imagine that they will conclude that on -- relationship thenalanine intake. I imagine that

they will reach that conclusion on Wilson's disease patients in relationship to copper intake. I

published on this a couple of times and if you set a copper limit based on Wilson's disease subjects you are going to have a level that is deficient for everybody else. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES: from the floor.

Thank you.

I see one question

If there are other questions, please Please go ahead, sir. Dan Mowery from the American I have a couple of

get to the microphone. MR. MOWERY:

Phytotherapy Research Laboratory.

questions about the funding of the studies if possible. We know that under Douche the burden of

proof ultimately rests with FDA on some of these issues. Are any other funds for the studies these

studies that we referred to today coming from FDA or from a government source? DR. HATHCOCK: I am not certain. I think I

know, but I am not certain, and I would prefer that the funding about the Columbia/Harvard study be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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answered by the principal investigator. speculation for me to preempt that.

That would be

The UL model development was funded by FDA principally through the National Academy. Its

application on ephedra was funded by the Council for Responsible Nutrition and we, as Dr. Fomus said, we are a trade association representing manufacturers. DR. MOWERY: Are you aware of any other

studies being conducted now besides the ones that you referred to on ephedra or ephedrine for that matter or ephedrine caffeine? DR. HATHCOCK: Since that is asking for an

awareness, maybe some of our federal colleagues up front here could answer. Are you aware of questions

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-- I mean, of studies of ephedra being funded by the federal government? DR. JONES: is a no. Thank you. DR. HATHCOCK: DR. JONES: COL. MYERS: Air Force. My answer was that I was not. It looks like the answer to that

Colonel Myers. Colonel Ester Myers from the

How will you address in your analysis the

departure from one of the major premises of the National Academy of Sciences which is to rely only on peer reviewed data? DR. HATHCOCK: We are relying principally on

peer reviewed data but we are also analyzing the AERs which are not peer reviewed. We all or acknowledging

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the status, peer review, or otherwise so the criteria -- scientific criteria being applied are there except for peer review and we are acknowledging whether or not the source was peer reviewed. But of course, all

AERs fit in that category of non-peer reviewed data. DR. JONES: Thank you. Thank you very much,

Dr. Fomus and Dr. Hathcock. We proceed now to Mark Blumenthal of the American Botanical Council. DR. BLUMENTHAL: Good morning, Dr. Jones, I am Mark Blumenthal,

members of the panel, audience.

founder and Executive Director of the American Botanical Council, a nonprofit research and educational organization in Austin, Texas, founded in MOFFITT REPORTING ASSOCIATES (301) 390-5150

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1988. ABC is an organization of the scientists interested in research and education on medicinal plants, herbs and phytomedicines and the dissemination of accurate responsible science-based information on these materials. ABC is a nonmember-based organization and is neither a consumer organization or a trade association but consistently deals with research, market, and regulatory issues about herbs and phytomedicines, issues of concern to consumers health care practitioners academia, industry, and regulators. ABC receives financial support from the general public, from the sale of educational materials MOFFITT REPORTING ASSOCIATES (301) 390-5150

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and from donations from individuals, foundations, and members of the business community including both herb and pharmaceutical industries. I have received no direct consideration or support from any member of industry for my expenses and appearance at this hearing. By way of introduction, as part of my role at ABC, I am also the editor of Herbal Gram, a peer reviewed quarterly publication on herbal research, market issues, and regulation, and that has covered these subjects since 1983. editor of a book called: I am also the senior The Complete German

Commission E Monographs, Therapeutic Guide to Herbal Medicine, and senior editor of a follow-up MOFFITT REPORTING ASSOCIATES (301) 390-5150

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publication, Herbal Medicine: Expanded Commission E Monographs, published this year. Finally I also served as an adjunct associate professor of medicinal chemistry at the College of Pharmacy at the University of Texas at Austin where I teach a course it herbs and phytomedicines to fifth-year of pharmacy students. I am most grateful for the opportunity to testify at this hearing. My goal is to contribute to

a rational view of the herb ephedra as it has been reported previously in articles published in the HerbalGram, plus additional information from the monographs of ephedra produced by ABC into two books cited above. These books are based on the evaluations MOFFITT REPORTING ASSOCIATES (301) 390-5150

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conducted on herbs and phytomedicines in Germany by the esteemed Commission E, an expert panel of physicians, pharmacologists, and pharmacists of the German Federal Institute of Drugs and Medical Devices, an agency analogous to the U.S. Food and Drug Administration. The Commission E evaluated all of the available scientific and medical literature that had been published on ephedra and its alkaloids up to and around 1990 and formulated a monograph to be used as a package insert for ephedra products sold as nonprescription drugs in German pharmacies. ABC is well aware of the concerns being expressed by various members of the public, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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organizations, and regulatory bodies over the potential risks involved with the use of this herb in dietary supplements in the U.S. During the past five

years HerbalGram has published at least 12 articles documenting the use and misuse of ephedra, the research on this herb, and its regulatory situation. In addition, we have published both the Commission E monograph and the expanded version and we are currently completing a more thorough literature review and assessment of clinical and therapeutic literature on ephedra for a series of monographs we are producing for continuing medical education for health-care professionals. The Commission E monograph published in MOFFITT REPORTING ASSOCIATES (301) 390-5150

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January 1991, limits the approved use of ephedra to "disease of the respiratory tract with mild bronchospasms in adults and children over the age of six." Of course, the contraindications, side effects,

and herb-drug interactions are also mentioned, consistent with those already noted in various presentations during this hearing. Of probable interest to you, however, as members of the expert panel is the dosage that Commission E has set for ephedra which I give you now: Single doses and single dosage form for adults are "herb preparations corresponding to 15 to 30 milligrams total alkaloids, calculated as ephedrine." And for children, herb preparations MOFFITT REPORTING ASSOCIATES (301) 390-5150

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corresponding to 0.5 milligrams total alkaloids per kilogram of body weight. The maximum daily dosage for

adults according to Commission E is 300 milligrams of total alkaloids per day; for children it is two milligrams total alkaloids per kilogram of body weight. The duration of use for this relatively high adult does is held to short-term use for the indication as just mentioned. In the second book cited about herbal medicine: expanded Commission E monographs, we have

added additional dosage information and numerous references to the primary and secondary scientific literature. I have provided copies of these MOFFITT REPORTING ASSOCIATES (301) 390-5150

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monographs and the articles from HerbalGram for your possible future reference and for the record. In reviewing the available medical and ethnobotanical literature for the preparation of the monographs on ephedra, we noted that despite considerable documentation in the ethnobotanical literature, from traditional Chinese medicine, there are few published clinical studies on this herb, most research having been conducted on isolated ephedra alkaloids already cited here, usually ephedrine and pseudoephedrine, or some Chinese herbal combinations of ephedra with other herbs, but not singly. We are aware of at least for clinical studies on the herb ephedra not including the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Harvard/Columbia study being referenced earlier.

The

first, White et al, 1997, dealt with the effects of powdered ephedra herb capsules in 375 milligrams capsules containing approximately a total of 26 milligrams of total ephedrine alkaloids. Conducted on

12 normal tensive adults between the age of 23 to 40. Although the authors concluded that "pharmacodynamic aspects of ingestion of ma huang in a normal tensive, young population was fairly benign," they also cautioned about the use of ephedra with other stimulants in high doses. The trial small size is an obvious weakness, indicating the need for further large-scale studies. The second trial, Nasser, et al, 1999, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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conducted at the Obesity Research Center, St. Luke's-Roosevelt Hospital Center, at Columbia University in New York, has not been published in a peer reviewed journal, at least not into our knowledge. We found the abstract in a FASEB This trial dealt with

publication in 1999.

thermogenesis using a commercial combination of herbal ingredients including ma huang called Metabolife 356 in an eight-week trial on 48 healthy subjects. total daily intake was 72 milligrams of ephedra alkaloids with 240 milligrams caffeine. Of the 48 people completing the trial out of 67 that had initially been randomized, 24 using this herb combination had greater weight reduction versus MOFFITT REPORTING ASSOCIATES (301) 390-5150 The

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the placebo, lower percentage of body fat and lower serum triglyceride levels. The authors concluded that

the herbal formula promotes weight loss but may also produce undesirable side effects is some subjects, noted as dry mouth, heart palpitations, changes in blood pressure, and insomnia. Because the study does

not appear to have been peer reviewed, we are not certain about what conclusions can be drawn. Gary Huber, M.D., of the Texas Nutrition Institute, has conducted to recent clinical trials which are currently in press which I believe he will discuss this afternoon during the hearing. We welcome

his efforts to conduct clinical trials on preparations containing herbal material, not merely the isolated MOFFITT REPORTING ASSOCIATES (301) 390-5150

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ephedrine-type alkaloids.

As has been pointed out in

this hearing and elsewhere, these ephedra dietary supplements are not single ingredient products -- they are chemically complex mixtures. Thus, it is

important that ephedrine and related alkaloids not be viewed and unassessed in a vacuum. Direct comparisons to the herb ephedra and evaluations of the herb should be made. It ABC

welcomes additional properly designed clinical trials that might provide more data about the potential benefits and potential risks of the herb ephedra. ABC also believes that dietary supplement products containing ephedra should remain on the market and that they may be required to be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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manufactured according to proper good manufacturing practices and we welcome FDA's hopefully eminent publication of final regulations in this matter. these products should be sold in reasonable dosage levels as already proposed by the American Herbal Products Association. Also, these products should be labeled with appropriate warnings, consistent with the label warnings issued by AHPA in 1994 and subsequently revised, plus other relevant policy from AHPA, as presented by Michael McGuffin at this hearing yesterday afternoon. Just as OTC drug products containing a ephedra-type alkaloids are sold to be used "only as MOFFITT REPORTING ASSOCIATES (301) 390-5150 And

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directed," we believe similarly that most consumers would adhere to appropriate label directions and warnings. In addition, we believe a consumer

education campaign should be conducted that presents potential risks and potential benefits and well-documented benefits in a reasonable and impartial manner. Finally, I present a brief statement from a member of the ABC Board of Trustees, Professor Varro E. Tyler, Dean and distinguished professor of

Pharmacognosies Emeritus at the School of Pharmacy at Purdue University. Prof. Tyler is well-known in the

United States as a leading advocate of rational herbal use. He was the author -- senior author of four MOFFITT REPORTING ASSOCIATES (301) 390-5150

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editions of the textbook Pharmacognosy and is the author or co-author of several leading books on herbal medicine. He was also the vice president for academic

affairs at Purdue and Dean of the School of Pharmacy for 20 years. Dr. Tyler says, "in general, ephedra is safe but should not be used more than about 125 to 150 milligrams of alkaloids per day, 25 milligrams at four to six times per day dosages. Before taking it,

people should be careful that they are not one of the people with the contraindications noted in label warnings. Is someone contemplates going on an

ephedra diet, they should first be checked out by a physician before doing so and monitored during the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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period of the diet.

If caffeine is going to be used

in any form during the use of ephedra, the dose of ephedra probably should be lowered." By lower amounts, Prof. Tyler told me that he believes that 100 milligrams per day appears to be a reasonable dosage as it would constitute a 20 to 33 percent reduction from the recommended maximum that he says is 125 to 150 milligrams. Also this 100

milligrams represents a 66 percent reduction in the maximum allowed for short-term acute purposes by the Commission E. Those are my comments. time and attention. questions if I can. MOFFITT REPORTING ASSOCIATES (301) 390-5150 Thank you for your

I will be happy to answer any

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DR. JONES: Blumenthal.

Thank you very much, Mr.

Questions from the panel? DR. SALIVE:

Dr. Salive. When you

Marcel Salive, NIH.

recommend a consumer education campaign based on well-documented evidence, what are you referring to? Could you outline it a little bit? MR. BLUMENTHAL: qualify that. Thank you. I would like to

To my knowledge, there is not

sufficient, well-documented evidence to develop a well-sought out consumer education campaign as far as the potential benefits all of ma huang and the risks and therefore that would have also to be subjected to waiting for proper clinical trials to be conducted and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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published, hopefully those been conducted by Dr. Huber and the ones that are from Columbia/Harvard might constitute sufficient documentation. We believe that peer reviewed scientific evidence, in addition to the ethnobotany, in addition to the pharmacology, in addition to the AERs, as a properly evaluated are part of a rational basis for conducting a campaign. But we believe that

well-controlled clinical trials would have to be part of that and right now we believe that the evidence is to the scanty for that at this point. DR. JONES: panel. Dr. McLaughlin. MOFFITT REPORTING ASSOCIATES (301) 390-5150 No other questions from the

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DR. McLAUGHLIN:

Yes, Mark, the answer I

gave to the question about the 12-week limitation for the duration of taking ephedra products was a speculative answer. I wonder if you can -- probably

should be discounted if you can give us a better answer to that. Where did the 12 weeks come from? As I remember, several

MR. BLUMENTHAL:

years ago, the state of Ohio was contemplating banning ephedra products and making them prescription only and I believe an accommodation with industry Ohio regulatory officials agreed to a 12-week maximum dosage for the duration of use of these products. I

do not believe that the 12-week period was based on any solid scientific footing, but I think it was just MOFFITT REPORTING ASSOCIATES (301) 390-5150

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basically a political or regulatory accommodation with the industry so far as I do. DR. JONES: MS. CULMO: Ms. Culmo. Cynthia Culmo, Association of Mark, what did the

Food and Drug officials.

translation of the Commission E monograph say about addiction in short-term use? MR. BLUMENTHAL: The commission E monographs

-- it's Commission E -- did mention that the herb ephedra might be addictive. We qualify that and I can

give you a quote on that, it did say ephedrinecontaining preparations are listed as addictive by the international Olympic Committee of the German sports Association. They noted that in the monograph ephedra MOFFITT REPORTING ASSOCIATES (301) 390-5150

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preparation should be used only on a short-term duration because all of tactical axis and danger of addiction. We qualified that and I believe that I

would differ to Dr. Adams' testimony as an expert in addiction as to whether or not that is bona fide. DR. JONES: Other questions from the floor?

[No response.] DR. JONES: much, Mr. Blumenthal. And now Paul Rubin is going to provide an introduction to a series of speakers that will start before lunch and continue after lunch. MR. RUBIN: Good morning. My name is Paul Seeing none, thank you very

Rubin and I am an attorney in the Washington, D.C. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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office of Patton Boggs and I am here today on behalf of Metabolife. I would like to thank the Food and Drug Administration, the Office on Women's Health, the distinguished panel and Dr. Jones for the opportunity to speak today. I understand that the focus of today's meeting is on the science surrounding ephedra rather than legal and regulatory issues and accordingly I am going to keep my comments brief and focus on the first and third questions posed by the Office on Women's Health. I would like to first mention that the Ohio law does mandate the 12-weeks duration of use in MOFFITT REPORTING ASSOCIATES (301) 390-5150

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response to the prior conversation. I would like to focus on the review of the AERs. FDA's review regarding the safety of ephedra is This is

based primarily on adverse events reports.

the case even though the concept of relying upon AERs to draw scientific conclusions and make product or ingredient specific risk assessments has been widely criticized. The United States General Accounting Office is the investigative arm of Congress and it is both independent and bipartisan. In July 1999, the GAO

issued a report condemning FDA's reliance upon AERs to conduct rulemaking and/or make scientific assessments regarding dietary supplements containing ephedrine MOFFITT REPORTING ASSOCIATES (301) 390-5150

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alkaloids. I am going to quote the GAO report and I am just choosing three quotations and there are many others that could have been chosen. GAO report, heading: On page 8 of the

FDA Analyses Relied on Poorly "The agency

Documented Reports of Adverse Events.

used AERs as the sole source of support for a specific dosing levels relied on weak information to set limits on duration of use, and did not perform a causal analysis to determine whether ingestion of a dietary supplement containing ephedrine alkaloids caused or contributed to the adverse events." Page 11 of the GAO report, heading: Adverse "The

Events Reports Were Incomplete and Inconsistent. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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AERs that we examined often lacked important information and the information that they did contain were sometimes inconsistent. These problems suggest

that AERs should be used with caution and their use can contribute to uncertainty in FDA's conclusions." Page 24 of the GAO report, heading Recommendations. "FDA needs to provide stronger

evidence on the relationship between the intake of dietary supplements containing ephedrine alkaloids and the occurrence of adverse events that support the proposed dosing levels and duration of use limits." I would also like to mention that the GAO focused its comments on the dosing levels and duration of use limits, but I do not believe that should be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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viewed as an endorsement of other aspects of FDA's proposed rule. If you look at the letter that

Congress sent to the General Accounting Office, GAO was only asked to look at those two issues. Nevertheless, despite the strong comments from the GAO, we are here today addressing the scientific validity of AERs. FDA has added that

numerous AERs to the docket and appears to be operating under the assumption that the scientific flaws associated with AERs might somehow be rectified merely by counting more of them. case. This is not the

Good science cannot be based upon faulty

underlying data regardless of the amount to faulty data collected. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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A large house of cards is no more secure a building block to formulate regulatory and scientific decisions than a small house of cards. We believe

rather than focusing on AERs the scientific focus should be on clinical trials and clinical research and that is what our panel will be discussing this morning as well as this afternoon. I should also mention that

we applaud and encourage NIH funding of additional research regarding the safety of ephedra. I would also like to note that Metabolife and regulated industry are proposing and recommending the adoption and enforcement by FDA of all encompassing standards for dietary supplements that contain ephedrine alkaloids, including warning MOFFITT REPORTING ASSOCIATES (301) 390-5150

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statements, dose restrictions, and claim restrictions that are deemed reasonable by industry and we urge the adoption of the standards. I would like to thank you for your time and I will now introduce the first of our very distinguished panel of speakers who incidentally cover a wide range of disciplines including, but not limited to, cardiology, pharmacology, toxicology, endocrinology, and clinical nutrition. Our first speakers are Dr. Carol Boozer and Dr. Patricia Daly. Dr. Boozer has received a master's

in nutritional biochemistry from Cornell University, a master's in nutrition from Harvard University and a doctor of science and nutrition from Harvard MOFFITT REPORTING ASSOCIATES (301) 390-5150

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University.

She is currently an assistant professor

in the department of medicine at the College of Physicians and Surgeons at Columbia University in New York and director of the energy metabolism core laboratory at the Obesity Research Center in New York. She has published numerous articles on obesity and weight loss and has recently submitted an article for publication on the efficacy of ephedra and guarana for weight loss. Dr. Daly is a graduate of the University of Washington Medical School and she completed her residency in internal medicine at the New England Deaconess Hospital in Boston Massachusetts and a fellowship in endocrinology at Beth Israel Hospital in MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Boston Massachusetts. Dr. Daly was an instructor in medicine at Harvard University until she relocated to York Hospital in York, Pennsylvania where she is a clinical endocrinologist. Dr. Daly's major research efforts

focus on the contribution of insulin resistance and sympathetic nervous system activity to the pathogenesis of obesity-related hypertension and the role of thermogenic agents in the treatment of obesity. If it would be acceptable, Dr. Jones, I know that Dr. Daly and Dr. Boozer would prefer to speak consecutively and then take questions from the panel after both of them have had the opportunity to speak. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES:

We did discuss that end we will

allow the two 15-minute presentations to follow one after the other and then we will do ten minutes of questions for simplicity. MR. RUBIN: DR. JONES: MR. RUBIN: Great. Thank you.

Thank you. I would also just like to

mention that although I am here on behalf of Metabolife, Dr. Boozer and Dr. Daly are not and they will, I am sure, address that in their presentations. Thank you. DR. JONES: please address that. DR. BOOZER: I would ask them indeed to Thank you. Good morning. Thank you Dr.

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Jones and panel members for the opportunity to speak at this meeting today. I have been asked to speak by

the Ephedra Research Foundation about several studies that I have conducted for them and they are providing funding for my time and expenses to do so today. They

have also provided funding for the studies that I will discuss. But I have personally no financial interest

in any aspect of the dietary supplement industry. As was mentioned in the introduction, my graduate training was in nutrition. interest is in obesity. My research

My research includes a

variety of aspects of studies of obesity including etiology, differential susceptibility, and treatments. I think it is important to underline here the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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importance of the current epidemic of obesity that we have in this country. We estimate approximately 40

million adults in this country are suffering from obesity. This is not a benign condition. The number

is increasing and we know that obesity contributes to numerous increased health risks contributing to increased mortality and morbidity. We also know that conventional weight loss treatments have limited effectiveness. Increasing

numbers of individuals are therefore turning to alternative methods for weight loss. Preparations

that include ma huang, ephedrine alkaloids are among the most popular. Ma huang in combination with guarana or MOFFITT REPORTING ASSOCIATES (301) 390-5150

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koala nut is the herbal equivalent to of the well researched weight loss treatments of ephedrine and caffeine. Although ephedrine and caffeine

combinations clearly produce weight loss in animals and in humans efficacy for weight loss of the herbal combinations have not been previously evaluated in clinical trials. The Ephedra Research Foundation,

therefore, decided to fund a six-month, multi-site, randomized, placebo-controlled trial to assess the safety and efficacy of a dietary supplement containing ma huang and koala nut. I was asked to conduct a separate eight-week clinical trial of Metabolite's product, Metabolife 356. I agreed to conduct these studies with the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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understanding that we would conduct an impartial study that would be published regardless of outcome. I felt

that results from clinical trials would contribute much-needed data to this highly publicized concerns currently based only on anecdotal information. Both of these studies are now completed. The results from the six-month study are currently under analysis. We will proceed with the usual

procedures for peer reviewed publication of those results. Dr. Daly, who directed the study at the Boston site, will talk more about the protocol. Results from the eight-week Metabolife study have been presented at the Federation of American MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Society's for Experimental Biology meeting that was held here in Washington last year. The manuscript is

now in final review by Scientific Journal end we fully expect it will be published this year. The review process for scientific papers is slow and sometimes frustrating. We ask your

indulgence, however, as we go through this process. Because to bypass it is to risk scientific credibility that is so important to bring to this emotionally charged area. While we cannot discuss data from a six

month study because an abstract has been already published for the Metabolife study I can provide those results. This was a standard protocol for clinical MOFFITT REPORTING ASSOCIATES (301) 390-5150

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trials, double-blind, placebo-controlled randomized two-arm design. The subjects were weight stable men

and women, aged 25 to 55 with BMI between 29 and 35. Sixty-seven subjects were randomized, 32 to placebo, 35 to Metabolife 356. Metabolife 356 is labeled to contain 12 milligrams of total ephedrine alkaloids and 40 milligrams of caffeine as ma huang guarana per ma huang guarana tablet. Although in its package insert,

Metabolife recommends a more gradual usage of its product. For this study we decided to start subjects

with the full amount, six tablets per day for a total of 72 milligrams ephedrine alkaloids per day and 240 milligrams caffeine. We did this to provide maximum

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opportunity to detect side effects. Forty-eight subjects completed the study, 24 per group. Of these those taking Metabolife had

significant -- statistically significant greater loss of body weight which amounted to 8.7 pounds versus a weight loss of 1.8 pounds in the placebo group. was a greater change of body fat in the actively treated group -2.1 percent versus a gain of .2 percent in the placebo group. There was a significant difference in triglycerides with a loss of 15.7 versus a gain of 8.5 milligrams per deciliter in the placebo group. Heart rate was significantly increased over baseline in the actively treated group with an MOFFITT REPORTING ASSOCIATES (301) 390-5150 There

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increase of 6.9 versus a decrease of 1.7 seven beats per minute. Mean blood pressure systolic and

diastolic did not differ between groups at anytime point nor were they different from baseline in either group at study end. When the rise over baseline for

all subjects was compared at each time point, mean systolic blood pressure was significant only at week 6 for active versus controlled. The difference of 4.1

versus -2.6 millimeters of Mercury. Repeated measures analysis of variance of completers, however, showed that the variability of the change in blood pressure was constant within subjects over groups. And the between group effect

was not significant unless weight loss was used as a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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covariant. To avoid any possible bias due to subjects who were lost to follow up intent to treat analysis was performed with all missing data imputed by carrying forward the last previous measurement to final observation. This very conservative treatment

of the data resulted in changes of the magnitude of differences between groups but did not change the statistical significance of the treatment outcomes. Eleven of the he 35 subjects in the actively treated group withdrew from the study. 32 placebo subjects withdrew. Eight of the

Of the eight placebo

subjects who withdrew to had recurring medical conditions that they had previously concealed from us. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Six left for what they reported as personal reasons. Of the 11 subjects withdrawing from the actively treated group, three withdrew for personal reasons, one withdrew for increased irritability, four for self-reported heart palpitations, two for self-reported palpitations and chest pain, and two for measured increases in blood pressure, that is, 140/90. Of those subjects who withdrew all who withdrew for self-reported palpitations had follow-up EKGs and none of the showed any abnormalities. Among the subjects who completed the study, there were no statistically significant differences in self-reported symptoms. There were however

differences with increased reporting of dry mouth and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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insomnia.

No subjects had any serious or long-lasting

adverse event in this eight-week trial. The measured heart rate, systolic blood pressure and self-reported palpitations, insomnia, and dry mouth side effects observed in the study could be anticipated based on earlier ephedrine caffeine studies and are consistent with a sympathomimetic action of ma huang. It would be expected that these

could be minimized by more gradual introduction of the treatment. In conclusion this trial clearly showed efficacy for loss of body weight and body fat of one herbal product containing ephedrine alkaloids. It

could not answer the questions of long-term safety. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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These questions are better addressed by our six-month clinical trial which Dr. Daly will now address. you. DR. JONES: Dr. Daly. DR. DALY: Thank you. Dr. Jones, members of Thank you, Dr. Boozer. Thank

the panel, ladies in gentlemen, I am a board certified endocrinologist and physician. My training after

medical school is in the field of internal medicine with subspecialty training in endocrinology and metabolism. During my subspecialty training and in

the subsequent 10 years I spent on the faculty at Harvard Medical School and at Beth Israel Deaconess Hospital in Boston, I spent my time doing clinical MOFFITT REPORTING ASSOCIATES (301) 390-5150

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research, seeing patients, teaching medical students and residents and fellows. My area of research interest has included the use of thermogenic compounds for the treatment of obesity. As a physician now in full-time clinical practice I see all of the morbidity associated with obesity. You'll hear later today from Dr. Bray who is

an authority in the field of obesity research about the increasing numbers of obese adults in this country and the serious health problems associated with obesity. In the early 1990s, I and colleagues at Beth Israel Deaconess Medical Center published results of a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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small randomized, double-blind, placebo-controlled trial of ephedrine and caffeine for treatment of obesity. This was a pilot study with a small number But we found no increase

of subjects participating.

in adverse events and found that the combination was effective with greater weight loss in the active group than in the placebo group. This was over eight weeks.

Unfortunately, funding to carry out the planned larger study did not materialize. In 1996, I

was approached by Science Toxicology and Technology and asked to design a protocol which will evaluate the safety of herbal mixture of ephedrine and caffeine. agreed to do so because I felt that this information was important both the field of obesity and from the MOFFITT REPORTING ASSOCIATES (301) 390-5150 I

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public health perspective. I worked with a statistician and two clinical toxicologist to design a study which will evaluate the cardiovascular, neuropsychiatric, liver, kidney and gastrointestinal effects of this combination. This study was funded entirely by the

Ephedra Research Foundation. We designed and agreed to carry out the study was no monetary interest in the study outcome and under the strict understanding that the results will be published regardless of whether they are favorable or unfavorable. The study was designed statistically to include enough subjects to be able to detect very MOFFITT REPORTING ASSOCIATES (301) 390-5150

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small differences in study parameters between the two groups. The statistician determined that to detect

these differences we needed to enroll at least 150 subjects. We have now completed the study and are in the process of analyzing a massive quantity of data. As Dr. Boozer mentioned, we are unable to discuss those results as yet, but when analysis is complete we will be writing a paper that we have every expectation of publishing in a peer reviewed scientific journal. I would like to review the study protocol for you to clarify the kind of data that we have collected at the time involved in carrying out this study and the analysis. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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As you have already heard this was a six-month, double-blind, randomized, placebo-controlled study which took place at two centers, New York Obesity Research Center at Columbia University under Dr. Boozer's supervision at Beth Israel Deaconess Medical Center, Harvard Medical School, under my supervision. A total of 167 subjects were randomized in the study. Baseline evaluations of the subjects

included 24-hour blood pressure and halter monitors, EKGs, and routine lab tests and urine toxic screens. Subjects with serious medical conditions were excluded from participation as is typical in clinical research and as is required by each of our MOFFITT REPORTING ASSOCIATES (301) 390-5150

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IRBs, institutional review boards. We recruited individuals, men and women, of all ethnic backgrounds, between the ages of 18 and 80 and included those who were mildly to severely overweight. In other words, with body mass indexes Subjects received either

ranging from 25 to 40.

active compound which was equivalent to a total of 90 milligrams of ephedrine at 192 milligrams of caffeine in three divided doses or a placebo. This is typical of the dose in over-the-counter herbal preparations and actually includes a slightly higher dose of ephedra than the Metabolife study that Dr. Boozer mentioned. And by

way of comparison, in my prior small study, we gave MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the individuals 150 milligrams of ephedrine and 150 of caffeine. In this current study, compliance was

assessed by pill counts at each of the follow-up visits. All of the subjects returned for follow-up, At

one, two, and four weeks after randomization.

those follow-up visits they filled out symptoms questionnaires, had 24-hour blood pressure and halter monitors placed and had physical measurements. After the first four weeks, which we refer to as the acute phase, subjects that returned on a monthly basis and those visits they filled out symptoms questionnaires, had EKGs, and physical measurements. Blood testing was also done on a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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monthly basis to look for deleterious effects on kidney and liver and pregnancy tests were done monthly on women of childbearing years. Because the cardiovascular effects of ephedra compounds are more likely to occur when these substances are first consumed, in other words tolerance or tachyphylaxes is thought to develop over time. Our protocol with cardiovascular evaluation was

most stringent during the first four weeks of the study when we are most likely to see cardiovascular effects. So blood pressure and halter monitoring which was used is quite expensive and is actually quite difficult for subjects. The subjects have to

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wear these monitors with the blood pressure monitor on the arm, taking blood pressures every 15 minutes during the day and every half-hour at night for the full 24 hours. They wear simultaneously a cardiac

monitor with EKG leads all of the chest which become quite itchy over time and they wear that for a full 24 hours and are unable to shower during the time that they are wearing this. So it is not surprising that we had some dropouts of subjects because they were unable or unwilling to wear these monitors over 24 hours. While we are not yet able to discuss our results I can tell you that no subject participating in this study suffered a life-threatening event such MOFFITT REPORTING ASSOCIATES (301) 390-5150

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as seizure, stroke, or myocardial infarction. As an endocrinologist I see a large number of obese individuals who suffer from diabetes, hypertension, coronary artery disease, hyperlipoidemia, stroke, and other complications. I

recommend weight loss to these individuals using diet, exercise, gastric bypass surgery, or pharmacotherapy as needed because I know that weight loss will improve their health and decrease their chance of dying of the complications of obesity. When I recommend

prescription drug therapy many of my patients are not able to afford to $100 plus per month cost and most commercial insurers do not cover these prescription drugs. An inexpensive, safe, and effective, over-theMOFFITT REPORTING ASSOCIATES (301) 390-5150

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counter alternative for treating obesity would have a tremendous public health impact. Our study represents a strong first step in answering questions about the safety of these products but more research in this field is needed. Given the

public health interest in these compounds, and the public health -- for the public interest in these compounds and the public health impact of an effective, safe, cheap, over-the-counter-dated treatment government sponsorship of support for additional research is also called for. Thank you for your consideration. be happy to take questions. DR. JONES: Thank you, Dr. Daly. Questions We will

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from the panel?

Dr. Philen. Thank you. I would like to know

DR. PHILEN:

if these people were on some kind of a specific diet or if you had dietary rules for them to follow? DR. DALY: Are you referring -- Yes, they

were all instructed both the active and placebo groups were all instructed in a low-fat diet and encouraged to exercise. DR. PHILEN: Was there a specific caloric

maximum they were to a hereto or anything? DR. DALY: DR. JONES: No, there was not. Dr. Lieberman. have got a few questions

DR. LIEBERMAN: for Dr. Boozer.

First I wanted to ask, did you MOFFITT REPORTING ASSOCIATES (301) 390-5150

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control caffeine intake in the volunteers in your study? DR. BOOZER: study? DR. LIEBERMAN: DR. BOOZER: During the study. To enroll them or during the

Yes, during the study, yes we

did ask them to -- you are at talking about the Metabolife study, the eight-week study? DR. LIEBERMAN: Yes, the one that you

actually presented the data from. DR. BOOZER: Right, yes. Yes, we did ask

them to limit their intake of coffee, any caffeinecontaining beverages. DR. LIEBERMAN: Okay. The other -- one of

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the other questions I had was, I think you may have said it and I missed it, how many subjects on the placebo group withdrew? DR. BOOZER: Eight. And then, to follow up on

DR. LIEBERMAN:

that, with regard to the subjects who withdrew in the active treatment group you listed a series of reasons that they withdrew, many of them were side effects typically associated with administration of ephedrine. DR. BOOZER: Right. Did the those subjects all

DR. LIEBERMAN:

withdraw themselves or were some withdrawn because you observed that their blood pressure was higher than would be permitted by the protocol? MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. BOOZER:

The two withdrew for elevated We asked them to withdraw That was a The

blood pressure we withdrew. when they reached that point.

predetermined cutoff point for our protocol. others who withdrew, withdrew voluntarily. DR. LIEBERMAN:

Okay, and the final point I

wanted to make was we have not seen your FASEB abstract I would suggest that you enter it into the record. DR. BOOZER: Sure. Thank you.

DR. LIEBERMAN: DR. JONES: Dr. Philen. DR. PHILEN:

Other questions from the panel?

Are you able to tell us, Dr.

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Daly, how many people completed your study? DR. DALY: I am sorry, I do not have the

number at the tip of my tongue, but I feel it is important not to have any of the data out until -DR. PHILEN: understand. Also, when you were working with the statistician do you recall the size of your type 1 and type 2 errors were? DR. DALY: I do not. I know that they were That's fine. That's fine. I

-- it was an important part of coming up with that number and I know that we used the most stringent measurement we were making was with the 24-hour blood pressure monitor, so we were looking at the smallest MOFFITT REPORTING ASSOCIATES (301) 390-5150

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difference to be able to detect a difference in blood pressure. DR. PHILEN: calculate your -DR. DALY: Because that was the thing that That was what you were using to

gave us the largest end basically. DR. PHILEN: DR. JONES: DR. SCHWETZ: Thank you. Dr. Schwetz. Bernard Schwetz, FDA. Do you

how an estimate of when the report from the six-month study would be ready to be submitted to a journal for review? DR. BOOZER: or two. MOFFITT REPORTING ASSOCIATES (301) 390-5150 We hope within the next month

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DR. SCHWETZ: DR. BOOZER: DR. SCHWETZ: DR. JONES: the floor. MR. MOWERY:

Oh, the six-month study? Yes. Thank you. Thank you. A question here from

Daniel Mowery from the American You talked about, Could you

Phytotherapy Research Laboratory.

Dr. Daly, about the IRB's review of this.

give us a little bit more insight on the concerns the IRB might have had or did not have given what we hear about the adverse effects of ephedrine and so forth, especially as has been brought up here in different sessions. I have some concern about what is going to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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happen with future research trials on ma huang at the IRB level. I know that in my own case I am working

with a couple of IRBs right now myself that there is some a grave concern based on what happened in 1996 and 1997 about ma huang. Can you just tell us a little bit about what you have seen, either one of you, on those issues, Dr. Boozer, Dr. Daly? DR. BOOZER: We go through the St. Luke's

Roosevelt Hospital IRB for our study because the Obesity Research Center is located in the hospital and we had no challenges to our protocol from the IRB there. MR. MOWERY: None at all? So apparently

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they're not concerned then about some of the things we have been talking about here, you know, the level of adverse effects that might occur in the general population after you've stripped away all of the susceptible people? I mean they have had no concern

whatsoever about that? DR. DALY: Well, I think that the protocol

was very conservative in wanting to exclude individuals with active coronary disease, known pre-existing hypertension, or previous strokes and things. So we addressed the issue that probably would

be anticipated to be concerns by the IRB before they had them. MR. MOWERY: Thank you very much.

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MS. MCAFEE:

Hi, I have a few comments.

I

am Lyn McAfee from the Council on Size and Weight Discrimination. Following up on what was just said,

you have taken out of huge chunk of the people who would receive any benefit from this drug by removing people with the comorbid conditions. So this is

absolutely the best case scenario, with that be a fair statement of that? DR. DALY: Well I do not think that everyone For example,

with a comorbid condition was removed.

individuals who have diabetes but are controlled by diet were included in the study. You know, it is

difficult, because to do a scientific study if you do include individuals with comorbid conditions those can MOFFITT REPORTING ASSOCIATES (301) 390-5150

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be confounders.

Uncontrolled diabetes would make

someone lose more weight and that we're not going to be able to tell what our efficacy is. So we are

really sort of between a rock and a hard place while you do want to know how these things work and whether they are safe in those individuals to include them in a scientific study, you know, it can change the science basically. So there are two issues. The safety concern

And wanting to be certain that you are not including someone who might have a harmful outcome and the efficacy of wanting to know that it is working because it is working but not because there is something else going all get that person. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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MS. McAFEE:

And diabetes is of particular And those are the people

concern and hypertension. who would most benefit.

I also wanted to address the issue of the length of the studies. and what was six months. I mean, one was eight weeks That is a very, very short And I know

time in the natural history of obesity.

the money issues, but what I am saying is, I do not know that we can extrapolate a whole lot. traditionally stops around six months. Weight loss

And what we

have seen in the other drugs in the Redux, Meridia, and Zenecalt drugs is a regain and if what we're looking for is health benefits we're not sure to what extent those health benefits will be kept as there's a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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gain effect people don't really look at that a whole lot. DR. DALY: I agree, a longer study would be

great and if funding becomes available I am sure you will find some of us who are happy to do that. I

think six months is relatively long by the standards of some obesity studies but, you know, two years would be great. MS. MCAFEE: It is hard for me to

extrapolate from that that there is really success there are in a long-term basis; I just wanted to make that point. DR. BOOZER: There is one additional study

that I have not mentioned that may throw some light MOFFITT REPORTING ASSOCIATES (301) 390-5150

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onto that -- that question.

Metabolife did fund a

follow-up study to this eight-week study and that was to bring people back 12 to 18 months after completion of the study just to find out what they did on their own. So we will have some results. MS. McAfee: DR. JONES: the panel. Excellent. Thank you.

We had one more question from

Dr. Richardson. DR. RICHARDSON: Yes, Mary Ann Richardson

from NIH. Boozer.

I just have one quick question for Dr. You said that there was an upper limit for But

blood pressure in the Metabolife study, 140/90. you said in the two groups over all the change in blood pressure was nonsignificant unless you MOFFITT REPORTING ASSOCIATES (301) 390-5150

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controlled for weight loss.

And when you controlled

for weight loss what did that looked like between the groups in terms of increased blood pressure and how high was that? DR. BOOZER: This is very -- as you can

tell, this gets very technical statistically and we try to be as conservative as possible in analyzing this in every way. We did get a significant effect in

the active group what we controlled for weight loss, so that there was then a significant difference between the two groups. answer it. DR. RICHARDSON: But that did not reach the I do not know how else to

significant level -- I mean the level for removing it MOFFITT REPORTING ASSOCIATES (301) 390-5150

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from the study? DR. BOOZER: It did reach statistical

significance for the ANOVA but whether a reach clinical significance is a judgment call. DR. LIEBERMAN: Just a follow-up on that.

When where to two subjects who had high blood pressure withdrawn? period? DR. BOOZER: One was early on in the first We sort of I think Was it before or after that six-week

week and one was after that period.

separated out the first week from the rest.

the second subject was I believe about week four. DR. JONES: from the floor? MOFFITT REPORTING ASSOCIATES (301) 390-5150 Very good in no more questions

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[No response.] DR. JONES: Doctors Boozer and Daly, thank We will look

you very much for presenting your data. forward to publication. Thank you.

Mr. Rubin, I would note that we are right before lunch. You have Dr. Bray, and Dr. Astrup who

will be presenting by video and Dr. Patrick whom you and I have discussed has probably even as we speak is just leaving a classroom. We had expressed concern

about his ability to get here at 2:05. Let me just see, are Doctors Hennekens and Soller in the audience? Would you gentlemen be

prepared to speak immediately after lunch if we were to take Dr. Bray now? Then we could break for lunch

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and we would bring you gentlemen back after lunch and then we would go to Dr. Astrup's video and then Dr. Patrick; would that be satisfactory, Mr.Rubin? MR. RUBIN: possible alternative. DR. JONES: MR. RUBIN: Sure. I know that in retrospect Dr. Dr. Jones, there is one

Bray was hoping to speak after Dr. Astrup's video. DR. JONES: MR. RUBIN: I see. So perhaps we could do to video

now if we have 15 minutes. DR. JONES: cued and ready to go? MR. RUBIN: It should be cued. If the video is there, is it

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If it is, I would just like to make a few introductory comments prior to -DR. JONES: Can someone either give me a

wave in the back, yes, it is cued, and, yes, it is ready to go? Terrific. Okay, thank you.

The lights here are so bright and, you know, if I were used to the Broadway stage it would be different. [Laughter.] MR. RUBIN: I would just like to briefly set I will provide a little Dr. Astrup first

up the video for everyone.

bit of background on Dr. Astrup.

apologizes for not being able to be here today but he is in Denmark and the trip was a bit difficult for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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him. Dr. Astrup is currently a professor of clinical nutrition at the University of Copenhagen Hospital, the president of the Royal Danish Nutrition Council, and adviser to the national boards of health under the ministry of health in Copenhagen, the Secretary and a member of the executive board of the International Journal of Obesity and the director of the Research Department at the Royal Veterinary and Agriculture University in Copenhagen, Denmark. He is a leading researcher in the safety and efficacy of ephedrine preparations and ephedrine caffeine preparations for weight loss in humans and has published many studies on the topic which FDA has MOFFITT REPORTING ASSOCIATES (301) 390-5150

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reviewed and commented upon. Dr. Astrup will be discussing his research and responding to FDA's concerns regarding ephedrine and ephedrine caffeine combinations. I would also like to mentioned that the initial videotape that we received from Dr. Astrup ran approximately 25 minutes in length and due to time constraints we had to edit it. We edited it down from

25 minutes to approximately 13 minutes and we wanted to make sure that our editing process did not alter the content, so we sent the transcript to Dr. Astrup to review to make sure that he was comfortable with it and I would like to read Dr. Astrup's comments into the record. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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"Concerning the video recording of my presentation of research on ephedrine caffeine according to our agreement the video has been edited for time purposes and I have had the opportunity to review the transcript of the edited version. I agree

with all statements being made and confirm that the editing has not change the content or conclusions" and it is signed Dr. Arne Astrup, August 8, 2000. DR. JONES: Mr. Rubin. Thank you for attending to that,

Again I would invite you, if you would

like to submit the full videotape to the record, we would welcome that as well. I will leave that to your

decision but with Dr. Astrup's concurrent statement that you read we are grateful for your 13 minutes -MOFFITT REPORTING ASSOCIATES (301) 390-5150

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MR. RUBIN: videotape now.

Thank you and you can run the

[Videotape shown.] DR. JONES: providing that to us. Dr. Bray are you ready? DR. BRAY: DR. JONES: I have to hook up my computer. Okay. And we cannot really ask We thank Dr. Astrup for

a question of Dr. Astrup. MR. RUBIN: Actually, if anyone has any

questions for Dr. Astrup I know that he is willing to respond. I mean, we cannot do it now, unfortunately,

but feel free -- we can relate any questions you have to him and we can have his responses put into the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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record if that would be helpful to you. DR. JONES: That would be helpful. We would

just get the questions of the record then and get a -Dr. Philen. DR. PHILEN: You probably know this already In

-- Rossanne Philen, Centers for Disease Control. Denmark is this caffeine ephedrine combination

available over-the-counter or is it a prescription item? MR. RUBIN: their board. than we do. DR. PHILEN: Right. Because it sounded like Prescription. It is approved by

They operate in a slightly different way

he was suggesting that it was a medication that was MOFFITT REPORTING ASSOCIATES (301) 390-5150

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dispensed through their health-care system. you. DR. JONES:

Thank

Were there any other questions

to enter in the record from the panel? [No response.] DR. JONES: Great that is helpful. I would

assume then that we do not really have to forward that to Dr. Astrup since we have -- I mean you would let him know, please, that we did ask. There is a question here Dr. Richardson or Dr. Schwetz. DR. RICHARDSON: Did he say how long the

treatment was in his study, his formal study? MR. RUBIN: Six months. Actually, I have

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the slide that I think I would have here, we were going to load two more slides from our Secretary but you're going to miss those because they are not here but I do have his your trial. He had a six-month

forearm placebo-controlled trial which he described followed by six months open label trial and at the end I had hoped to have it on here but I do not. I have

most of the other slides but I do not have that point. Can someone hook up -- oh, I am there look at this. Let's see, this being my first time doing

this, there are some real experts somewhere in the back I guess. So our next speaker is Dr. George Bray. Dr.

Bray is a graduate of Harvard Medical School and did MOFFITT REPORTING ASSOCIATES (301) 390-5150

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his residency in internal medicine, his specialty is endocrinology, diabetes and metabolism and he is currently a Boyd Professor at Louisiana State University and a professor of medicine at Louisiana State University Medical Center. He has received

several grants to study dietary, genetic, and hypothalamic obesity and he holds a patent for the treatment of selective weight control and for selective regional fat deposits. Dr. Bray will be discussing the history of youth, safety, and efficacy of dietary supplements containing ephedra for weight loss. DR. BRAY: Good afternoon, Dr. Jones. For

those of you usually hear me talk I do not use notes, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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but because this is going into the record and having edited my own transcripts, today I am going to read my comments into the record so that they will be precise and the poor person who has to transcribe it will not have to edit them. Dr. Jones, panel members, and members of the audience, thank you for the opportunity to present to you this afternoon. My name is George A. Bray, M.D. I am a Boyd

Professor and professor of medicine at Louisiana State University and was executive director of the Pennington Biomedical Research Center in Baton Rouge, Louisiana from 1989 through 1999. My appearance at this panel is supported by MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Metabolife. By way of background I received my undergraduate education at Brown University where I graduated summa cum laude in 1953 and I continued with my medical education at Harvard University where I graduated magna cum laude in 1957. Following an internship at Johns Hopkins I completed my medical residency and research training at a number of institutions including the National Institutes of Health, the National Institute for Medical Research in London and the New England Medical Center in Boston, Massachusetts. Since 1965, I have been funded continuously by the National Institutes of Health which is where MOFFITT REPORTING ASSOCIATES (301) 390-5150

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almost all of my funding comes from and I will be funded with my merit award through 2006 and with the show trial through 2009. As a result of my research on obesity I have contributed more than 1300 publications, chapters, reviews, and abstracts to the medical literature. central theme for my research program has been to understand the development of obesity and how it can be effectively treated. I'm here today to argue that the continued availability of over-the-counter products containing ephedra alkaloids is one tool to help combat this problem. Let us not throw out the baby with the MOFFITT REPORTING ASSOCIATES (301) 390-5150 My

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bathwater.

Obesity is a major epidemic. Although the relative weight of human beings

has been increasing slowly for nearly a century, sometime in the 1970s the rate of increase exploded. Obesity is now recognized as a chronic disease that is increasing in prevalence. Both the World Health

Organization and the National Heart, Lung and Blood Institute have labeled obesity has epidemic. More

than 20 percent of adult Americans are now obese and the prevalence for obesity in children and adults has increased by nearly 50 percent in the past decade. The progress of this epidemic in the United States is shown on the next two slides. The slide

down by my artwork taken from a paper in JAMA in MOFFITT REPORTING ASSOCIATES (301) 390-5150

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October 27th of last year, shows the prevalence of those using BRFSS survey with less than 15 percent, less than 10 percent, 10 to 15 percent, and more than 15 percent reporting 30 percent overweight in their states. Note that there are four states were 8 percent of the reporting states having obesity by these criteria in 1991. Note that by 1998, all but 10 of the states, 80 percent, were now in this category with 30 percent of a BMI of 30 in 15 percent of the groups. So it has

been a major increase within even this decade and there is no evidence that it has slowed down. Obesity is also a stigmatized disease. MOFFITT REPORTING ASSOCIATES (301) 390-5150 The

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common view is that obese people are lazy and weak willed. It is also believed by many that if the fat

people just had the willpower to push themselves away from the table they would not be obese. I reject this

view, although it is widely held by the public and by health professionals alike. The stigma of obesity is supported by the clamoring of women to be lean and by the more than $30 billion spent in health activities related to obesity. A recent report emphasizes the impact of quality of life in this problem. The next slide will show this data published in JAMA late last year on 40,000 women in the Nurses' Health study. In this group they divided them into MOFFITT REPORTING ASSOCIATES (301) 390-5150

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those who gained more than five pounds, those who were stable within five pounds and those who lost more than five pounds. Among those who gained more than five

pounds in the four years of this follow-up between 1992 and 1996 there were a number of problems that you can see that were significantly worsened in this group of the 38 percent of the women. Their physical function was lowered, their vitality was reduced and they had increased bodily pain. In the group that lost weight all of these same quality of life functions improved. So obesity is a stigmatized disease with significant impact on quality of life. Obesity also

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poses major risks to health.

One major consequence of

obesity is an increase in mortality. One major consequence of obesity is an increase in mortality. In this same JAMA issue that

had those maps that I showed you a moment ago, Allison, et al, working with two previously published studies showed clear evidence that between 280 and 325,000 extra deaths could be accounted for each year by obesity. The relationship of excess mortality to obesity is best described by a J-shaped curve; and I do not have the slide here, but I have published one like its many times. As body weight increases there is a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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curvilinear increase in mortality.

This relationship

exists for men, for women, and for all ethnic groups. Obesity also increases the risk not only for mortality but for a variety of diseases particularly diabetes melitis, heart disease, hypertension, gallbladder disease, and some forms of cancer. The ails that obesity brings both social and physical are reversible with weight loss. For most of

the markers of ill health care is a proportional improvement with each unit of weight loss. To obtain

significant benefits may require as little as five to ten percent weight reduction. The longer the weight

loss lasts the greater the benefits; that is, you shifted to appearance of the risk associated with MOFFITT REPORTING ASSOCIATES (301) 390-5150

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obesity to a later time frame even if weight is regained. The basic cause of obesity has been recognized for centuries. It results from an intake

of energy as food that exceeds with the body needs. The excess is stored as fat. We reach our peak energy

needs in her late teens and early 20s thereafter energy needs gradually decline at about 10 kilo calories per day per year. If we do not make our adjustments in energy expenditure our weight gain is about a pound per year or a little less over most of our adult life. The current backbone of therapy for obesity for the stigmatized and risky problem is diet, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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exercise, and behavior therapy. these treatments one at a time.

And I will deal with

The first popular diet book was published nearly 150 years ago by a man named Banting and new diets appear almost every month. It must be obvious

to anyone who thinks about the problem that if any of these diets lived up to their claims people would throng to them and there would no longer be a problem of obesity. Quite the contrary is true. Obesity is at

epidemic proportions leading to the inescapable conclusion, at least on my part, that none of these and diets meets their claims. Exercise is the second part of the -- of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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obesity treatment.

As modern society has become ever

more mechanized few humans have been willing to maintain the activity levels of their forbearers. Few

of us would want to go back into the field to harvest sugar or rice as we grow it in California -Louisiana. We must conclude that in part there's something aversive about exercise. Few people want to

do it although those who do exercise can maintain a lower bodyweight. It is noteworthy that exercise that

is effective increases heart rate and this is indeed one of the ways to evaluate if it's effective on cardiovascular fitness. Exercise also increases blood pressure, one MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of the things we've been talking about, since it is needed to move increased quantities of blood to peripheral tissues. The third element of weight control is behavior therapy. Its principals were put into

practice more than 30 years ago at the onset of the current epidemic of obesity. Although there are many

reports of successful weight loss, programs with behavior therapy, while it is being actively pursued, like any treatment that is stopped, fewer than five percent maintain more than half the weight that they lost. Given this epidemic of obesity the fact that obesity is a stigmatized condition in a world that MOFFITT REPORTING ASSOCIATES (301) 390-5150

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prizes

thinness and youth, not weight and age, it is

no wonder that Americans spend more than $30 billion annually on diet-related products and services. Since I cannot yet prevent the epidemic of obesity it is incumbent on us to offer what support we can with therapy. At present the pharmaceutical

industry, as many of you know, is actively working on new strategies for treatment, but even if they had drugs in the pipeline now it would be the late this decade before anything would be available. If they could, we would have ideal an medication which would be effective, inexpensive, and safe. What you heard Dr. Astrup say a moment ago is

that the combination of ephedrine and caffeine that he MOFFITT REPORTING ASSOCIATES (301) 390-5150

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has been working on comes as close as anything we currently have to meeting those criteria. I would thus submit that over-the-counter herbal preparations when used judiciously and according to recommendations meet these criteria. The initial reports of an effective ephedrine caffeine preparation for the treatment of obesity came from the Danish pill called the Elsonor pill that was used to treat asthma, but that also produced weight loss. It contained 40 milligrams of

ephedrine and 100 milligrams of caffeine and was given three times daily. From this initial lead Astrup

whose work you just heard described pursued the use of ephedrine and caffeine and used several different MOFFITT REPORTING ASSOCIATES (301) 390-5150

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combinations to develop the one that he tested in his protocol which I will show at the very end. It was 20

milligrams of ephedrine and 200 milligrams of caffeine given three times daily. With this combination there's a small increase in thermogenesis of about 8 percent and a small increase in blood pressure -- systolic blood pressure of 9 beats per minute which gradually declines as the beta one, beta two receptors are down regulated with exposure to this sympathomimetic drug. It should be noted that exercise too increases heart rate and blood pressure to levels similar to those seen with this a acute response to the ephedrine caffeine combination. With continued

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treatment in his trial there was a four to 11 millimeter drop in blood pressure and a one to two millimeter drop in heart rate in the first 12 weeks, again reflecting this adaptation to beta one and beta two receptors. During their 24-week double-blind placebo-controlled trial subjects lost about 17 and a half percent of their bodyweight compared to about 14 percent with placebo. The efficacy would also appear

to be supported by the rapid growth in the use of the over-the-counter products that we have been discussing in the last day and half. If these compounds were not

meeting the needs of consumers there would be no momentum for the sale of the 3 billion doses that we MOFFITT REPORTING ASSOCIATES (301) 390-5150

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heard described from the survey yesterday. Costs. The second need in a product for the The over-the-counter route has By making products available

public is low cost. real advantages here.

directly to the consumer the costs will be substantially lower than if consumers must go through the prescription route and involve physicians. The herbal over-the-counter preparations were meet this goal. Safety. The major thrust of the hearings

that we have had yesterday and today have been on the safety of these preparations. During the pass day and

half I have listened to a number of experts review the available information and have listened to them come MOFFITT REPORTING ASSOCIATES (301) 390-5150

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to divergent conclusions.

I am also old enough to

have lived through the rainbow bill pill problem more than 30 years ago, the poor quality of protein that in very low-calorie diets that led to the problems of the 1970s and Fen-Phen problem of the 1990s. In all of these cases there was a clear relation between the health problem and the product that was implicated. As I looked at the chart with

the logarithmic growth in the use of herbal ephedrine caffeine preparations presented yesterday and the few reports of adverse events which do not seem to have risen, it seems clear to me that none of the issues that surrounded the other problems when the FDA took action in these early events are in place now. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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The experience with ephedrine and caffeine in Denmark provides additional reassurance. As Dr.

Astrup said, it has been on the market for ten years there and that an estimated 2 percent of the population or more than 60,000 people have had an exposure of some period of time with few significant adverse -- with no significant adverse and events and a few minor ones. This experience needs to be added to the database that we are evaluating when deciding on the effectiveness or use of these products by the public as over-the-counter products. Caffeinated beverages have been consumed by humans for centuries and there is nothing to suggest MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that they need to be regulated.

Ephedrine has been

used in the treatment of asthma since I was a house officer more than 40 years ago. From the data I

reviewed I must conclude that over-the-counter preparations of ephedrine caffeine are safe when used according to the directions. If I may, I will show the Astrup slide. Thus, in summary I would argue that the balance of the risk benefit fulcrum is clearly on the side of benefit. I would thus urge the panel to allow those

people, particularly the individuals who would not qualify for the use of agents in the prescription category to continue to have access to herbal preparations. It will improve their quality of life. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Again, let us not throw out the baby with the bathwater. DR. JONES: It was Dr. Bray who had

responded to some of the earlier questions about Dr. Astrup's studies and now he is showing a slide. Dr. Bray, if you would briefly describe? DR. BRAY: This is Dr. Astrup's data. He

has two separate papers, one showing the parallel arm trial, the yellow is the placebo group, the white are the caffeine, the red the ephedrine and the blue are the ephedrine -DR. JONES: the stage, please? DR. BRAY: -- for six months. Then at 24 Can you turn the lights out on

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weeks the subjects of whom there were 45 initially in each group, I believe there were about 120 complete -he said 40 dropped, so there must have been 140 completed. They were given the opportunity for all of them to go on an open-label, six-month extension to examine continuing (a) effectiveness, and (b) safety. The colors are coded for the groups on which they were originally treated to show you what happened in each group. At the end of the six months of

follow-up that is 50 weeks the groups were not significantly different in any of the four treated groups; all had maintained or improved their weight loss over where they had been at the end of the sixMOFFITT REPORTING ASSOCIATES (301) 390-5150

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month double-blind randomize placebo-controlled trial, and there had been no significant adverse events in that second six-month treatment. DR. JONES: from the panel? DR. BRAY: present. [No response.] DR. JONES: Dr. McLaughlin. DR. McLAUGHLIN: Nature Sunshine Products. Yes. Jerry McLaughlin from Seeing none, from the floor? Thank you for the opportunity to Thank you, Dr. Bray. Questions

I am sitting here stewing

about this cardiac affect of the ephedra in caffeine canceling out each other on the tachycardic because MOFFITT REPORTING ASSOCIATES (301) 390-5150

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mechanistically this doesn't make sense. wondering if he have an answer as to how mechanistically this could take place?

I am

I mean this is

different in all of the pharmacology texts that I have ever read on these. DR. BRAY: Actually, you should be

addressing that question to Dr. Astrup, because it is his beta that shows the affect is there. One of the

beauties of science is that we sometimes find things that we don't expect to find from our mechanisms. Astrup is one of those very, very careful investigators and if he's made the observations I'll have to revise my my theories to fit the observation. I don't have a mechanism for you either but I don't MOFFITT REPORTING ASSOCIATES (301) 390-5150

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think that he does. DR. McLAUGHLIN: I would like to ask him

about the mechanism because it doesn't make sense. And I think the panel should realize that that's going to be a tough one to really validate. DR. JONES: MS. WOOD: Thank you. Ms. Wood.

Doctor, the only other country

that you compared with here was the doctor who said in that country, Denmark I believe it is under prescription that this is used by the public. are

there any other countries you have compared because the argument hear is you say it has to be over-thecounter and we believe it has to be at the FDA approved prescription? Have you compared your

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statistical research with other countries where the success rate was good as Denmark on which is under prescription? DR. BRAY: data that exists. MS. WOOD: DR. JONES: questions? [No response.] DR. JONES: Bray. Very good. I thank you, Dr. Thank you that's all. Thank you. Any further You have essentially seen all the

We appreciate your flexibility and I will call If we return at 1:45 this

it for round figures 12:45.

will be the order of the presentation, Dr. Soller and Hennekens, I believe I spoke with you and that was the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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order you wished to go in?

Soller.

Okay, thank you.

Not only are the lights bright but the hearing has quit too. Dr. Soller then Dr. Hennekens and then Dr. Patrick should have arrived by that time and we will hear from him and then we will continue with the schedule with Dr. Huber. One note as you go to lunch

and return, please return through the Independence Avenue entrance. These badges for this meeting do not

get you in through the other entrance for visitors. There's a whole lot of rigmarole there. So, please

come back around, a few extra steps is probably good for us all -- back in through the Independence Avenue entrance, please. And we will see you at 1:45.

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Thank you. [Whereupon, at 12:45 p.m., the meeting was recessed to reconvene this same day at 1:45 p.m.]

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A F T E R N O O N

S E S S I O N [Time noted: 1:45]

DR. JONES:

Welcome back from lunch.

We

have changed the afternoon just slightly.

We will

start with Dr. William Soller, then Dr. Hennekens and then we will hear from Dr. Patrick. we ready? We will have 15 minutes and five Q&A as this continues our abstract session as we were during earlier. Dr. Soller, thank you. DR. SOLLER: Thank you very much. It will So if we can, are

take me a moment just to set this up.

Thank you very

much, Dr. Jones, members of the panel, ladies and gentlemen. I am Dr. Bill Soller, senior vice MOFFITT REPORTING ASSOCIATES (301) 390-5150

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president and director of science and technology for this Consumer Health Care Products Association, a 119year-old trade organization representing manufacturers and distributors of dietary supplements and nonprescription medicines. The issue of ephedra safety as raised by this meeting affects CHPA members who market of ephedra-containing dietary supplement products as well as other members of CHPA who market certain over-thecounter OTC nasal decongestants and weight control products. By my introduction the core issues surrounding the consideration of ephedra safety relate to the use of adverse experience reports or AERs as a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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foundation for public health decisions about products availability and labeling. CHPA manufacturers take

very seriously the financial report about their product safety and we certainly feel compassion for those who believe that they have suffered from the use of dietary supplements or OTC medicines. As scientists, however, we have the obligation to view data objectively and often in the abstract so as to come to a deliberate decision about the quality and strength of the underlying data that might be the basis for public health decisions about ingredient safety. Fortunately, there is an accepted process of how to undertake the scientific regulatory decisions. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Scientific regulatory decisions on ingredient safety are made case-by-case in a weight

of all evidence data-driven, dialogue-driven process that includes all the relevant data and information. Such public health decisions that may affect ingredient availability or labeling must be based on data that are scientifically documented, clinically significant, and important to safe effective use of product by the consumer. This is a logical, long-standing policy of FDA as it relates to consumers product issues. The

ensures that all the evidence is brought to bear on the issue and that the ultimate public health decision is based on scientifically-documented data. MOFFITT REPORTING ASSOCIATES (301) 390-5150 This

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accepted scientific regulatory approach should be used by FDA to exert its ample enforcement authority to ensure safe and beneficial dietary supplements remain on the market. It is by using this approach that we consider a ephedra to be safe when formulated, manufactured, and labeled according to the industry's voluntary program and when used according to label directions. However, FDA's approach in this matter has been fragmented and inconsistent with this accepted scientific regulatory process. It undermines this

particular process, FDA appears to have selected information to include in the docket, blurred the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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case-by-case assessment by introducing irrelevant information on other sympathomimetic and asked it consultants to come to a public health judgment based on partial data. Let's take these one at a time. FDA appears

to have selectively included information in the docket. The correct issue here is the weight of all

the evidence, the incorrect issue is the selection of some of the evidence. FDA reopened the ephedra docket only a week ago requesting comment on the epidemiologic hemorrhagic stroke project study which addresses phenylpropanolamine or PPA. FDA entered only this

study into the docket and not even by reference MOFFITT REPORTING ASSOCIATES (301) 390-5150

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included the voluminous information that we have submitted on PPA over the last 10 to 15 years into the PPA docket for the OTC review. And, in fact, FDA's review on the pharmacology review of ephedra did not include most of the pivotal information on PPA that we submitted to the Agency. And given that FDA has entered only

selective information on PPA into the ephedra docket I would like to emphasize that as with every ingredient safety issue each individual AERs and study must be considered in the context of the totality of the evidence on the ingredient. For PPA the totality of the evidence overwhelming supports the safety and effectiveness of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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PPA when used as directed on product labeling and this conclusion is based on approximately 40 clinical studies and well with 3,000 subjects including healthy volunteers, obese and hypertensive patients in singleand multidose regimens as well as two supportive epidemiologic studies all of which are detailed in our submissions that we have made to the agency. PPA-containing products have been used literally by millions and millions of consumers over the past 50 years with a very low incidence of serious side effects. But should the ephedra docket include certain safety information on other sympathomimetic, let's remember that it is a case-by-case evaluation MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that should be the basis for public health decisions on ingredients safety. FDA's review of published literature includes about 50 plus cerebral and cardiovascularrelated references, 34 percent or so which relate to ephedrine the others sympathomimetic. The inclusion

of a large amount of information out of the sympathomimetic agents and the HSP, the hemorrhagic stroke project study in the ephedra docket implies that evaluation of a safety profile of other marketing sympathomimetic is important in the context of ephedra's safety. We do not agree that this is the cases since the intended use of an ingredient is fundamental to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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its safety evaluation and different marketed sympathomimetic have different intended uses based on their very well-known pharmacological structure activity relationships. The fact is while ephedra may include several sympathomimetic agents with different relative ratios with Alpha and Beta receptors -- activities it is the mixture of these agents in the final ephedra product, not the activity of any one ingredient, per se, that is relevant to the intended use or misuse of the product and consideration of its safety. Hence, notwithstanding the fact that PPA is a minor component of ephedra a partial review of PPA in FDA's report is also of limited value in the review MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of ephedra and potentially misleading.

Likewise,

introducing the hemorrhagic stroke project study in the ephedra docket is also of questionable value. Even if the study were of a quality to enhance our understanding of the safety of PPA. On this latter point there is serious limitations to the HSP study but is important to note that the HSP study did not established a causal relationship between hemorrhagic stroke and the subsequent ingestion of PPA and the subsequent development of hemorrhagic stroke and collected no information on ephedra. As Dr. Charles Hennekens will directly follow me with the more detailed review of the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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strength and limitations of the HSP study it should suffice for me to say that chance bias and confounding are each plausible alternative explanations of the findings from the study. Thus as a stand-alone study the data from the HSP are not sufficiently informative to draw any conclusion either about the PPA or ephedra. Another concern relates to FDA instructing its consultants to review selection of AERs and determine whether ephedra is safe; that is, to make an overall public health assessment based essentially on selected AERs. inappropriate. First, it is well-recognized that in general MOFFITT REPORTING ASSOCIATES (301) 390-5150 This direction from the agency was

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AERs are individual reports often lacking in important details or presenting details giving more likely explanations of the reported events. As such, they are considered mainly as hypothesis generating and not hypothesis testing data sets certainly not rising in and of themselves to the level of scientific documentation needed for an overall public decisionmaking. The AER database on ephedra is inadequate and only a small subset of reports have sufficient detail for appropriate causation analysis. Different

reviewers -- FDA reviewers saw different sets of AERs and among the reviewers there were wide differences in opinions about the causation judgments relating to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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individual AERs showing the highly subjective nature of this database and their analyses. A careful review

of the AERs as we think was done by the Ephedra Education Council shows the great limitations to these data as a basis for any causality assessments supporting significant or unreasonable risk attributable to ephedra. Second, in this regard, as mentioned, an important hurdle in coming to a public health decision about ingredient safety is the scientific documentation phase of the scientific regulatory process. In this phase all the relevant information

must be gathered and evaluated for credibility and completeness before a public health judgment can be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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made.

Therefore, FDA should have either given its

consultants all the information and ask the overall question on safety, or asked the consultants only about the nature of the scientific documentation of the AERs. As a result the conclusions reached by these consultants are necessarily limited if not frankly in question. Parenthetically, I might add that at least one of the FDA's expert reviews of AERs reportedly associated ephedra place pharmacological plausibility as top criterion of the attributional assessment. This bias is the review against ephedra since nonephedra-related health problems can have an MOFFITT REPORTING ASSOCIATES (301) 390-5150

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endogenous sympathomimetic component by first deciding if the AER has a sympathomimetic-related course of events sympathomimetic mediated conditions can falsely be attributed to ephedra and there is a tendency to not look for other more plausible explanations. These concerns are important. FDA has

approach its assessment on ephedra in a fragmented way undermining the accepted scientific regulatory approach that evaluates each ingredient on its own merit, focuses on the scientific documentation first, and relies on the weight of the evidence. Important information on ephedra is still being developed by the industry and we have heard this from other speakers at this meeting and this should be MOFFITT REPORTING ASSOCIATES (301) 390-5150

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included in any assessment of ephedra for regulatory decisions are taken. Finally, CHPA members' companies that market ephedra-containing dietary supplements have adopted a voluntary program for their ephedra containing problem products relating to formulations of labeling. This

was the first adopted by the American Herbal Products Association and subsequently by CHPA, the National Nutrition Foods Association and the Utah Natural Products Alliance. The industry voluntary program was reviewed by previous speakers and I just highlight some of the elements of that including serving limits, standard constituent identification, quantitative listing of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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actives, a stipulation for no synthetically derived ephedrine alkaloids, no claims relating to an altered state of consciousness, euphoria, or as a legal alternative. And then special warnings that have as

components age restriction, pregnancy, nursing warning, warnings regarding contraindicated indications conditions, drug, herb, interaction warnings, and warnings regarding exceeding recommended serving and finally in-use precautions concerning emergent side effects. On balance then, in the context of the significant and legitimate concerns about the quality and strength of the AER data set, the nature of FDA's method of review and the estimated usage of ephedra we MOFFITT REPORTING ASSOCIATES (301) 390-5150

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can come to no other conclusion then when formulated, labeled, and used according to industry's voluntary program, ephedrine-containing dietary supplements are safe. CHPA recommends that FDA adopt these industry

recommendations into regulation. Thank you very much. And, Dr. Jones, I am

happy to take questions or to turn it over to Dr. Hennekens and then we can take questions together. Whatever your pleasure is. DR. JONES: Thank you.

If the panel has no objections,

the two presentations do good together, and so if the panel is agreeable, and I would ask the audience but I think we will just go ahead. Pragmatically do your

two together and we will to 10 minutes of questions MOFFITT REPORTING ASSOCIATES (301) 390-5150

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and answers. DR. HENNEKENS: name is Charles Hennekens. Florida. Thank you, Dr. Jones. My

I reside in Boca Raton,

On November 4, 1999, the first draft of the

hemorrhagic stroke project or HSP became available. Since that time I have served as a paid consultant to the consumer health care products association or CHPA, who also paid my travel expenses. I received my M.D. from Cornell University Medical College. Had clinical training a internal

medicine at the New York Hospital, Cornell University Medical Center. I served two years as an EIS medical Later had research

epidemiologist with the CDC.

training in epidemiology in public health at Harvard MOFFITT REPORTING ASSOCIATES (301) 390-5150

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including receiving a doctorate of public health in epidemiology. I was the chief of preventive medicine at Brigham and Women's Hospital, and of course, John Snow, and Eugene Brownsald professor of medicine at Harvard Medical School. I have written or edited

several textbooks including one entitle Epidemiology in Medicine which is widely used in medical schools and schools of public health. I am currently visiting professor of medicine and epidemiology in public health at the University of Miami School of Medicine. I wish to

comment on the findings of the HSP or hemorrhagic stroke project on phenylpropanolamine or PPA in view MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of FDA's request for comments on the study’s relevancy to the safety evaluation of dietary supplements containing ephedrine alkaloids. Yesterday Dr. Love of FDA emphasized the dietary supplements containing ephedrine alkaloids were the focus of this meeting. I was concerned

however by her slide entitled "published clinical investigations on ephedrine alkaloids" on which the HSP on PPA was the first she described. There are

clear and important differences in structure and activity between PPA and other ephedrine alkaloids. These are actually outlined in a letter for my colleague, Professor Brian Hoffman, of Stanford, a world-renowned molecular pharmacologist who concludes, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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"I would encourage you to not paint all sympathomimetic with the same brush." I would also like to point out that the principal investigator of HSP, Ralph Horowitz, has not yet submitted his manuscript to a peer reviewed journal, although a study report was submitted to the FDA Center for Drug Evaluation and Research several months ago. I understand that the study is currently

being evaluated by this Agency. Since November 4th, 1999, I have had a series of communications and discussions with the researchers conducting the HSP so there is nothing I will tell you today that has not been communicated either orally or in writing to my colleagues and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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friends at Yale including Ralph Horowitz and Larry Brass as well as their colleagues, Walter Kernan and Catherine Viscoli. The views I am presenting here today also are virtually identical to those of an independent panel of five world-renowned academic experts in epidemiology who reviewed and commented on the report in detail to CHPA and then finally one other wellknown epidemiologist and two neurologists have also offered virtually identical views. So overall, based on my analysis of the available data, I conclude that HSP has numerous methodologic issues that limit this interpretability. The results of this study are not sufficiently MOFFITT REPORTING ASSOCIATES (301) 390-5150

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compelling to drive any public health decision regarding reported PPA use either as cough or cold suppressants or as appetites suppressants with the subsequent development of hemorrhagic stroke. I would like to summarize to you briefly the reasons for these conclusions, focusing on confounding bias and chance all of which are likely to affect the findings. Now, these investigators used best efforts in the conduct of this large study, and indeed assembled approximately 700 cases and 1,400 controls. Nonetheless, as I said, numerous methodologic issues and concerns limit the interpretability of the study findings. As regards confounding, for example, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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despite matching on gender, ethnic group, and age, there remain marked differences in the characteristics between the cases and the controls. Cases of the

study differed from the controls in socioeconomic status or SES. For example, 39 percent the cases with 62 percent of the controls were college graduates. In

cigarette smoking habits 51 percent the cases and 30 percent of controls; history of hypertension, 39 percent of the cases and 20 percent of the controls. Family history of stroke, 9 percent of cases, 5 percent of controls, as well as alcohol consumption, 14 percent of the cases, and 7 percent of the controls and history of caffeine consumption, 7 percent of the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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cases, and 3 percent of controls; inadequate or inappropriate control for these confounders could easily explain any observed association with PPA use. It needs to be emphasized, however, that although the study was large, there was a very small number of exposed cases and this simply does not allow for appropriate control of any, if not all of these variables. For example, SES differences alone may

explain the differences in who gets the disease as well as who uses PPA. Several sources of bias could also have influenced the results including selection and observation. Selection bias was present due to the

low-end unequal participation rates, about 42 percent MOFFITT REPORTING ASSOCIATES (301) 390-5150

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among the cases, 30 percent among the controls. Observation bias was present because cases had experienced a catastrophic event, hemorrhagic stroke, and controls were selected by random digit dialing. Persons who had an event such cows hemorrhagic stroke could be far more likely to have made a stronger effort to recall what products they had used. This

may have led to differential overreporting in PPA by cases. Further, 44 percent of the cases had some degree of aphasia, possibly limiting validity and reliability. As regards chance, the small number of exposed cases limits the ability to statistically MOFFITT REPORTING ASSOCIATES (301) 390-5150

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control for even the available confounding variables in this study. This situation also greatly increases

the possibility that chance alone could be a plausible alternative explanation for any apparent association between use of PPA and subsequent development of hemorrhagic stroke. Having said that, it should also be emphasized that in the study overall there was no significant association between use of PPA and hemorrhagic stroke based on 27 users among cases and 33 among the controls yielding a 2-sided P value of .17. Statistical significance can be achieved in this study but only in the subgroup of women who use MOFFITT REPORTING ASSOCIATES (301) 390-5150

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PPA in appetites suppressants where the comparison here is six cases versus one control, yielding a twosided P value of .03. Curiously, one of these women, also used PPA in a cold remedy and had she been so classified, even the remaining extreme relative risk would no longer be statistically significant. Since the overall findings

for the primary hypothesis was null, selective emphasis on particular subgroups with even smaller numbers may well be misleading. Furthermore, even if real, the population risk associated with PPA and hemorrhagic stroke would be exceedingly small. One might even question the

clinical implications of such a relative risk even if MOFFITT REPORTING ASSOCIATES (301) 390-5150

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they derive from a randomized trial, not a retrospective case controlled study because the numbers were so small. Thus, these data are not sufficiently informative to draw any definitive conclusions, it is quite possible that all of the observed effects could be attributed to confounding, bias, or chance, due to selected emphasis on particular subgroups. Thus, my colleagues and I believe that the results of the HSP are not sufficiently compelling to drive any public health decisions regarding reported use of PPA in cough or cold suppressants or as appetites suppressants and subsequent development of hemorrhagic stroke. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Lastly, and perhaps most germane to the deliberations of this meeting, there were no direct questions concerning ephedrine and other dietary supplements asked in the HSP, so all of these considerations lead me to include a lack of relevance of the HSP to ephedrine alkaloids. I thank you very much for your attention. DR. JONES: Thank you, Dr. Hennekens.

Are there questions from the panel? [No response.] DR. JONES: Seeing no questions from the

panel, any questions from the floor? [No response.] DR. JONES: Dr. Soller, if you would, and I

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was shuffling papers myself as you were booting up and making your initial remarks, and I'm sure you did state the Consumer Health Care Products Association, the nature of it again, please? that. DR. SOLLER: The Consumer Health Care I just did not get

Products Association or CHPA is a 119-year-old trade organization representing the manufacturers and distributors of dietary supplements and nonprescription medicines. DR. JONES: Very good. Thank you.

Are there any other questions from the floor? Dr. Philen. DR. PHILEN: Just a very small question. I

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could not hear you very clearly when you were referring to a doctor from Stanford. name? DR. SOLLER: Hoffman. DR. PHILEN: And one more detail. There Brian Hoffman, Professor Brian What was his

were 27 users among the cases, and how many in the controls? DR. SOLLER: DR. PHILEN: DR. JONES: panel? [No response.] DR. JONES: Thank you Dr. Soller. Thirty-three. Thirty-three. Thank you.

No other questions from the

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Dr. Hennekens. DR. HENNEKENS: DR. JONES: Thank you.

Are you Dr. Patrick?

Mr. Rubin, I guess you're going to do another introduction? MR. RUBIN: Yes, exactly. Thank you.

I just want to introduce the last of our speakers today. Dr. Graham Patrick. Dr. Patrick

received his B.S. in pharmacy and a Ph.D. in pharmacology from the University of North Carolina. He is currently a professor of pharmacology and toxicology at the Virginia Commonwealth University Medical College of Virginia. As a pharmacist, Dr. Patrick has observed MOFFITT REPORTING ASSOCIATES (301) 390-5150

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patient reactions to ephedrine alkaloids and other alkaloids and as a professor, Dr. Patrick has studied sympathomimetic amines such as ephedrine as well as the drug dependence and motor effects of stimulant drugs. He has been involved in reviewing FDA's

adverse event reports for ephedrine for the last five years. Dr. Patrick will be discussing the safety profile of dietary supplements containing ephedra and ephedra-caffeine combinations including his review of the adverse event reports compiled by FDA. DR. PATRICK: Dr. Jones, panel, and guests,

I would first like to acknowledge that my review of the adverse event reports and my appearance here today MOFFITT REPORTING ASSOCIATES (301) 390-5150

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is sponsored by Metabolife.

Other than that, I have

no financial interest in ephedra products or other dietary supplements. First, as an overview of the positive and adverse physiological actions of ephedra I would like these describe the pharmacology of ephedrine. Ephedrine is a sympathomimetic agent that mimics the effects of sympathetic nervous system stimulation and produces effects similar to those of adrenaline or epinephrine. It does so both directly by stimulation

of adrenergic receptors and indirectly by promoting release of the neurotransmitter norepinephrine from sympathomimetic nerve endings. sympathetic nerve endings. MOFFITT REPORTING ASSOCIATES (301) 390-5150 Excuse me, from

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Also included in many ephedrine products are the alkaloids pseudoephedrine and norephedrine or phenylpropanolamine or PPA. These compounds are

pharmacologically similar to ephedrine itself in most respects but they have proportionately less cardiac stimulant effects relative to their vasoconstrictor effects. The effects of all three of these ephedrine alkaloids are dose-related and increase in magnitude as the dosage is increased. And that is unimportant

pertinent point in relation to evaluation of the effects. Potential positive effects of ephedrine alkaloids include therapeutic applications of ephedra, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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topically as a decongestant, orally as a bronchodilator in treating asthma. Ephedrine has been

used intravenously to raise blood pressure and to treat shock and hypertension, particularly that associated with anesthesia. Ephedrine has been used orally as an appetite suppressant and to increase energy. Potential adverse effects of ephedra at appropriate doses are typically minor. These include in the use

of ephedrine-containing dietary supplements, increased blood pressure, particularly systolic blood pressure associated with beta adrenergic stimulation of the heart, increased heart rate, associated with the same effect, urinary retention and constipation associated MOFFITT REPORTING ASSOCIATES (301) 390-5150

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potentially with alpha adrenergic stimulation, nervousness, dizziness, insomnia, anorexia, or loss of appetite, tremor presumably associated with effects on adrenergic receptors in the central nervous system. These side effects are no more serious than those that will be expected from any over-the-counter products that contain pseudoephedrine or norephedrine or PPA and some of these side effects are similar to those that will be expected for over-the-counter products containing caffeine or in caffeine-containing beverages. In appropriate doses ephedra dietary supplements are highly unlikely to cause serious adverse events. For several decades the FDA has MOFFITT REPORTING ASSOCIATES (301) 390-5150

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approved ephedrine sulfate as an over-the-counter bronchodilator at a dosage of 25 milligrams with a maximum daily dosage of 150 milligrams. The UST for

U.S. -- dispensing information or USPDI, an official compendium of drug information recognizes single doses of 25 to 50 milligrams as appropriate for bronchodilator effects in healthy adults. The dosage of ephedrine alkaloids in most ephedra supplements is significantly lower than that in over-the-counter products. For example, a typical

ephedra supplement contains approximately 12 milligrams of ephedrine alkaloids per serving and the label recommends a maximum daily intake of 96 milligrams. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Some products do include us much as 20 milligrams of ephedra per does or ephedrine alkaloids per dose and those recommend no more than 100 milligrams per day. Again, below the approved dosage

levels according to the FDA and to the USP dispensing information. Moreover, on a milligram-per-milligram basis ephedra which contains the multiple ephedrine alkaloids may be safer than synthetic or pharmaceutical ephedrine because ephedrine itself is the most potent of those ephedrine alkaloids. So to

the extent that other alkaloids are included in the preparation the potency will be diminished. In addition, it has been suggested, that the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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rate of absorption of ephedra alkaloids from herbal preparations is slower than from pharmaceutical preparations which may lead to a later and lower peak effect and thus a lower incidence of acute adverse effects. Although this hypothesis has not been

adequately tested. In addressing some of the specific potential adverse effects, doses of 60 to 90 milligrams of ephedra per day do not elevate the blood pressure of healthy adults to clinically significant levels. According to an extensive literature review of by Jewel and Binramache the pressor effects of sympathomimetic amines a single dose of 60 milligrams of ephedrine is required to cause a significant MOFFITT REPORTING ASSOCIATES (301) 390-5150

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increase in blood pressure in healthy adults.

The

magnitude of this increase was 10 to 15 millimeters of Mercury pressure, no greater than would be seen with moderate exercise. Single doses of 20 to 25 milligrams of ephedrine alkaloids are equivalent to doses of 60 to 90 milligrams of ephedrine per day have caused heart rate increases of approximately 8 to 12 beats per minute. This again is not clinically significant and

will be insufficient to trigger cardiac arrhythmias in healthy individuals. A heart rate increase of 8 to 12

beats per minute is far less than will be seen with moderate exercise. Severe adverse events such as the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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cardiomyopathies bear no relationship to the appropriate use of herbal ephedra products. The rate documented cases of dialadicordimiomthy have involved extremely high doses of ephedrine a minimum of 400 and to a maximum of 2,000 milligrams per day over a period eight years or more. The occurrence of stroke bears no relationship to the appropriate use of ephedra dietary supplements. Given that several studies have shown

that a 20 milligrams dose of amphetamines administered intravenously does not cause a significant decrease in cerebral blood flow and keep in mind that not only is it a more potent but given by a route that gives a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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more pronounced affect it is unlikely highly unlikely that ephedrine in oral doses of that same magnitude could cause any ischemic type of stroke. To my knowledge, there have not been direct measurements of effects of ephedrine on cerebral blood flow. Given the 20 to 25 milligrams of ephedrine does

not significantly affect blood pressure is highly unlikely that ephedrine and recommended doses could cause a hypertensive stroke. The best documented

cases of stroke associate ephedrine alkaloids have been attributed to excessive dosage and abuse of these compounds. The preponderance of these cases have actually involved norephedrine or PPA rather than MOFFITT REPORTING ASSOCIATES (301) 390-5150

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ephedrine itself and PPA does remain freely available in OTC appetite suppressants. In addition, according to the USP dispensing information, a history of stroke is not a contraindication to the use of ephedrine. Incidence

of psychosis bear little or no relationship to the appropriate use of ephedra dietary supplements. My review of reports of psychosis associated with ephedrine alkaloids is revealed that the majority of these cases, more than 80 percent, involve usage of ephedrine alkaloids for a year or more, in some cases up to 25 years with an average daily consumption of 510 milligrams of ephedrine per day. So this is

more than five times the dosage recommended on dietary MOFFITT REPORTING ASSOCIATES (301) 390-5150

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supplements. The minimum reported dosage of these cases was 125 milligrams per day still in excess of the dosage included in herbal dietary supplements and in many cases the dosage was more than 1,000 milligrams daily. The reviewed literature does not contain a

single case of seizure where use of ephedrine is clearly causal. Also, note, the USP dispensing

information does not list the history of seizures as a contraindication to the use of ephedrine. There's little or no evidence that duration of exposure to ephedrine is related to the incidence of any serious adverse events at the dosage of ephedra alkaloids that are contained in herbal supplements. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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FDA's adverse event reports provided insufficient data to conclude that ephedrine alone or in combination with caffeine at the dosages in herbal products cause any series adverse events. My review of these reports indicates to me that the FDA's adverse event report do not provide a sound scientific basis for establishing a causal relationship of ephedra to the adverse events for the following reasons: First, the sampling was not

randomly selected from a representative population, a but rather was self-selected. Secondly, the reports often lacked information essential to evaluating causation such as dosage, duration, and the temporal relationship MOFFITT REPORTING ASSOCIATES (301) 390-5150

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between consumption and adverse event. Thirdly, very few of the reports contained information regarding the magnitude of exposure that is reliable information regarding that; the quantity of ephedrine alkaloids contained in the product; and the dosage or the frequency with which they consumed. Fourthly, they often lacked any medical corroboration such as medical histories, objective professionals evaluations, diagnostic tests or quantitative measurements. And finally, many of the cases involve confounding factors such as pre-existing disease or concurrent use of drugs which were as likely own more likely to be the precipitating cause of the event than MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the ephedrine alkaloids. The adverse event reports in the categories and FDA labels supportive often lacked information critical to the determination of whether of ephedrine alkaloids were a contributing cause to the reported adverse event. Of the 260 adverse event reports that I reviewed from the FDA docket there was only one serious event where ephedra could possibly have been the causal factor. Even in that case, however, there

was insufficient information to clearly establish causation. The alleged psychosis in that case was not

consistent with the published relationships of ephedrine, in that the dosage were only about twoMOFFITT REPORTING ASSOCIATES (301) 390-5150

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thirds that reported as a minimum in the medical literature. And the subject had a family history of

bipolar disorder. Of the 260 adverse event reports previewed there were only 12 nonserious events such as anxiety, increased heart rate and insomnia, for which there was sufficient evidence to evaluate causality. There were

also 30 or 40 nonserious events that could plausibly be related to the use of ephedra. But the reports of

these events lack sufficient information to evaluate the likelihood of causality. These events do not

appear to differ in type nor in magnitude from those that might occur with over-the-counter products containing ephedrine, PPA, pseudoephedrine or MOFFITT REPORTING ASSOCIATES (301) 390-5150

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caffeine. My conclusions regarding this safety profile of ephedra-caffeine combinations are the dietary supplements containing ephedra and the recommended dosage appear to be safe for healthy populations when used as directed. There is no evidence that herbal preparations of ephedra are more dangerous than pharmaceutical preparations of ephedra. In fact, as

mentioned earlier the herbal ephedra alkaloids may be less potent than pure pharmaceutical ephedrine to the extent that the alkaloids contained in the herbal products are alkaloids other than ephedrine itself. The scientific literature and FDA's adverse MOFFITT REPORTING ASSOCIATES (301) 390-5150

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event reports failed to provide evidence of any serious or unreasonable risk associated with ephedra caffeine combinations. There is no epidemiological

evidence that any serious adverse event occurs significantly more frequently among users of such combinations than among users of ephedra or ephedrine alone among users of over-the-counter ephedrine alkaloids preparations or for that matter among nonusers of these products. There's no difference between taking a dietary supplement that has a combination of herbal ephedra and caffeine and taking an over-the-counter asthma medication containing ephedra and along with coffee or other caffeinated beverages and the dosages MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that are included in such products.

To the extent

that minor side effects from ephedra alone or from ephedrine caffeine products combinations in the dosage of these compounds that are encountered in dietary supplements occur they are not much greater in magnitude than the side effects of caffeine and quantities that may be consumed in dietary beverages or in over-the-counter preparations. Concerning the populations that may use these products, the two main groups of user of ephedra products appear to be young to middle age, overweight individuals, and young individuals who are engaged in programs for exercise. Neither of these group should

exhibit inherently greater sensitivity to a ephedrine MOFFITT REPORTING ASSOCIATES (301) 390-5150

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alkaloids than healthy individuals unless obesity is sufficient to constitute a cardiovascular risk. Most ephedra preparations like many other dietary supplements and over-the-counter products for weight reduction do include labeling and warning that medical advice should be sought prior to using such products for weight reduction. This warning should

preclude use by individuals who may be at an increased risk. Finally, it is possible that there may be rare individuals who exhibit extreme sensitivity to the effects of ephedrine alkaloids. But ephedra

containing products are no different from other OTC products containing ephedrine or other ephedra MOFFITT REPORTING ASSOCIATES (301) 390-5150

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alkaloids nor any different from many other readily available products in this regard. DR. JONES: Patrick. Lieberman. DR. LIEBERMAN: Dr. Lieberman, U.S. Army. You I Thank you.

Thank you very much, Dr. Dr.

Are there questions from the panel?

had a question about an analogy you made.

suggested that it would be one of the factors which suggested that ephedrine would not be a factor in causing strokes was the fact that a fairly high doses of amphetamine did not reduce cerebral blood flow, are there other areas where you think it might be possible to use data from amphetamine to make a judgments about to ephedrine? For example, with regard to risk of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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heart attack. DR. PATRICK: With regard to heart attack.

My point was that amphetamines is a more potent drug, and if it does not produce an effect that is unlikely that ephedrine caused that same effect. Amphetamine

as a more potent drugs will be more like to induce any serious event that is associate with sympathomimetic effect. For example, the history of amphetamines

induced psychosis is much greater than -- far greater than anything that has been seen with ephedra alkaloids. DR. JONES: DR. PHILEN: Disease Control. Other questions? Dr. Philen.

Rossanne Philen, Centers for

You keep commenting that natural MOFFITT REPORTING ASSOCIATES (301) 390-5150

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ephedra is more likely to be less potent because of the mixture of alkaloids than synthetic ephedra. I'm

wondering if you can address the issue of is natural ephedra a racemic mixture or is it a DNL? or is it L, or a synthetic racemic? DR. PATRICK: This is going back to my Or is it D,

basic pharmacology. I'm not certain that I remember. I believe that be naturally occurring ephedra is L ephedrine. DR. PHILEN: Has there been any work done

like in laboratory animals to compare the L ephedrine versus a racemic mixture ephedrine? DR. PATRICK: The active isomer would be

mor active than the racemic mixture, or would assume MOFFITT REPORTING ASSOCIATES (301) 390-5150

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to be more active. DR. PHILEN: So, then is the natural ephedra

is L and L is more active, then it's probably more active than a racemic synthetic mixture. DR. PATRICK: That would make sense. I

honestly don't recall the potency ratio between the two. DR. PHILEN: Well, then that contradicts

your earlier statement that tbe naturally occurring ephedra might be less potent. DR. PATRICK: To the extent that the -- I'm

not quite certain what the composition of the pharmaceutical ephedrine is either. DR. PHILEN: Thank you.

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DR. JONES:

Other questions from the panel?

[No response.] DR. JONES: Questions from the floor? John Cartilina, the Council I just want to make a

MR. CARTILINA: for Responsible Nutrition.

point about synthetic ephedrine stereo selective synthesis L-ephedrine is readily available so that not all synthetic ephedrine in the marketplace is necessarily racemic. The advances in stereo selective

and stereo specific synthesis now make available those kinds of compounds in the single are desired. you. DR. JONES: Thank you. Thank

Question, Dr. Philen? MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. PHILEN:

Do we know then though if the

Primateen Mist or other synthetic ephedra you buy is D or L or racemic? I mean, how can the consumer know? I can't answer that

MR. CARTILINA:

question specifically for the any given product unless it is labeled on the product but I do know that in the last ten years these specific kinds of compounds are now very readily available by stereo specific synthesis. DR. PHILEN: DR. JONES: Thank you. Thank you. Other questions from the

Other questions? floor? [No response.]

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DR. JONES: Dr. Patrick. Richmond.

Very good.

Thank you very much,

I am glad you made it here safely from

Going 55 miles an hour, we know. [Laughter.] DR. JONES: Okay. Let's see where we are.

Dr. Huber, is here and then his remarks and then Q&A. Now, let me just ask you, sir, I believe you have brought three of your patients, three clients? DR. HUBER: DR. JONES: That's correct. Do you want us to do your 15

minutes, then Q&A of you and then have the comments as shown in the agenda from the folks who came with you, or would you prefer that we hold the Q&A until you're all finished? MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. HUBER: DR. JONES:

How ever you wish. We will follow your presentation

then, and then we will invite your patients to come forward. DR. HUBER: DR. JONES: DR. HUBER: Thank you. Thank you, Dr. Huber. I am Gary Huber. I'm here soley

as the founder and director of the Texas Nutrition Institute. I am an internist by training I graduated

from the University of Washington and then went and spent nearly 14 1/2 years at Harvard. I was trained

in internal medicine and pulmonary subspecialty in Boston and spent ten years as chief of the pulmonary services for two of the Harvard hospitals. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I spent 11 years on the faculty of the University of Texas Medicine and the last five or six years directing the Texas Nutrition Institute which is a not-for-profit entity in East Texas. I have board certification in internal medicine and I have also passed my boards, written and oral in the American Board of Geriatric Medicine. The problem has been much more clearly outlined by Dr. Bray then I can emphasize. Approximately one in five or 20 percent of Americans are now obese in this country; we do have an obesity epidemic and perhaps as many as 100 million or more Americans are overweight the obesity epidemic continues at enormous cost to our economy prevention MOFFITT REPORTING ASSOCIATES (301) 390-5150

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and treatment have remained very elusive. This is a patient mine and every patience seen over the past five or six years at the Texas Nutrition Institute has been enrolled in one research protocol or another with informed consent and initially he came to see us as a part of Fen-Phen clinical trial and that's his picture on he left. then he left, he lost some weight and he came back about years later, and he's actually here today and will talk to you. And I did not recognize him and he An

said, "Doc you've got it all wrong you're doing the wrong thing. products." Let me tell you about these herbal And that led us to think about what we

were doing and to design some studies and conduct some MOFFITT REPORTING ASSOCIATES (301) 390-5150

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studies which we've done almost now exclusively with our time over the past two to three years. we have studied over 300 patients. We have three studies that I will mention today and the very extensive, I obviously can't present all of the information, but I will submit to you as much as I can with the written addenda. Some All tolled

of these are already in the public domain and we can submit that as well. The first study was a six-month trial of three herbal products. This study was totally self-

funded by the patients, the only support we received were the herbal products themselves from the manufacturers. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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It was an open-labeled study, the patients were randomized to the different herbal products and it was prospective in nature. This study should be

really viewed as a series, I believe of case history collections. The dietary supplements all contained

herbal formulations and they were commercially available. We compared the results of the outcome of

the six-month study, retrospectively, the data that we had accumulated on patients that were matched for weight and age and everything, who had taken Fen-Phen or pharmacologic agents as I'll mention in a minute. The second study has two phases. Initially

six-week study which we have completed for the most part and a six-month phase which is still in progress. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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We received a very small amount of funding through the American Nutrisutical Association for the study and they in turn have been support supported by one herbal manufacturer. small. But the amount of funding is very

This study is double-blind it has a placeboIt

control and the patients were randomized.

evaluated four dietary supplements herbal products and a placebo. One of the dietary supplement products was

the same product to products with the same products in different doses. This study had about a 9 to 10-week

observational period, where the individuals were untreated before they were initiated either on placebo or one of the herbal containing products. The third study again more of a case history MOFFITT REPORTING ASSOCIATES (301) 390-5150

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analysis retrospectively of patients that had taken and then prescribed compounded USP pharmaceutical grade caffeine or ephedrine for one reason or another. A tolled, we have somewhere between three in 400 patients. The studies are very extensive and you can ask the patients about that. To enroll in the studies the patients have to be overweight or obese and the degrees of obesity are graded. There are three pages

of absolute and relative exclusion criteria and inclusion criteria so in that way the patients are not our subjects are not representative of the general population that could walk into a store and buy a product. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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We did include, however, patients with comorbid obesity-related diseases if they were controlled. For example, if patients had

hypertension and they were under control they could be included in the study. The same is true with patients

with diabetes whether or not they were on insulin if their comorbid disease was controlled they were included in the study. They had extensive monitoring they received a comprehensive physical examination and a 60-page medical history all tolled they ended up filling out about 150 pages of questionnaires. We used various

questionnaires and tools that had been recommended by various NIH committees. The Institute of Medicine, the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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American Society of Geriatric Physician.

They were

evaluated by a physician every two weeks until stable and then followed up at 4- to 6-week intervals thereafter throughout the 6-month period of studies. They have had extensive metabolic analysis including biochemical analysis and metabolic heart studies. Each patient received an exercise -- graded

exercise tolerance test before entry into the study and while they were on the herbal products in followup. they received a number of physical -- including

anthropometric measurements, hydrostatic weighing, they received fasting insulin levels, 24-hour urine collection and the like. We have placed an emphasis on evaluating MOFFITT REPORTING ASSOCIATES (301) 390-5150

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potential adverse events. I'm only going to mention this in passing actually the protocol that we adapted I received from one of Dr. Bray's protocols at the Pennington at a meeting a couple of years ago in Colorado. And these

were compounded caffeine ephedra capsules prepared by a pharmacist who was certified in compounding these medications. They were prescribed in the patients

were followed as they were in the herbal dietary supplement protocols. The only thing I really want to

say about it and only because of the limitations in time, is that we had -- they were less efficacious than the herbal products in terms of weight loss and they had a higher adverse risk profile, particularly MOFFITT REPORTING ASSOCIATES (301) 390-5150

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in terms of gastrointestinal acid secretion and the like. This is the first study. This was the openThere's

label, sort of series of case collections.

about 30 to 40 patients in each of the herbal product groups which I have labeled Nutri1, Nutri2 and Nutri3 and we've compared these two patients that were weight and age matched and sex matched for Fen-Phen, in our phen fen trial in amphetamine alone trial and I've listed here the cost per day -- is there a pointer? No pointer? The cost per day each of these products. We

identified individuals arbitrarily whether or not they responded to the product and it was just an obituary MOFFITT REPORTING ASSOCIATES (301) 390-5150

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definition of a half a pound. A responded was defined as a half a pound per week old greater sustained weight loss over the six-month period of trial. The herbal products

compared favorably with the existing available pharmaceutical products. This value is perhaps a

little bit low because one other things, I think, that we observed as we conducted the study is that patients who previously receive the Fen-Phen and were less responsive to sibutramine than patients who had not. We observed that in retrospect. Amount of weight loss to in this slide is expressed as the amount of excess weight above a body mass index of 25 that was lost over a six-month period MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of time. So, in this open labeled study the product seemed to compare favorably cost-wise and were effective. The second study had a nearly 10-week

observational period over which time the patients gained on the average about a half a pound a week. Some of those patients lost weight but the amount of weight loss was very marginal. There was a placebo

throughout the period of observation and those patients lost about three-tenths of a pound a week. And then there were four different study groups; product A and product B are the same product just in a different dose. This group received 36 milligrams of

ephedra per day, this group 72 milligrams. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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The maximum amount of a ephedra in any of these products is 72. Procut C had no caffeine in it

and the maximum amount of caffeine that was in this product was 200 milligrams a day. And again the

taking of these products appeared to be efficacious in losing weight at a more significant level than placebo-controlled. We at every visit and in the observation period, and for the placebo group as well, on their presentation to the clinic each patient filled out a questionnaire that contains all total above 150 questions. And I obviously can't provide all that

information today, and I just picked a couple things to share with you. Most of this, for the first study,

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is already in the public domain.

It was presented as

a poster assessment in Charleston last year the NSAO meetings and it was presented more extensively at the American Society of Geriatric Physicians and the second study will be presented this fall in part at the meeting here in Washington in September of the American Obesity Association and in October here in Washington at the American Society of Geriatric Physicians meeting. We intend to submit both of these studies for publication within the next month or two and I want to include as much of the data as I can which is really quite extensive end our report to you. The 150

questions I think it is really important to remember MOFFITT REPORTING ASSOCIATES (301) 390-5150

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to include some kind of observational period in the placebo because it was remarkable to me how there was a diminution which I did not expect and complaints of blood pressure and these are self questionnaires by the patients. Some of the patients indicated they had

edema but we were not able to confirm that by physical examination so they did not have it at the time of presentation. And this is presented as the frequency within each group during the period of the study and then we've expressed these data as a ratio to the untreated group giving this a value of one and then some relative risk of ratio for each section. I was the most surprised person in the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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world, that blood pressure did not go up.

Blood

pressure was monitored on each visit with an appropriate measured cuff, size cuff. It was measured

in the supine and upright position, apical pulse rates were checked by oscillation over a two-minute period of time, and there were no significant change to my surprise in any of treatment groups in any of the studies. Two patients were dropped from the second study because of increased blood pressure and when the code was broken both of them had receive placebo. One

of the patients had gained 14 pounds over the period of the study and her blood pressure had gone up. Another patient was dropped because of prostitutism MOFFITT REPORTING ASSOCIATES (301) 390-5150

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and urinary tract obstruction, and to my surprise he to was on placebo. One patient on active product presented to the emergency room and I was called that the patient might be having the heart attack. I turned out she

had arm pain and a bruise from hitting her arm on a table and her cardiovascular status was not significantly altered. There was a dropout but the dropout was primarily in the long washing period as patients were tired of waiting for the products. Just mention a couple of other things; I was also surprised that there was a not more anxiety and nervousness and sleep disturbance. Again these were

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expressed as relative ratios for the treatment group relative to the observational period and was remarkably free of side effects from anxiety, depression, insomnia, and sleep disruption and the like, again to my surprise. Not all of the patients,

but the selected patients had received a battery of psychometric testing prior to initiation of the herbal products and then while they're on the herbal products I have not included those analyses today but when they are available we will submit them to you. I brought this slide along because about 30 percent or more of the overweight or obese patients complained of some problem of sexual dysfunction on the presentation. And again a bit to my surprise

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there was a marked diminution in that over the period of treatment which I do not necessarily attribute to the herbal products themselves but rather to the significant loss of weight that these individuals have had, but these are one of the things that we followed and then had to a very positive responsive pattern. DR. JONES: If you could move to wrap up,

Dr. Huber, your 15 minutes are up. DR. HUBER: My summary is that these

assessments were comprehensive, the dietary supplements appeared to be effective, they appear to be safe they are cost effective, they have a relatively low adverse profile the studies remain in progress. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I had these reservations about these studies, patients were very carefully screened, they were relatively short duration no longer than six months, the number of subjects studied was limited 30 to 40 in each of the herbal groups, the number of products evaluated out of those available was limited, more information more research is needed, thank you. DR. JONES: Thank you, Dr. Huber.

You did state that the first study that you reported on was self-funded by patients, the second study you had a small award from the American Nutrisutical Association, I believe you stated, if my notes are correct and I can read my writing. DR. HUBER: All of these studies were self-

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funded except for the one study we received about $10,000 from American Nutrisutical Association. in turn have received, I think, a grant from TeleBrands which is the manufacturer of one of the products. DR. JONES: And, just for the record, we've They

asked all presenters the source of their support today to be here today in addition to your work? DR. HUBER: expense. I came, at this point, at my own

I've requested that Ephedra Education

Council pay for the cost of bringing my patients and they've agreed to do that. I will ask them for

reimbursement for my travel expenses, as well. I came to your previous meeting at my own MOFFITT REPORTING ASSOCIATES (301) 390-5150

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expense. DR. JONES: Huber. Questions from the panel? DR. PHILEN: Dr. Philen. Very good. Thank you, Dr.

Thank you, Rossanne Philen, Can you tell me how many

Centers for Disease Control.

patients were in these last tables that you were showing us? DR. HUBER: DR. PHILEN: 136. And in this particular part of

the study where you were showing us to tables was very any caloric restriction on the patients? DR. HUBER: That's a really good question

because when I presented the first data last fall to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the NASO and to American Society of Geriatric Physicians that question was asked about both physical activity and dietary; because initially we did that. I mean it was a comprehensive weight loss program. So

we deliberately in this study deemphasized any kind of nutritional dietary counseling in the initial six-week phase as well as any prescribed physical activity. encouraged people to exercise, told that was a good thing, but didn't prescribe any. We did a dietary We

analysis and generally shared the results of that with patients to emphasize what maybe good eating habits are, but we deliberately went out of our way. We

wanted to see just what the effect of taking these products was. And then, of course, as you add as we MOFFITT REPORTING ASSOCIATES (301) 390-5150

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did later in the study we added dietary counseling it became more efficacious. DR. PHILEN: DR. JONES: DR. HUBER: Thank you. Other questions, Dr. Richardson. There were two things that sort

of stick in mind as surfacing as side effects that I'm not fully understand. One is the patients feel very We measured metabolic

warm and they sweat a lot.

rates and they did not increase as much as I had anticipated. It was very small, or not at all.

But the other thing, several of them, about 10 to 15 percent have had nocturnal leg cramps, and I can't explain the reason for that. It's not anything

I can detect in terms of calcium, magnesium, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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potassium, or other metabolism. DR. JONES: question? DR. RICHARDSON: I was just curious about Dr. Richardson, you had a

the washout period the nine an a half week to washout period. Were they excluded from for taking any sort

of caffeine or products during that period? DR. HUBER: They were evaluated and then

recall at different periods of time when they were initiated on the products. So there was no

intervention whatsoever after their evaluation; they weren't excluded at that washout period from doing anything they didn't do otherwise in the life before then. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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When they were initiated on a product whether it was placebo or one of the products did not contain caffeine. They were advised that the product

may contain caffeine and they were -- it was suggested to them and documented in the chart that they should be aware of that and if they consumed a lot of caffeine that they needed to be aware of the side effects of caffeine and titrate their caffeine intake downward. DR. JONES: Other questions from the panel?

[No response.] DR. JONES: Ms. Wood. MS. WOOD: Doctor, of the 136 patients that Questions from the floor?

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you mentioned you evaluated did they receive the same equal psychiatric evaluation before they went through your program? DR. HUBER: Yes and no. In terms of the

questionnaires in terms of depression scales and other things like that, yes, they all received those, as well as other evaluations of readiness for weight loss, emotional status, stress and like in terms of administered psychometric tests we could not do that for all patients, it was just a manpower thing, but on that we did short-term memory recall, we did a battery of about 15 tests and about a third of the patients received psychometric testing objective psychometric testing before and after they were replaced on the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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herbal products. MS. WOOD: DR. HUBER: MS. WOOD: DR. JONES: But not all 136 patients? No. Thank you. Other questions?

[No response.] DR. JONES: Dr. Huber, would you like to

introduce the three people who have come with you? DR. HUBER: themselves. DR. JONES: DR. HUBER: That will be fine. The first one I have already Can we put up the -- I guess Sure. Or they can introduce

shown you a picture of.

it's the second slide or third slide with the picture MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of Mr. Martin.

He can introduce himself and the other

two patients can introduce themselves. Mr. Martin received -- out of interest -product A in the first study, which he basically had brought to my attention, and one of the other patients received product B in the second study and then was converted eventually to product E, and the other patient received product E throughout. DR. JONES: Thank you. You will each have Three minutes,

up to three minutes for your remarks. thank you. MR. MARTIN: Good afternoon.

My name is I own an air

John Martin and I am from Tyler, Texas. duct cleaning company there.

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I've been very heavy all my life and today I just admitted to myself that I used to be obese. don't think I ever used that term before. Until a few years ago, I had been struggling with my self-confidence and my own personal discipline. For years I was told that a good diet and consistent exercise would control my weight; and for years I tried everything from 1000 calorie-a-day diets and hours of exercise to starvation diets fat gram diets and then ultimately Fen-Phen. All produced I

minimal success and always the weight came back and much more; so much more that I ballooned to over 300 pounds. I'm not quite sure how much over because my But when you weigh that much

scale pegged out of 300.

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you don't want to invest in a new scale to see just how much more. [Laughter.] MR. MARTIN: I will never forget the day I

met Dr. Huber and I started to take the Fen-Phen products. I went home with tears in my eyes because I

thought at that point in time that my curse was finally over. The reports of big weight loss really

excited me and gave me great hope. After several months and some success with weight loss with Fen-Phen, my memory loss was much more than I could handle. So I made the decision to I was totally crushed

go back to might cursed life.

by that decision and at that point I had completely MOFFITT REPORTING ASSOCIATES (301) 390-5150

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given up. Two and a half years ago a friend in the weight loss product business asked me to try these new capsules, yes, the capsules contained ma huang. I

took them begrudgingly, but yet consistently because he asked me to and he was my friend. After 90 days, to my surprise, people started asking me if I was okay, if everything was all right, it looked like I was starting to lose weight. Surprisingly after 30 days -- or, excuse me, 90 days, on the scale I had lost 30 pounds. See

people that are very heavy don't get on the scale so I really didn't notice because I didn't expect to actually lose any weight, because I had in the past. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Well, after four months with people continuing to ask me if I was ill I became convinced that I was and that I had cancer or some other terrible disease. So I

went in for a check up with a physician and he said I was fine just keep up what I was doing, because it was working. After five months I began to get excited and

I decided that I was going to help the product by actually watching what I eating. After seven months I actually began to exercise. My Christmas present to my wife that year I'm going to move forward since

was my 100th pound. my time is up.

I can now with the help of ephedra

discipline myself to maintain my weight, by watching what I eat, and consistent exercise, and I can now MOFFITT REPORTING ASSOCIATES (301) 390-5150

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live like a normal person and enjoy everything life has to offer. Thanks. Thank you, Mr. Martin.

DR. JONES: Ms. Crocker. MS. CROCKER:

I am Darynda Crocker, and I am

from Benwheeler, Texas, close to Tyler, and I've been heavy pretty well all my life. And I've done a lot of

weight loss programs and a lot of diet pills and they all make me so irritable that people can't stand around me. My husband would come home and say, "Are

you taking diet pills again" you know, it's horrible. So when I heard about this program through a co-worker thought, well, you know, fat people will try anything. So, I get into this program and the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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paperwork all the medical history and all the medical tests and it was really a lot. So we got all that

done, and I started and I began to lose weight; I've lost about 35 pounds. I'm not irritable you know they

don't do me like the diet pills I had taken before. In fact, since '94-95 I have been taking blood pressure medication for high blood pressure and after a started this my blood pressure was dropping; it was really low so I now the medication has been cut in half. So when you need to lose as much as I need to lose you need statement that doesn't make you so irritable, something that you stay on for long period of time. And the blood pressure alone would be worth MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the benefit. DR. JONES: Mason. MS. MASON: My name is Molly Mason I'm 51 Thank you Ms. Crocker. Ms.

years old and I've always had a weight problem too. Like Darynda, I've tried everything diet pills, Weight Watchers, you name it, everything and I've heard about it from a co-worker too and I contacted Dr. Huber's office and filled out the many hours of paperwork. also had a lot of testing, blood work, urine tests, physical testing, bodyweight measurement in the water and with the calipers and I was in the other category first for about two months and I didn't lose any weight on that and then he put me in the category that MOFFITT REPORTING ASSOCIATES (301) 390-5150 We

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Darynda and I are both in now. pounds

And I have lost 24

it's really exciting to me because I have a back injury and I need to lose the weight but it is really hard to exercise and do anything when you have the back injury. Also treatment for my back injury includes epidural injections which is usually cortisone; and is really hard to lose that and I'm really excited about it and I've not noticed any adverse effect to mean, except maybe one of those does to a little sweating. But I work for the Postal

Service and I'm used to that. [Laughter.] MS. MASON: I really am excited about its

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because it doesn't affect me I can't find any effect to it all and I'm not nervous on it, I don't feel apprehensive and it's a good thing for me and I hope to stay on the it. Thank you. Thank you very much, Ms. Mason.

DR. JONES:

This concludes our third abstract session for the day and we are scheduled for actually about a half hour from now but I say we take it now, about a 10-minute break and then we will return for public comment session C, and some concluding remarks so I our aim is to be back at -- I have about 3:06, for round figures let's say 3:15, thank you. [Brief recess at 3:06 p.m.] DR. JONES: Testing the reliability of

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certain government-issued devices that fall downstairs and how many they can fall down and still survive, but, welcome back. We are ready to get started.

Let's see we have public comment session C, just getting underway and at the front of the room we have Dr. Roy Brabham, Gayla Heflin and Kimberly Jerrow. And Dr. Brabham requested 10 minutes to present some of his clinical experience, as I'm recalling your abstract, sir, and then Ms. Heflin and then Ms. Jerrow we will hear from, thank you. Please, for the record, introduce yourselves, the source of your support for getting here today and for your research as that is relevant, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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thank you very much. DR. BRABHAM: Thank you. I am Dr. Roy

Brabham, I'm from Baton Rouge, Louisiana, I'm a plastic surgeon in private practice there. I received

a medical degree from the LSU School of Medicine and then I did residency training in general, and plastic surgery at the University of Wisconsin, Medical Center in Madison, Wisconsin. I'm certified by the American Board of Plastic Surgery. I serve on the Science Advisory

Board of Changes International, which is a division of TwinLab Corporation. My trip here has been funded by Changes International. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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My goal in this presentation is to give you some perspective on dietary supplements containing ephedrine alkaloids from a practicing physician who has worked with patients that are taking these. My product experience is limited to the three Thermolith products from Changes International. Two of these contain 25 milligrams of ephedrine alkaloids while the other is ephedrine free. The two

forms containing ephedrine are a capsule and a quickdissolve caplet. composition. It has been very interesting to me that the effect of the ephedrine in these two different forms seems to be quite different. So I think there is some Otherwise, they have the same

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area where the delivery system is going to affect the impact of these compounds and probably needs some more study in that regard itself. All of the products

contained guarana extract which is a natural caffeine source and white willow bark which is a natural source of an aspirin equivalent. And the recommended dosage

of these products from the company is two per day. I was introduced to the company and its products by a patient of mine who experienced a dramatic weight loss and health turnaround with the help of the ephedrine-containing capsule version of the product Thermolith. His history is illustrative

of my experience with this product, so I am going to summarize it. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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This gentleman, HF, found himself in January of 1997 weighing 255 pounds on a 5'8" frame at age 53. He had progressively gained weight over a four-yearspan from a starting point of 195 pounds. He was

intolerant of exercise or heavy work and he was frequently short of breath. headaches. He regularly experienced

His blood pressure was elevated an average

156/92, but he had refused, and essentially avoided taking anti-hypertensive medications. He experienced

a classic episode of angina pectoris while he was at work in 1995. He actually began taking the product

independently and he was taking two of the Thermolift capsules per day starting in January of 1997. He did not consciously alter his eating MOFFITT REPORTING ASSOCIATES (301) 390-5150

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pattern or pursue a structured exercise program. Within three months he lost 3 pounds and his blood pressure had dropped to an average of 124/84. He went on to lose a total of 60 pounds over a six-month period and he has maintained a weight at that level of 195 pounds since that time. He states

that he experiences more energy and now exercises regularly and he does heavy work without problems. I had seen him at his maximum weight shortly before he started taking the Thermolith product. at the three-month point when he had lost the 43 pounds. I was amazed and really couldn't believe the And And

change and asked him how exactly he had done it. when he told me about this product, I began to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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research particularly the product ingredients.

And as

I learned more, and saw him continue to have good benefit from the ongoing use of the product, I started recommending these types of products to other of my patients who wanted or needed to lose weight. It was interesting in addition to his blood pressure situation, I found later that he has an incredibly strong family history of heart disease with his father and numerous aunts nad uncles related to his father having died at the late 40s and mid-50s of heart attacks. He also had a brother with a heart

attack and bypass surgery at age 56. As I have gone on and seen how these people are taking these products and using them, I've MOFFITT REPORTING ASSOCIATES (301) 390-5150

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developed some guidelines of my own for the use of the products. I usually get a history from these people

if they've ever taken any of the cold remedy medications over-the-counter that contain ephedra and ephedrine components. Most people have had experience

with these and I think that that can give a good guideline as to how these type of products tend to affect them. Some people definitely do become jittery

and experience some nervousness, and in those particular people I try to do either an adjustment of the type of these products that they take or reduce the dose. I always have them start off with one per day which is a 25 milligram per day of ephedrine MOFFITT REPORTING ASSOCIATES (301) 390-5150

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alkaloid dose with this particular product line. they do okay with that, and it seems that they'll

If

tolerate two a day, I believe that's more ideal for the weight management and I have them go up to that so that they're getting a total of 50 milligrams per day. If they have a problem with the capsule form, I go to the caplet. I don't know exactly why it doesn't seem

to affect them as much as the capsule, but I suspect that it's a quick dissolve and there must be some influence from the gastric juices and acidity on the active compound. And some people don't tolerate even

that, and we do have this ephedrine freeform which has many of the other herbal components have been mentioned in passing, and seem to have some help for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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these people as well. I have been recommending to these patients that they go to the ephedrine-free version every two to three months for about a week of time just essentially to avoid problems with any tolerance they might develop to the effects of the ephedrine. People who are hypertensive, I have not had any problem with them. If they have been on

medication, I've had them continue their medications and just haven't seen problems with them relative to their blood pressure and in fact, this patient I showed and several others have actually seen a lowering of a hypertensive state. I think that it's important to remember that MOFFITT REPORTING ASSOCIATES (301) 390-5150

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obesity carries its own significant health risks. believe I've heard it stated in some of the earlier sessions, yesterday in particular, that we need to have some health benefit derived from using these

I

products, and I think the people that actively control their obesity do derive health benefits by reducing the associated health risks which, as we know include heart disease, hypertension, diabetes, degenerative arthritis, mental and emotional disorders and others. In conclusion, based on my experience as just a regular physician out in practice, and I recognize my experience is only anecdotal, but I believe that the ephedrine-containing dietary supplements are safe and effective for use in weight MOFFITT REPORTING ASSOCIATES (301) 390-5150

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loss.

I think the risk benefit analysis of these

products dictates that they continue to be made available to the consuming public in an inexpensive, non-prescription basis. Thank you. MS. HEFLIN: Ms. Heflin. Good afternoon, esteemed panel. I'm 39 years old and I'm I am a distributor of, and

My name is Gayla Heflin. from Derider, Louisiana.

funded by, Changes, a TwinLab Company. I am going to tell you how an ephedra product did help me lose weight and helped me avoid a truly serious adverse event. I wish my two sons, Aaron, 15 and Ryan, 11, were here today to tell you how thankful they are for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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me finding an ephedra product -- ephedra-containing weight management product called Thermalift. Now my story. It starts in 1997. I was a

housewife who had been horribly overweight for seven years. I was severely depressed to the point of At one point I locked myself in

considering suicide.

my bedroom and stared at a rifle considering suicide, which I felt resulted from weight and poor selfesteem. I was extremely nervous and suffering from I also had

chronic sinus and bronchial infection.

chronic fatigue syndrome and horrible fluid retention. I was dangerously becoming reclusive. Basically I was living through my children and soap operas. I asked God for help and soon after MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I was introduced to an ephedra product. I took it as directed and I lost 63 pounds in nine months. I went from a size 16 to a size four.

I now have no symptoms of the problems I mentioned earlier. I was not once diagnosed even with a hint of My doctors were

hypertension while on this product.

astounded at the difference in me physically and emotionally. I've taken the product for three years. Taking off once a month and using a non-ephedra product for three to seven days. I have kept my

weight off for two years using this same product without any adverse effects. I now am a successful

Changes kiosk owner and motivational speaker. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I stand here today and I tell you that truly I am an ephedra miracle. MS. JERROW: Thank you. I

My name is Kimberly Jerrow.

am from Colorado Springs, Colorado, a distributor of and funded by Changes, a TwinLab company. Ephedra is one of the reasons I am here on earth today. Ephedra helped save my life. I have

lost 60 pounds in seven months and have kept it off for three years. Once in the middle of the night

looking into a full-length mirror the reflection staring back at me was, at best, depressing. My weight at this point was still increasing. My health was declining, but had no prior health conditions before my weight gain. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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My cholesterol and blood pressure were high. My legs were in pain every day. I had difficulty

breathing and could not walk ever for short distances. I had developed a debilitating depression that left me severely withdrawn from society. For days I would not

leave my house in fear of hearing more terrible remarks about my weight. It is an extremely brutal

blow when you hear people laugh at you when you walk by, when they treat you different because you are not at your correct weight, and when they call you "fat." My doctor offered me no real hope. offer of prescription medicines to lower my cholesterol and they gave me a battery of expensive tests to try and solve my leg pain. I knew that that The

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was not a solution to these problems. to exercise and walk it off.

I was also told

But tell that to a five-

foot woman that is 165 pounds and see how far you could walk before getting extreme shortness of breath, fatigue, and have lost motivation for life. I seriously contemplated suicide and prayed to God to take me so my pain would end. found another way for me. ephedra-containing product. Luckily, God

I was introduced to an Willing, I tried knowing

I can longer live the life I'm living. To my astonishment, not long after using the Thermalift product, I lost my first five pounds, and then ten, 15, and so on. Till, finally after seven

months, I reached my goal of losing 60 pounds and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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getting into my size four, all the way from a size 16. Without any type of prescription medicine my cholesterol returned to normal, my leg pains are just a memory, and I am at my correct weight. I am With my

healthier than I have ever been in my life.

weight loss I realize I have gained in other aspects of my life. My self-confidence has returned, and any

time I walk down the street, or do my everyday activities, I will never take them for granted. I am glad to be alive and I am glad to be living life. I have earned the respect of many,

sometimes even being told I am a role model for them. If you ask me if I would do it all over again, my response, without a doubt would be, yes. I am only

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just an example of one in a million who have acted responsibly in taking this product and have had fantastic results. I will continue on telling people of this wonderful ephedra-containing product because in my eyes it is nothing short of a miracle. DR. JONES: Thank you.

Thank you, Ms. Jerrow, Ms.

Heflin and Dr. Brabham. There are a couple of other changes on the public comments session. We were informed that Ms.

Mitchell scheduled at 4:04 p.m. is not able to be with us today and I understood that -- and I have a typo here, it says, Enteemah Ellis, it's Fatima. apologize Ms. Ellis. Are you here indeed? I do Because I

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had understood you were running late because of a train problem. We thought it was just United Airlines

canceling flights. Are we ready then? Ms. Sciuto. MS. SCIUTO: Carol Sciuto. Good afternoon, my name is I

I am here on behavior of Metabolife.

wanted to relate my experiences with the product to you. I also wanted to let you know that I did volunteer to come, I am not in any way being paid for what I am doing today. You have pictures of several of the people that are going to speak after me up there. There is

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not a before picture of me, but I did bring along a part of an outfit that used to be mine. These were my

slacks, and this was what I was before I started with Metabolife. I am 52 years old and at the age of 49 and three quarters, for Christmas, my children had gotten me a work jacket and it was a size 24. button around me. It would not

I was horrified, I was devastated,

and I made up my mind at that point that something had to be done. Like the rest, I was depressed, my self-

esteem was in my shoes and I really had no motivation at all. I had tried a lot of diets, I had been overweight all of my life, particularly ballooning MOFFITT REPORTING ASSOCIATES (301) 390-5150

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after my third child and I again started on a diet regime of what I thought was healthy habits. In several weeks I lost 25 pounds, but I found that I had hit the normal plateau, and once again it was starting to set in with the tiredness and, gee, this is not working, I think we're not going to keep trying this because I'm getting nowhere, I'm getting no results here now. This is probably the

ideal weight for my body, this is what my body wants to be. Then someone told me about Metabolife. Said,

try it, see if it doesn't work, and then I had heard some advertisements on the radio regrading it, how it boosted your energy level, it kept you from becoming depressed, and that type of thing, so I went to the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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doctor with it.

I showed him what I was going to do,

he gave me the okay, and I went on with it. Within a week, or two weeks, I'm sorry, I was back to losing a pound, a pound and a half a week. My personality improved, I was no longer irritable. The people at work certainly enjoyed that. I call on an even keel. I was what

I had a very optimistic

outlook and the weight just continued to fall off without any effort at all. The dieting was -- my only

part of dieting, change in appetite, or diet was replacing my sandwich with a salad at lunchtime. Otherwise, I ate normally. In the past year and a half I have lost over 85 pounds. I weighed 248 pounds and I had since MOFFITT REPORTING ASSOCIATES (301) 390-5150

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gained ten pounds back because friends and relatives told me that I was too thin. I'm considering taking It has changed

those off again because I felt good. my life.

I cannot tell you how it has changed my

life, it has changed my career. I am a professional trainer, I can walk into a corporate group of Chrysler representative and feel as though they're not looking at the size, they're looking at my credibility. I can tell people to

motivate themselves into becoming role models and achieving their goals without having them look at me and say, "you've got to be kidding." So it's done a

lot for me personally, it's done a lot for me professionally. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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I am continuing on with my college education. I have purchased a sailboat, and taught

myself how to sail and can do that all by myself now. Last summer I also realized a lifelong dream and began taking flying lessons. I would not have done any of these things had I still weighed 248 pounds. I would have hid

behind people, wore a lot of black, and a lot of beige so that I blended in with the woodwork. what Metabolife has done for me. But that is

It has changed my So,

life and I will never go back there again, ever. thank you. DR. JONES: Ms. Ellis. MOFFITT REPORTING ASSOCIATES (301) 390-5150 Thank you, Ms. Sciuto.

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MS. ELLIS:

Yes, my name is Margo Ellis and I am not being

I am a consumer of Metabolife 356. paid to be here today. fat.

I was 267 pounds of unhappy

Metabolife has affected my life in so many It has given me a whole new outlook

different ways.

in my personal life as well as my career. Things have changed for me and I enjoy it. I have given hope back to women who have a weight problem by virtue of them seeing and recognizing my weight loss. They know that it can be done with the

Metabolife product. I am so much more energetic and healthier. I am proud of myself as well as the other women who have tried and successfully lost their weight through MOFFITT REPORTING ASSOCIATES (301) 390-5150

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this product.

Whether it's ten, 20, or 91 pounds, This product

this is an accomplishment for all women.

has put hope back into weight loss for anyone who might have a weight problem. I know it has for me.

It has given me a sense of confidence in myself and how others view me. Before I lost weight, I had a lack of confidence as well as self-esteem. my career. I felt stagnant in

Now I have lost weight and my career has I have had the courage and

changed dramatically.

confidence to apply myself to higher goals in life. At one time when I walked into a room I was just a normal, everyday person. When I walk into a

room now, people notice the confidence and the level MOFFITT REPORTING ASSOCIATES (301) 390-5150

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of high self-esteem.

I would like to say that I am

proud of myself and any other woman or man who has succeeded, successfully losing their weight by using Metabolife 356. 99 pounds. As of today, I have lost a total of

Thank you, Metabolife. DR. JONES: Thank you, Ms. Ellis. I show

Lynn McAfee next on my presentation, do you want to go at the end, can we bring you a hand-held microphone? MS. McAFEE: DR. JONES: handy? Hand-held microphone. Hand-held microphone. Is that

There he is, he's holding it up in the back. MS. McAFEE: I am Lynn McAfee. I am

director of Medical Advocacy for the Council on Size and Weight Discrimination. The Council does not take

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funding from the weight loss industry under any circumstances. So we are clean today.

And after you hear what I say, you can imagine why they wouldn't want to give me money. And I tore up the notes that I originally made, my speech that I originally had, because so much has come up in the last few days, and I don't envy you your decision. We're a group that doesn't try to make

decisions for people about whether a drug is good or bad, take this, or don't take this. Because life has

not been simple and obesity has been so oversimplified and that has not served us well. So what I want to talk about is some concerns I have and a wish list I have at the end. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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And I want to speak first about the other public speakers. You know, I'm happy when anybody gets what they want in this world. It's a tough world, and I'm

very happy when anybody loses weight and keeps it off, that's pretty much been my life work. And I commend

all the people who came here today to share their stories and add their perspective to the public record. I mean, I can certainly relate to the

suicidal feelings and the emotional pain, and the brutality that we suffer at the hands of other people. I don't think that a medical solution to that is really appropriate. But what concerns me is the companies that MOFFITT REPORTING ASSOCIATES (301) 390-5150

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these people basically represent, the products they represent. And those companies doing the kinds of

miracle stories, one person in time in this venue, I think is deeply inappropriate and deeply offends me. This is what has been going on for 100 years. You

have no data to show me, you have little data to show me, but, look, this person did it. And, in fact,

these companies in addition to the rest of the weight loss industry has never tracked long-term effectiveness. Never.

And I can tell you from the last two and a half years of negotiating through the FTC was that, that that is true and I have sat across the table from the senior attorney for Weight Watchers who said it MOFFITT REPORTING ASSOCIATES (301) 390-5150

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would be too depressing for them to track the longterm effectiveness rate. Our position is that if people will begin to track this, begin to track the safety profiles and make subgroups of people rather than following the prejudice that you all look alike, you all must eat alike, your bodies are all the same. Clearly, the new

science of obesity is showing that there are biological subgroups as there are in any population, and that there needs to be approaches for that. It's very clear to me and very clear to anybody, I think that George Bray, will back to me up on this, biologically you're different when you have childhood obesity. My body does not experience hunger

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I'm quite sure in the same way yours does.

It is very

important to track that and we are deeply concerned that they have not done that. They simply go with the Cinderella story and I will guarantee you for every person here who has successfully lost weight I can go out and bring in 100 who did not. So, show me the data.

Obesity is certainly associated with very serious health risks. I am a 500-pound woman I have

very serious health-related problems that would be made much better by permanent weight loss, but then that is the key. And, in fact, nobody is doing this They are doing it for

stuff for a 500-pound woman.

women who are on the lower end, and that is the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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problem. I am going to write up my wish list and I will make it available to you when it is a little more coherent, thank you. [Applause.] DR. JONES: DR. JONES: MS. ELLIS: Thank you, Ms. McAfee. Ms. Fatima Ellis. Hi, my name is Fatima Ellis. I

am a consumer of Metabolife and I was not paid to be here. I am a 22-year-old college student, I am a

wife, I am a mother of an 18-month-old boy. Prior to having my son, unlike most of the people here I did not have a weight problem I exercised as a hobby. After having my son the stress

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of being a new mother and trying to balance that with everything else in my life I began compulsive over eating and I gained 25 pounds on top of the 25 pounds I had still remaining from my pregnancy. Six months after I had my son I was still wearing my maternity clothes. I tried to lose weight. weight was 130. not work. It was around that time

I was as to 185 my normal

I tried a couple of diets they did

I felt like I was beginning to weight loss

struggle I did not understand before, you know, but now I definitely understand it. I tried Metabolife and what it did for me the first change that I saw is it gave me some of that control back. I felt like I could control of my MOFFITT REPORTING ASSOCIATES (301) 390-5150

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appetite and I could control the over eating before it got too ugly. The energy that it gave me lifted me

out of that depression that I was beginning to really get deeply into and over the course of a year I lost 50 pounds. Now I am pretty much at my ideal weight and because of the new understanding that I have for the weight loss struggle that a lot of people go through, I'm currently studying to be a personal trainer so that I can help other people lose weight because it hurts and it is really hard. I am also trying to

achieve my ultimate goal to be a professional singer and I know that if I did not loss that weight I would not have the confidence to pursue that and that is MOFFITT REPORTING ASSOCIATES (301) 390-5150

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what Metabolife has done for me. DR. JONES: Sands. MR. SANDS: James Sands.

Thank you very much. Mr.

Thank you, Ms. Ellis.

Good afternoon.

My name is

I appreciate the opportunity to have a

few minutes with you this morning or I am sorry this afternoon. I, too, am a consumer of Metabolife 356.

I am not affiliated nor employed by Metabolife 356. They have, however, reimbursed me for my travel expenses here today. I am 55 years old, I reside in Michigan, I am married, I have for children ages 24, 19, 9 and 6. Additionally, I have two grandchildren 31/2 and the newest addition being 7 months. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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Approximately three years ago I weighed over 260 pounds with a waist size in the excess of 45 inches and a 171/2 inch neck. My cholesterol was over

260 and I had elevated blood pressure and I suffered from acid reflex and snoring during the evening, at night. Our company doctor, Dr. Mueller, who gives us our physical exams described me and I quote, "as a grossly overweight male, who was woefully out of shape." I could not tie my shoes without being out of

breath I could not play with my children as they wanted me to and I would have liked to. I felt

something had to be done and if I could be blunt, my lovely wife, Rita, was not exactly an enamored with MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the rotund fellow which I had become. In search to find a path toward health and hopefully a happier existence I began to try a series of odd and often extreme diets each being a more dismal experience than the last. Next I turned to the

supplement drinks where you substitute a drink for a meal. I found all of this to be unhealthy and

unrewarding punishment, and not in the least effective. Finally, a friend introduced me to Metabolife 356 and I immediately realized the significant difference between this product and my previous experiences. First Metabolife 356 tells you this is not MOFFITT REPORTING ASSOCIATES (301) 390-5150

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something you take in place of eating.

Next they tell

you and direct you that you ought to get into a healthy diet and into an active fitness program. the beginning I knew I had made a good choice. From I felt

invigorated, more alert, and was not lacking in my dietary intake. Metabolife 356 lead me to where I am today, I have shed over 80 pound, lost 12 inches from my waist, my blood pressure is typically about 115 over 75 or better. My cholesterol is below 200 and I sleep

at night like the proverbial baby. And, oh, yes, Rita enjoys the changes also. I enjoy playing basketball. I love buying rack-size clothes. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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In my entire experience with Metabolife 356, has been positive, there has not been a negative. additionally those friends and associates who have enjoined me in the program have similar experience. As example, my good friend Fred Westen and his wife Linda, daughter Meretha, and son Todd, have together lost enough weight to equal or exceed my current weight of 178 pounds. And on a selfish note the best thing is I am no longer asked to play Santa Claus at the neighborhood Christmas party, thank you very much. DR. JONES: Cohen. MS. COHEN: I am a 36 year old, I have two Thank you, Mr. Sands. Ms. And

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kids one is 6 and one is 11. DR. JONES: record. MS. COHEN: Yes, my name is Debra Cohen. Please state your name for the

I am a satisfied consumer I am not being paid to be here today, however, I am being reimbursed for my travel expenses. Believe it or not, these pants that I have right here, which are 26 wide, these use to be my pants. Now, I am a size 5/6. several diets to lost weight. Before I tried

I lost but,

unfortunately, the weight came back, especially after having my two kids. I broke my ankle in three places,

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and I have a steel plate and six screws on each side of my ankle bone. around. It was impossible for me to get

Then I met an old friend at a party who I asked her, What do you do?" She

looked great.

said, "I took Metabolife 356 and it really works." My doctor has always said, "Before starting any diets, please always check with me first." did and my doctor said that was fine. The date I started Metabolife 356 was May 18th, 1998, the day my life changed. When I started I So I

was 251 pounds, my total weight loss is 117 pounds. Metabolife 356 cut my appetite, gave me lots more energy to walk longer distances, and not be out of breath like I used to be. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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During the course of two years of the weight loss I had her checkups with my doctor and at the end of my weight loss I had a complete physical. Everything came back great and my doctor said I have never looked better or been healthier. I feel so much better I have lots of energy and because of this I am able to work out on a regular basis. I am a lot more confident in myself. It is

such a wonderful feeling to go shopping and fit into anything I look at which can be kind of dangerous. While I was losing the weight people would come up to me and say, "Wow, you look different. did you do?" What

It would make me feel good to tell them

what I have done and possibly get them started on the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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same path.

In closing I would like all of you to know that I now weigh 134 pounds and I have never felt better about myself or have been happier in my whole life. Thank you for your time. DR. JONES: Piazza. MS. PIAZZA: Hi, my name is Lori Piazza. I am not I Thank you Ms. Cohen. Ms.

am here on behalf of Metabolife as well. being paid for being here today. My story is a little different.

My whole

life I've been overweight, my mother is overweight and from the age of eight I remember being teased about my MOFFITT REPORTING ASSOCIATES (301) 390-5150

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weight by other children in my class. not stop there.

The weight did

Seventh and 8th grade were awful I

went to a parochial school and I was a cheerleader and had to where a uniform. I was so large that our

suppliers at our school didn't even make uniforms large enough for me. So, in 7th and 8th grade my

mother had to make my uniforms and my cheerleading outfits which never looked the same as the other girls; the material was often off a tad so you could tell that it was a tad different and it was embarrassing to me. I have tried everything from exercise to diet programs and even Fen-Phen for about six weeks until it was taken off the market. Nothing worked and

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I never went below 175 pounds as an adult. After hearing about Metabolife I decided to give it a try. There was a lot of success stories I began in

about the people who had taken Metabolife.

October of 97 after receiving my wedding pictures back. A 237-pound bride in a size 22 dress wasn't anything in those pictures that I could order and want on my mantel. The product worked exactly how I was told. I began to have increased energy and never felt hungry and I lost the weight. It was amazing. The first two I felt

months of Metabolife 356 I lost 15 pounds.

wonderful, the increased energy, I felt, was a wonderful addition to my life. I began to go out and

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experience life again.

My eight-year-old daughter

told me she likes me better now that I take Metabolife 356. I don't just come home from work and sit on the couch and watch TV. We actually do things now. I

go to the beach, ride a bike, play baseball, soccer, and I'm a certified scuba diver. I am a much better

mother now and spend quality time with my daughter doing things. So I'm going to try and change the

cycle in the next generation, exercise and good eating habits. Metabolife 356 has changed my life. I just My

turned 30, I'm in the best health I've ever been.

blood pressure has gone down 30 pounds or 30 points a MOFFITT REPORTING ASSOCIATES (301) 390-5150

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direct contribution to losing the weight. promoted three times in the last 18 months.

I've been I always

had the intelligence to do my job, but I was lacking the confidence in myself to try new things. I am in happy, healthy relationship; no more mental abuse from any man again. Metabolife 356 has

enabled me to lose weight and change my whole life. Over the last two years I have lost 107 pounds going from 237 pounds to currently the 130. DR. JONES: Sandra Lynn O'Brien. MS. O'BRIEN: Hello, my name is Sandra Thank you. And

Thank you Ms. Piazza.

O'Brien and I am a happy consumer of Metabolife. I am not being paid to be here today. MOFFITT REPORTING ASSOCIATES (301) 390-5150 I

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want to share my story. Last year at this time I was an unhappy 175 pounds, just existing in this life, not interested in anything, unmotivated to do anything but work, eat, and sleep. As I look back on that time I guess I was

in a minor depression. One day I met this attractive and physically fit country singer who showed me a little attention. I realized that I still liked positive feedback from the opposite sex and suddenly I became aware of my appearance. I did not like what I saw. I was determined

to look in feel better in case is cowboy ever came back through town. I knew I need to make the dreaded

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commitment to diet, but all my past attempts had failed miserably. Then I heard about Metabolife on I thought to myself, okay,

193 POC country radio.

I'll give it a try but if it does not work I know where you are. I am really glad that I decided on

Metabolife because I was able to lose 35 pounds within the first six months and during the rest of the year I lost another six pounds. Within 20 minutes of taking Metabolife, I experienced a boost in energy without the nervousness. I was in a good mood for a change and I wanted to get out of the house and do things, like take a walk around the neighborhood. This increase in physical

activity caused me to become thirsty for water and at MOFFITT REPORTING ASSOCIATES (301) 390-5150

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mealtime I was satisfied with one plate of food instead of two. I can eat whatever I want but no longer do I have to take comfort by over indulging in food. I can

still eat chocolate and potato chips, but I just don't eat the whole bag anymore. All of my friends are so

impressed with the results their first question is: how did you do it? I have one? Now several of my friends are also happy consumers of Metabolife. And not one of us has I'm very happy And their second question is: Can

experienced any negative side effects.

Metabolife, but more importantly, I'm happy with myself. Thank you, Metabolife. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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DR. JONES:

Thank you, Ms. O'Brien. I had not gotten

That's the last scheduled.

word that anyone else had requested public comment. So I will begin a few concluding remarks. want to recap first of all that this was not a hearing, this was a public forum in which information, particularly scientific information and data, was solicited to be presented. And I have to say, we are I

not disappointed in what we've heard in these two days. We believe that indeed we did hear some new We heard some studies that are soon to We very much look forward to the

information. be published.

publication of those studies and we're very pleased with the information that we have received during this MOFFITT REPORTING ASSOCIATES (301) 390-5150

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meeting. As you know, going into this meeting, we were asking four specific questions and we've got, now, I believe, two full days of transcripts to draw on to see how well our questions were answered. The Office on Women's Health convened the forum because of our concern about women's use of dietary supplements containing ephedrine alkaloids for weight control, but also we're interested in how indeed men and women differ in their approaches to products to their reasons for use, to their understanding of products, and where we are alike, where we are different. A, you know, in this

particular case, it seemed appropriate for us to MOFFITT REPORTING ASSOCIATES (301) 390-5150

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undertake hosting this forum. be able to do so.

So we were pleased to

And the purpose of the meeting being informational and not regulatory we hope that we have provided through our structure and through trying to allow enough time for both public comment, as we've just concluded a session, as well as questions and answers both from a panel of colleagues from within the government as well as from the floor that we have succeeded in getting many things out before all of us for all of us to hear. I would like to remind you as well that for any subsequent comments, thoughts about the meeting, thoughts about information that might become MOFFITT REPORTING ASSOCIATES (301) 390-5150

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subsequently available or just other reasons that you might want to provide further comment, please provide those to the FDA docket, the public docket, that opens as of tomorrow. If the you send those to our

contractor our contractor, the Miatech Corporation, who did all the logistics for the meeting, they will simply forward them. They have to go into the docket

anyway. So save a step we had some problems with illegible faxes, some that got sort of sideways. And just so that we don't risk multiple generations, send things directly to the docket after this meeting so that you can be assured that your information is accurately taken in and reflected in the docket and can be subsequently displayed. MOFFITT REPORTING ASSOCIATES (301) 390-5150

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We've requested the meeting be transcribed, and as I'd said the transcript will be available, we hope -- we expect within 15 working days and information about how to access the public docket and submit your comments is included. I believe there was

an information sheet on the table outside in the registration area Now, the panel that we have put together represents many of the agencies within the Public Health Service; The National Institute of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, as well as the Department of Defense, people with expertise that I and/or my office, the Office on Women's Health doesn't MOFFITT REPORTING ASSOCIATES (301) 390-5150

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necessarily process, and we asked the panel to join us to hear what was being said and to ask the clarifying questions to help us to be sure that the information was contained in the record could indeed contribute toward answering the questions that were in the original meeting notice. So, my office, the Office on Women's Health, will be developing a report of the meeting based on what we have heard. -We will be providing that report

developing that report and submitting it to the

Office of Public Health and Science and it will become then also part of the public docket. And let me just say then in terms of what we have heard. As I've said, we've been very pleased MOFFITT REPORTING ASSOCIATES (301) 390-5150

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that we believe we've heard some information that was new; it was certainly new to a lot of us here. also had reviewed the docket. We had extensive We

materials available to us and we were pleased that you all brought what you did from industry from academe even private citizens who brought their experiences. We've heard a lot about the adverse event reports and that because of the way the system is structured for collection of adverse event reports being largely anecdotal it is of limited scientific usefulness for analysis purposes. But as is often the

case in anecdote, the plural of which is not data and yet very often can inform the development, developing a hypothesis, it's a starting point for research, for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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devising and improving systems for surveillance, and so forth. And we heard many people in their

presentations suggest that there is more work that needs to be done in this arena. That current use of dietary supplements containing a ephedrine alkaloids for weight loss and ergogenic goes beyond traditional uses in traditional Chinese medicine. While some of the thermogenic

effect was suggested in some of the early text, as a couple of speakers suggested, the traditional use did not take into account the uses in which we see the products being applied today. Several industry presenters called for good manufacturing practices, labeling, and one even MOFFITT REPORTING ASSOCIATES (301) 390-5150

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generously provided information about his product and his adverse event data. And if helped us really

realizes and reflected the fact that industry really is a critical partner in monitoring potential adverse events. A number of research needs were identified, needs for long-term studies, for clinical research on efficacy on looking at the mechanisms and interactions of a ephedrine and caffeine at the isomers, and the differences between natural and manufactured products, and the role that different members of the class, the stereo isomers, the different most-basic chemical activities occur, the role of those different family members of the family of ephedrine alkaloids and the MOFFITT REPORTING ASSOCIATES (301) 390-5150

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role that they might play in either providing benefit or even being associated with risk if risk is indeed detected. So these are all research questions. There were many, many other questions that were raised that couldn't be answered because of the lack of data. And I think there will be, you know,

very rich information in the transcript that will help all of us in generating some research questions. The information presented does make it difficult to quantify human exposure and to monitor trends. Because, as was well-acknowledged, in

industry presentations and in Q&A, the doses don't necessarily translate to numbers of people. You can

infer some numbers, but, you know, we all know we need MOFFITT REPORTING ASSOCIATES (301) 390-5150

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much better systems. there as well. in that effort.

And so we have a ways to go

And, again, industry can be a partner

We heard calls for public education and better understanding of the risks of the labeling guidance that's provided on the products and so forth to help the public better understand what it is they're using and how they use it, and several calls as well for a systematic review of the literature that, again, could further contribute to a research agenda. So, you know, in our view and in my view personally, it's been a very rich two days. time very, very well spent. It's been

And I want to thank you

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all for what you've brought to the meeting. I just wanted to share with you three things that you might be interested in, in terms of what is going on. Many of you have asked about research

funding or protocols, would we be interested in protocols and so forth. And my panel colleagues from

NIH have shared with me that there is an RFA, a request for applications -- I always call them RF whatevers because I can never keep track, but I think

it is request for applications that is available for botanical and it is accessible through the web site for the National Center for Complementary and Alternative Medicine. You can access that HTTP:

NCCAM.NIH.Gov, or if you simply go to NIH.gov navigate MOFFITT REPORTING ASSOCIATES (301) 390-5150

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yourself through, you can search the Web site on botanical and get to that announcement. In addition, the botanical centers program that NIH funds will be addressing issues of standardization of botanical products for clinical use, and there may be subsequent announcements under that effort as well, that some of you may have some interest in. So, again, go into NIH's home page on the web and look at what is available. Then finally for those of you interested in hearing about some of what we are learning about women's use in particular of complementary an alternative medicines, dietary supplements, and other MOFFITT REPORTING ASSOCIATES (301) 390-5150

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products for their health, there is a conference this fall called "A Community Prevention Research in Women's Health Conference" that is cosponsored by a long list of us in the Public Health Service in the Department of Health and Human Services as well as by the American Heart Association, the University of Alabama School of Medicine here in Bethesda, October 26 and 27 at Maseurr Auditorium. I have one brochure with me on that. It's a

preliminary program but October 26 and 27, Community Prevention Research in Women's Health and it will be reviewing what we have learned from the women's health initiative, from the study of women's across the nation, and then from a small study that my office MOFFITT REPORTING ASSOCIATES (301) 390-5150

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particularly led on behalf of many agencies in the Public Health Service looking at conventional and complementary alternative medicine practices around menopause. So those of you who are interested in those subjects we've got tons of data that will be shared with you over those two days. I recognize we had planned for the meeting to go on a bit later and never wanting to be one to absolutely closed the door on any further opportunity for issues or concerns to be raised in the context of this meeting, I would offer that it's about 4:15 and if there are issues or concerns that people wish to get on the record now, if you would proceed to aisle MOFFITT REPORTING ASSOCIATES (301) 390-5150

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microphones and state your case quickly, we will do that and we will plan to close by 4:30 so that people have time to break down the equipment that's here, people need to be catching airplanes or trains or other scheduled transportation can do so. MS. ZECHZER: Hanna Zechzer, I just have a

couple of questions about the people that were here from Metabolife. Some of them said they were not

being paid, but they did not clarify who was funding their trip. DR. JONES: We will note that in the record.

MR. BETZ: Secretary Jones, and panel members, my name is Mike Betz and I'm being paid today -- I'm an attorney and I'm being paid by Omninutrition MOFFITT REPORTING ASSOCIATES (301) 390-5150

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International, Inc. in Dallas, Texas. I had signed up to speak and when I got here my tag was at speakers table, but I was not on the agenda. And I'm not quite sure why that is, but since

I have his brief opportunity. DR. JONES: If you were late signing up,

that may have been, because we did actually cut off at one point. But I apologize. MR. BETZ: I have this opportunity now.

Briefly and you should receive a copy of it, I've submitted it for the record. Omnitrition previously has had several experiences with these AERs and had been on the AER list and I've been dealing with the FDA and following these AERs for some time and one of MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the topics that you all had asked about was the available data. And I just want to comment briefly on the available data. Both with respect to the prior AERs In 1996, I

from 1996-97 and the more recent AERs.

believe it was, I attended a meeting of the working group of the food committee of the Food and Drug Administration. I think that's what they called it,

they kept changing the name. At that time there were 20-some-odd places where Omnitrition appeared in the AERs with ephedrarelated effects. People who had ephedra-related, And of those 20-

supposedly ephedra-related symptoms.

some-odd reports, I actually went through them all MOFFITT REPORTING ASSOCIATES (301) 390-5150

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one-by-one because the company was very concerned about them. As a responsible distributor was Well, 12 of

concerned that they had these reports.

the reports the percents contained ephedra whatsoever. They were Vitamin C supplements, things that contained absolutely no ephedra. And I stood before the FDA and

one-by-one, I went through these AERs, and I watched them all write them down. take these off the list. And I told them, please, This is just you're trying

to make big numbers out of this. And I came back a year later and I said -and they now handed us new AERs. And there they were,

the same ones that I watched everybody write down were still on the list. These products that had no

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ephedra.

And I said, "How can it be that I'm back

here a year later after I flew all the way here and watched you all write it down and you still have all these products that contain no ephedra." And the reason I say that is because we need to look at and question the reliability of the available information contained in the AERs. This time there's two AERs that affect Omnitrition that I want to briefly discuss and then I'll close. Dr. Ruth Strauss, a cardiologist has prepared a report which I have submitted, or comments which I have submitted on two of the AERs. One

involved a woman who smoked a pack a day, was obese, MOFFITT REPORTING ASSOCIATES (301) 390-5150

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had hypercholesterolemia, hyperlipoidemia, exiting hypertension, severe hypertension and took these products and ultimately ended up in the hospital and needed bypass surgery. number on it is 12452. That's one of the AERs. The

And they claim that -- I guess

the claim is that somehow this woman's health problems are related to the small amount of ephedra she was taking twice a day at about 24 milligrams. Actually,

it turned out the amount that she was taking was substantially less than that, it was about 12 milligrams twice a day. The second place in the AERs, and I say this just to point out the available data that the FDA has assembled, the woman had two prior brain surgeries and MOFFITT REPORTING ASSOCIATES (301) 390-5150

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had a history of seizures, took the product and had a seizure and, of course, the seizure, I guess, it's implied by its presence in the docket was somehow responsible for, or was caused by the woman's use of two rounded teaspoons of a product containing ephedra alkaloids -DR. JONES: If you could wrap up in about 30

seconds, the timing -MR. BETZ: Certainly. Both of these reports

are contained -- or comments on both of these reports are contained in Dr. Strauss' analysis of the AERs. would ask you to look at those. I would ask you just I

to consider, and I would ask you, Dr. Jones, to consider when you submit your report to the FDA about MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the available data, consider the quality of the available data that is there and the fact that there are significant problems with the available data. I

mean, you've discussed the post hoc -- problem with the type of analysis that comes from these AERs, but I want to tell you, it goes beyond that. It goes beyond

that in terms of just the flawed data that's in there with products that don't contain any ephedra whatsoever where they're reporting these types of incidents. I thank you for your time. DR. JONES: MS. WOOD: Thank you, sir. Dr. Jones, members of the panel,

I am here to thank you from the bottom of my heart for MOFFITT REPORTING ASSOCIATES (301) 390-5150

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the opportunity to be here for the last two days and to share with you my personal experiences as a victim of ephedra. I have been thin and healthy all my life,

as I said earlier, and ephedra did help me lose the temporary gain which I had as a result of hormonal imbalance, but my concern when I leave here today, because I am a graduate student and I plan to do a lot of research for female hormonal imbalance, menopause, and now ephedra is going to be on my list of research. My concern is, if ephedra could put me in a dangerous mental zone, I am so scared for all the truckers that take ephedra, for all the teenagers that take ephedra, for people who go to health food stores and 7-11 and take ephedra and get on the road and can MOFFITT REPORTING ASSOCIATES (301) 390-5150

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cause severe accidents, mental breakdowns, I am concerned for that aspect of ephedra effect. And I

would request you to please pay consideration to that aspect of ephedra. Thank you. Thank you, Ms. Wood. Ms.

DR. JONES: McAfee. MS. McAFEE:

The one thing in this meeting

that I really feel strongly needs immediate follow-up is the nortoxicity presentation by Dr. Ricaurte when there hasn't been a lot of talk about. I really want

to see if somebody else can duplicate that, I want to know what that means, there's a lot more work that needs to be done on that, and I think that should be a very high priority because of the number of people MOFFITT REPORTING ASSOCIATES (301) 390-5150

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these medications.

If there is a damage, even perhaps

a very subtle damage, that's just something that we need to know about. DR. JONES: Thank you, Ms. McAfee.

Seeing no one else rising from the floor, I wish to thank you all very much for your coming, sharing your time with us, your experiences, your data, all the other information that you had to present. It has been a very productive two days.

Thank you all very much. [Whereupon, at 4:45 p.m., the forum was concluded.]

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C E R T I F I C A T E This is to certify that the foregoing public meeting on The Safety of Dietary Supplements Containing Ephedrine Alkaloids, held on Wednesday, August 8, 2000, was transcribed as herein appears, and this is the original transcript thereof.

____________________ Gerald Brooks Court Reporter

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