Vol. II pg. 190 Dr. Blackburn
"I want to see whether if we vote for any of these levels, recommended levels that have come down 10-fold in 2 days, or in 10 months [since the 1995 working group meeting], down to 2 milligrams, what we're really doing, and I think only the people from the industry can tell us. Then if we know what we're doing, then we go ahead and do it. If we reduced it to those kind of doses with these kind of restrictions and this sort of quality control, is there going to be any market and are we banning the drug for use as a good supplement, in which case we might as well go and vote that way?"
     But, the banning of ephedra herb products is not possible under DSHEA because the FDA has only very poor quality and unconvincing evidence that using ephedra herb products per label instructions poses a substantial and unreasonable risk to those using it.  It cannot meet its burden to prove these alleged risks. Hence, the FDA now wants to reduce the permitted label single dose and permitted label total daily dose and permitted label number of days of use so that none of the benefits of using ephedra will be obtainable by consumers, thereby causing these troublesome (to the FDA) products to dissappear from the market.  This is a ban by the back door.

Vol. II pg. 209 Dr. Jasinski
"...my view is that you're probably going to wind up with a dose of no more than 40 to 60 milligrams of total ephedrine alkaloids per day.  The reason for this, just doing this and coming back again, from being a pharmacologist and a clinical psychopharmacologist and looking at this in terms of what we know about ephedrine, we know that from studies which have been done over the last couple of years that you can take anhydrous caffeine and give it to people and get amphetamine-, cocaine-like effects, maximizing at about 200 milligrams, between 100 and 200 milligrams."
     Right. Note that the FDA approved dose of caffeine in OTCs like NoDoz is 100 mg. to 200 mg.  An unwanted overstimulating effect would be particularly noticeable to an adult who had not experienced coffee before, just as most adults in the U.S. probably have not experienced ephedra herb before.  However, in the U.S., most adults already have tried coffee and, if they had an unpleasant reaction, avoid it.

Vol. II pg. 210 Dr. Jasinski
"...somewhere about 2.5 milligrams of amphetamine...is equivalent to about 10 to 15 milligrams, 12.5 milligrams, of ephedrine. So one would look at this to keep it in this dose range of what people are using as the average or maximum sort of caffeine dose."
 

Vol. II pg. 221 Dr. Ricaurte
"I think it's telling that just from October '95 until here we are 8, 9, 10 months later, we've already gone from an estimated safety level down 10-fold, and I'm not quite sure on what basis we're doing this."

Vol. II pg. 222 Dr. Ricaurte
"With the issue of a margin of safety, I'm left at somewhat of a loss because for a margin of safety you really have to have some indication and what I've heard this afternoon is that all purported purposes of use are being taken off the table and it leaves you with, well, what the heck are we going to use this for. If there's no clear answer to that, then the margin of safety, quite frankly, has to go to infinity because you can't do a risk/benefit when we don't have a perceived benefit." (emphasis added)
     The FDA has made this conclusion inevitable by requiring that the committee disregard any evidence concerning the efficacy of ephedra for those purposes for which it is being most widely sold: weight loss and energy.  When you cannot consider any benefit, then of course even small risks will seem unacceptable.

Vol. II pg. 222 Dr. Ricaurte
"Question number 3 [the possibility 'of significant harm' and 'serious adverse effect in at least one individual']--I'm not sure that there's many compounds that can satisfy that requirement, so the answer is, no, I can't, but I'm not sure that it's entirely a fair question with regard to the ephedra alkaloid per se."
     And it is not the definition of harm mandated in DSHEA, either.

Vol. I pg. 145 Mr. Israelson
"... the standard you are asking us to look at is significant harm, which has two sub-definitions, I'm just curious how you arrived at that definition, specifically in its two subparts, which is different from the statutory definition within the law." (emphasis added)
     Because FDA has chosen to charge the Committee with a definition of harm contrary to that intended by Congress, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that fits within the ambit of Congress's will, and re-propose a new Rule.

Vol. II pg. 231 Dr. Ziment
"So my recommendation is that ephedrine, as such, has always been prescribed by orthodox physicians in a dose of about--a minimal dose of 15 milligrams 3 times a day for adults and proportionately less for children. That should be the baseline dose for the orthodox, and I believe it's safe even if used for a prolonged period of time because I certainly used it that way. I've looked at the literature and I don't see much evidence that that dosage is harmful."

Vol. II pg. 236 Dr. Wang
"What margin of safety? What I did is just took a 10-fold safety factor from the OTC maximum level per day basis for, again, ephedrine alkaloid."
     It would be interesting to consider what would be left on the market if all products had to be taken on the basis of a 10-fold safety factor.  Oxygen, water, sugar, and total daily caloric intake all fail the tenfold safety test.  DSHEA does not authorize the FDA to impose a 10X safety margin, either.

Vol. II pg. 249 Dr. Jasinski
"Thirdly, I think there is a telling point which was made that you have to be very cautious. I have been both historically and been involved in people that have made decisions that have driven things underground.  I think what amazed me is watching the anabolic steroids of people passing laws because they got concerned about athletes using these. We have now a whole underground economy with anabolic steroids being imported which are being used which are less pure than those which were manufactured as pharmaceuticals coming in, and that's creating public health problems and uncertainties."
     Remember that Dr. Jasinski is an expert on drug abuse.  Heed his warning.

Vol. II pg. 249 Dr. Jasinski
"And I would think it would be better to encourage industry to come in with a position which they can defend on what they're going to do voluntarily and that this would be legitimate to set the standards. It would be much better than trying to impose a policy."
     Far better, and far more effective.  The FDA seems to think that if it makes a rule and points enough guns at enough people, any rule will work.  This one won't.  It will cause far more harm than it prevents, an all too common result at the FDA.

Vol. II pg. 250 Dr. Croom
"We've got to find a better way, I would say, to come together and talk about how do we impact the public health because there are benefits coming here and not just risk..."

Vol. II pg. 255 Dr. Dentali
"When I came here, I understood that my mission is the common-sense one, is to reduce the risk with these products. So when I got the updated version of the adverse events, I wanted to do a rigorous analysis of those, particularly with respect to the October [1995] recommendations.  For me, that would be to look at the adverse reactions that are consistent with ephedrine use and to eliminate the ones that are not, to look at ones that are consistent with the levels of ephedrine that were recommended in October or that were proposed by a few members and eliminate those that were not, to look at the ones that were combined with other known stimulants and eliminate those reports, to look at the ones that were resulting from clear abuse and to eliminate those, to look at the ones that were made with only the herb and the herb extract and to include those and exclude all the others, and to exclude the ones that were resulting from chronic use.  And I feel that that wasn't done and I feel that that was very important for me to be able to have a handle on beginning to look at the risk as it was presented to me regarding the adverse effects for us to determine for traditional use and traditional forms what is the danger of using this botanical."
     A very cogent objection.

Vol. II pg. 262 Dr. Ricaurte
"So the pendulum has swung from one extreme of being very cynical to trying to regard this as a product, a dietary ingredient that should be used by consumers and not be over-regulated, not be in a position where the FDA or the medical profession or the scientific advisory group is put into a position of over-regulating something that adult Americans may wish to use under safe conditions. Those have not been defined."

Vol. II pg. 262 Dr. Ricaurte
"I think as long as the concern for some of the use is misuse and abuse, I find it somewhat, again, disingenuous to make recommendations, well, we're going to limit the dose from 20 down to 10 or down to 5. As a consumer, I don't have to be particularly adept in mathematics to realize that if now the tablet or capsule or a spoonful contains only 5 milligrams, I take 2 or I take 3 or I take 4. So the dose considerations and frequency of use suggestions, while I recognize that they're well-intended and I appreciate what the efforts are in terms of looking at the reality of the use of the product by a population of individuals who may be predisposed to misusing or abusing the product, I don't think those are particularly effective safeguards."
     They are worse than ineffective; they will substantially increase the risk of harm by destroying the integrity and credibility of all the label instructions and warnings on ephedra dietary supplements.

Vol. II pg. 265 Mr. Israelson
"...I share the view that has been expressed that if you ban this product, you'll drive it underground and create a bigger problem."

Vol. II pg. 270 Dr. Woosley
"...as I think you pointed out, Dr. Ricaurte, there is no risk/benefit ratio you can establish when you don't have a known benefit..."
     There are benefits known to the Committee; the FDA just refuses to allow the Committee to consider them, thereby guaranteeing a proposed Rule that is not based on reason or evidence.

Vol. II pg. 274 Dr. Inchiosa
"...in the experiences in Ohio, the Canadian study, even the information collected was that young people who are abusing the drug largely get it from ephedrine hydrochloride from over-the-counter preparations. I heard that statement made that a large number of the use by young and abuse by young was from over-the-counter preparations, not the difficult process of extracting something from a nutritive supplement."

Vol. II pg. 197 Dr. Kessler
"It's [the judgment on a safe level of ephedrine] based on the record before individuals. We have alot of different individuals with a lot of different expertise. We'll take that into account. For some, it'll be the information that  has been presented over the last two days. For some, it'll be information that has been presented both in the working group and over the last two days. For others, they certainly can draw upon the literature that they're familiar with and their own expertise, but  it's the record before them as has been presented. I think that the starting base is over the last two days, certainly."
     But the data supplied over the last two days is of very poor quality and, as admitted by Dr. Love,  has not yet been peer reviewed.  Moreover, vital OTC adverse event safety data has been expressly removed by the FDA.

Vol. II pg. 204 Dr. Chassy
"We are talking about a dietary supplement which I as a consumer, when I walk into a store that sells these products, have every reason to believe are at least as safe as the foods in my diet that I mean to supplement and so I would hold them up to a very high standard of expected safety."
     As we have shown, ephedra herb dietary supplements are already much safer than foods in common form.  The bottom line is that consumers have unrealistic beliefs about the presumed safety of foods and need badly to be educated about that.  Educating consumers about the risks of foods is of far greater importance than that of dietary supplements, on the basis of the record, yet the FDA has done a very poor job of providing needed information on food risks to consumers.

Vol. II pg. 157 Dr. Jasinski
"...the critical question has been the relationships of these deaths and your data and the particular interpretation versus the interpretations we've heard, and there has been a conflict."
"...and the essence of the scientific culture is we have peer review."  (emphasis added)

Vol. II pg. 158 Dr. Jasinski
"My question is have you prepared a report on your data, how you collected it, how you interpreted it and what conclusions you've made, and have you submitted this to internal review within the agency or outside the agency?  And, similarly, have you taken the report from this ad hoc committee and submitted it to a peer review?" (emphasis added)

Vol. II pg. 158 Dr. Love
"We, of course, intend to do that, but we were analyzing this data even over the weekend to supply the information to you at this committee meeting here." (emphasis added)
     They were in such a tight schedule that they didn't have time to do the internal review or submit the data and their conclusions to peer review.  So they just rushed into the meeting without that.  Where is that peer review that they intended to do?

Vol. II pg. 248 Dr. Jasinski
"...I have been disturbed to some extent by what is really the lack of either scientific scholarship or scientific quality through all of this. ...it's like the question I asked Dr. Love in terms of did she write a report, was it reviewed, was it peer reviewed, making this available before you start getting these discussions." (emphasis added)

Vol. II pg. 26 Mr. Betz
"...although I pointed out last time [meeting in 1995] that these three products contain absolutely no ephedrine alkaloids, they're still in the report as part of this larger report."
     The report that the FDA  provided to the Committee was carefully purged of data pertaining to OTC drugs containing the same ephedra alkaloids as the dietary supplements, but apparently little or no care was taken to remove adverse reaction reports for dietary supplements that contained no ephedra alkaloids whatsoever.  The FDA's report would never pass peer review.  It must be noted that the FDA report as given to the Committee would not meet the Supreme Court's Daubert criteria for weeding out junk science.

Vol. II pg. 53 Mr. Shapiro
"...it has also been widely reported that the individual [college student who died in Florida] ignored clear warnings on the product and took at least twice the daily dose all at once. Those same reports indicate that his companions all took three times the daily dose without incident. In addition, according to the police report, cannabis and another product, Nexus, consisting of the herb kava-kava were found in the hotel room."  "It is noteworthy that the autopsy report contains no findings at all relating to the presence of other substances such as cannabis, cocaine, amphetamines or barbiturates. It appears that no tests were performed for the presence of these and other substances which is most certainly very strange."  "Yesterday, Dr. Love said that the tests were performed. If so, the results were not made a part of the autopsy report." (emphasis added)
"The Ad Hoc Committee on the Safety of Ma Huang submitted to you as part of their package the declaration of Dr. Joseph Brazelica, a toxicologist, which sets forthe many deficiencies in the autopsy report and concludes: 'That it is not possible to determine from the report of autopsy to a reasonable degree scientific certainty that the cause of death was the ingestion of some quantity of a product containing ephedrine.'" (emphasis added)

Vol. II pg. 110 Dr. Askew
"Clarification of the autopsy."  (This refers to the autopsy mentioned earlier in which there was some question as to what the coroner found in the consumer's bloodstream.)

Vol. II pg. 110 Dr. Love
"The clarification of the autopsy report is that information on the consumer's negative ethanol and cannabis levels are in the record."

Vol. II pg. 147 Dr. Love
Dr. Love clarifies the Florida autopsy report, which found ephedrine alkaloids and caffeine positive, while a long list of others tested for were negative, including cocaine, amphetamines, strychnine, cardioregulatory drugs, and others.

Vol. I pg. 229 Dr. Fukagawa
"...in letters that we've received from Mr. Appler from the Ad Hoc Committee on the Safety of Ma Huang and from Mr. Shapiro at Bass and Ulman, who also referred to the 20 year old from Florida, suggest that his situation was perhaps not as clear-cut with the presence of other compounds in his hotel rooms etc., and the lack of  toxicological reports or analyses." (emphasis added)

Vol. I pg. 229 Dr. Love
"Actually all of his blood levels for anything else were negative, and the coroner directly attributed it to the use of this product."  "Now, where is the exception is this is the highest level of ephedrine alkaloids that we have analyzed in any product." (emphasis added)
     Why didn't the FDA show the autopsy report?  Mr. Prochnow said that this data was not in the autopsy report.

Vol. II pg. 65 Dr. Calvin McCausland from Enrich International, Orem, Utah
"...if you look at the 20-year old in Florida and the autopsy report, you will find reasonable doubt. That reasonable doubt has been spelled out by Dr. Borzelica, from the Medical College of Virginia and it's in those three volumes that you have before you."  "There are other deaths that have been listed that have reasonable doubt. They took ephedrine a week before, reportedly. There is none in the tissues of the autopsy. Reasonable doubt."(emphasis added)

Vol. I pg. 59  Michael Davidson, M.D.
Dr. Davidson's qualifications and his review of the adverse event reports on behalf of the NNFA.  See Adverse Event Clinical Summaries at Tab F referred to by Dr. Davidson.  He reviewed the case files underlying 191 of these adverse event summaries.  Of these 191 case files, he categorized 84 of the events to be serious and 107 not to be serious. "Of the 84 serious events, I found that 13 were not related to ephedra. I classified eight as unknown for lack of information. Thirty-four were remotely related; 22 were possibly related, and seven were probably related."
pg. 61 "Six deaths were possibly associated with ephedra. In two cases, not enough information was provided to consider an assessment. Two deaths were related to consumption of toxic doses of ephedra."  "Of the six deaths possibly associated with ephedra, three were due to sudden death and cardiac abnormalities were present on autopsy in all three individuals.  Two of the possibly associated deaths were due to strokes. One of these deaths was due to a strong [stroke?] that occurred in an obese individual male who was using multiple other supplements and who had basilar artery atherosclerosis on autopsy. Another was a fatal stroke that occurred in a 44 year old female due to a left internal carotid artery occlusion. She had a very strong family history of strokes. The sixth possibly associated individual whose death was from a seizure was also on phenteramine, Apidex, a prescription drug for weight loss.  All of these six possibly associated deaths occurred on the high dose ephedra products."  [How high?]
     "There were ten cases of non-fatal myocardial infarction. Of these ten cases, four, in my judgement, were not related to ephedra. In another three reports, there was not enough information provided to make an assessment. In three cases of myocardial infarction, a possible association with ephedra exists. In all three of these reports, post-myocardial infarction angiograms revealed normal coronary arteries.  All three individuals were consuming high-dose ephedra in combination with caffeine.
     There were 17 reports of non-fatal strokes. Three cases were unrelated or remotely related to ephedra-containing products. In four additional cases, not enough information was available for me to make an evaluation. In the remaining ten cases, a possible association with ephedra products exists.
     In four of the ten possibly associated cases, these individuals had significant hypertension of hyperlipidemia diagnosed prior to the stroke. One case involved a male with a dilated left ventricle as a possible source of emboli. The remaining five cases involve premenopausal women. At least two of these women were on oral contraceptives. One of these was noted to be a cigarette smoker and the other was diagnosed as having a positive lupus inhibitor. In the three remaining possibly associated cases, oral contraceptive use is unknown and one was a cigarette smoker, and one of these women was on the product for over a year before she suffered as intracerebral hemorrhage. All but one of these stroke patients--the exception being the woman with a positive lupus inhibitor--were on the high-dose ephedra containing products.
     There were 16 reports of seizures. Of these cases, the majority of seizures occurred in individuals with either a history of seizures or an abnormal EEG on follow-up. As I am not a neurologist, I made only a limited evaluation of these cases.
     In summary, with the exception of two cases of toxic exposure to ephedrine, there appears to be only infrequent possible associations of ephedra-containing products with severe adverse reactions. These infrequent possible associations are characterized by coronary or cerebral thrombosis and seizures.
     Of the 105 non-serious adverse events that I reviewed, these are characterized by increases in blood pressure, tachycardia, nervousness, and dizziness. These symptoms are expected potential side effects of ephedra-containing products. These side effects appear to be dose-related, occurring in greater frequency in the high-dose ephedra-containing products.
     To test the hypothesis that low-dose ephedra products below 15 mg. per dose, which is the recommended dose of the working panel, do not have a significant rate of adverse events, I reviewed the adverse events associated with the ephedra product containing less than 15 mg. per dose.  These products account for over one-third of all the ephedra-containing products, but only approximately 7% of the adverse events.  Of these 42 adverse events on low-dose products, there were only two serious events that were possibly related to the product.  I mentioned one was the young woman who had a stroke who also had a positive lupus inhibitor, and the other was a 55 year old female who had a seizure.
     Based on my medical review of the ephedra adverse event reports, I have the following opinions:
     Number one, last year's [1995] recommendation of the ephedra working group and those of the dietary supplement trade associations are appropriate. The two main issues that appear to affect adverse reactions are the dose of the ephedra and the quality assurance of the product.
     The proposal to lower the ephedra alkaloid content to 60 mg. per day with 15 mg. of ephedra per dose, expressed as ephedrine equivalents, provides a margin of safety based on the fact that the vast majority of both serious and non-serious adverse reactions occurred with products that exceeded these dosage thresholds.
     Improved good manufacturing practices and quality assurance will provide dosing consistency within product batches. Because dosing consistency is important, I would add to the recommendation that products that can be easily mis-dosed not be permitted. (emphasis added)
     The ephedra working group also recommended very appropriate warnings and labeling instructions. I would also include on the label cautions against the use by smokers, those taking oral contraceptives, and those with a history of cardiovascular or seizure disorders.

Vol. II pg. 107 Dr. Georgitis
"Dr. Love, I have a question for you, in terms of the serious aadverse events below the median value of 20 milligrams per serving of the ephedrine alkaloids, do you have a percentage as to how many of those out of the total adverse events?

Vol. II pg. 107 Dr. Love
"We haven't expressed our data in that form because, of course, we have only a relatively few samples where we've been able to collect the sample that the consumer was using at the time of the injury and be able to analyze that." (emphasis added)
     This is clearly a very important question concerning how the numbers of reports of adverse events related to the amount of ephedrine actually consumed.  Here, the FDA admits that it doesn't know that.  This is a very poor reflection on the follow-up of the FDA after receiving such reports.

Vol. II pg. 108 Dr. Kessler (to Dr. Love)
"...you asked for relatively clean cases that didn't have a lot of confounding factors--where you have a medical examiner, where you have a sample--could you just go through those cases and at what levels you saw significant adverse reactions?

Vol. II pg. 108 Dr. Love
"Well, unfortunately, I don't  have all the data in hand here, but there are a number including very recent cases for which we yet don't have all information on how the consumer used the product but a more recent death, again, it appears to be a cardiomyopathy case. The total alkaloids in that case are 10 milligrams, total alkaloid. As I stated a death from what appears to be long-term use of a product containing 10 milligrams of total ephedrine alkaloids."
     The FDA here mentions a single case of what "appears" to be long-term use of a product containing 10 milligrams of total ephedrine alkaloids. No information is provided on what else the individual was taking or how the FDA knows how much of the product the individual was using, or how often.

Vol. II pg. 109 Dr. Kessler (to Dr. Love)
"And just go through that case. I mean just so we have some--I mean the best data that we have."

Vol. II pg. 109 Dr. Love
"Well, as I stated I don't have all those details."

Vol. II pg. >


Transfer interrupted!

'm sorry."

This is a shockingly small amount of total information on what is supposed to be their best or one of the best cases providing evidence concerning adverse reactions versus dose.

Vol. I pg. 228 Dr. Chassy
"I'm trying to get at something that gives us some feel for where we begin to see a dose-response correlation, because as it stands now, you have effects all across the board. But you do have fewer products with very high amounts of ephedrine alkaloids in them, and where you have fewer of those products on the market, you seem to have around the same number of cases of adverse effects reported, which suggests that there is a dose-response relationship."

Vol. I pg. 234 Dr. Jasinski
"...you're showing this increase [in relative incidence], and how much of this increase is actually an increasing showing that we're getting a growing public health problem that's going to project, or how much of this increase is related to the change in the way you've done things in publicizing this and asking people to report in?"
     Indeed, the FDA's publicity concerning the adverse events reports they received in which injuries were associated with (but not necessarily caused by) the use of ephedra alkaloid containing dietary supplements has resulted in reports on CNN and a recommendation not to use ma huang in the July 1997 Reader's Digest (pg. 85).  The FDA's warnings have also appeared repeatedly on network TV.  There has been no similar FDA publicity during this period concerning adverse events reports the FDA has received for ephedra alkaloid (ephedrine, pseudoephedrine, or phenylpropanolamine) containing OTC products.

Vol. II pg. 277 Mr. Guzewich
"...I want compliment Dr. Love on what she's trying to do in running a surveillance program. I've been doing that for 16 years for food-borne disease. It's not an easy task and she  has a very difficult and often thankless  job, and you're reporting for poor quality data and when it's the only data you can get ahold of and you're trying to make decisions on that kind of data..."
     Yes, the data are poor quality, and the FDA cannot improve the quality of these data by dumping them into the lap of a hapless committee, which is then told to ignore any benefits of the products.  Moreover, the FDA failed to present the committee with other available and important information.  The FDA could have prepared a report on the adverse events and had the data peer-reviewed, but it did not.  The FDA should have had data available on the spontaneous occurrence of MIs and strokes and seizures in the population using the ephedra products, but did not.  The FDA should  have had data available on the occurence of adverse side effects in the OTC ephedrine containing drugs for comparison, but they did not.

Vol. II pg. 282 Mr. Guzewich
"...sophisticated choices about products that might be at risk to them, I think, is more than we can reasonably expect consumers to have to assess when they choose between different bottles on the shelf. Therefore, consumers should be able to purchase a product in the market and find it safe at normal use, and even at abused levels..." (emphasis added)
     More and better information on labels and in labeling and other methods of education for consumers so that they can make choices is a far better and safer choice, in our opinions, than to treat consumers as unmitigated idiots that must have decisions made for them by committees assembled by the FDA and given by the FDA poor quality data and unreasonable limitations (eg., do not consider any benefits) to make decisions for them.  The final point made by Mr. Guzewich, that a product in the market should be safe at virtually any dose is impractical and ridiculous.  Consumers must be expected to assume some personal responsibility for their use of products, at least extending to their compliance with label instructions.  Moreover, DSHEA requires that dietary supplement products not be unreasonably unsafe when used as directed, not to be safe no matter how badly abused.

Vol. II pg. 285 Dr. Chassy
"Several [committee members] have noted the quality of the data, and without blaming the FDA staff in any way because they are to be commended, they need to build a cause-and-effect relationship, however hard that may be. I think they especially need to do it because DSHEA sets us in a situation where they [FDA] may find themselves in court being asked to bear the burden of proof that the ephedra alkaloids have done damage in a specific case, and they may find themselves doing that again and again and again."
     The above comment speaks for itself.  FDA data from this Committee meeting would never meet the Supreme Court's Daubert criteria for weeding out junk science.  Because of this, FDA must withdraw the Rule, re-convene the Committee, provide sound peer reviewed data to the Committee members in advance, reach a new conclusion that fits within the ambit of Congress's will, and re-propose a new Rule.
     It doesn't seem that the thousands of pages of materials that the FDA presumably distributed to each of the committee members before the meeting were actually read by most of them,  judging by the questions asked of the FDA during the meeting.  These questions included what are the background numbers of cardiac deaths and seizures among the population using ephedrine-containing dietary supplements and what were the levels of adverse reports for OTC products containing similar amounts of ephedrine as ephedrine-containing dietary supplements).
     The answers to these questions are key information in interpreting the meaning of the adverse reports.  Yet, at the meeting, Dr. Love (FDA) did not have this information.  Either the committee members did not do their homework or the FDA did not have key information available either before or at the meeting or both.

.pa
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.fo Version of 14 August, 1997, 12:13 AM PDT;     page #

    SPECIFIC PROPOSAL FOR A CONSTITUTIONALLY ACCEPTABLE LABEL

     The FDA cannot ignore the limits placed on it by the First Amendment of the U.S. Constitution.  We have discussed these limitations at some length (often quoting Supreme Court Justices) in a prior section on general labeling considerations.  The FDA has no constitutional authority to prohibit statements that are true and not misleading.  The FDA does have the authority to prohibit statements that are false or misleading, and to require reasonable disclosure of hazards on the labels and labeling of dietary supplements sold in interstate commerce.  This discussion considers the application of these limits and powers to a specific product.

     Commenters Pearson & Shaw license formulations containing approximately 1.8 grams of ground ephedra herb per one tablespoon serving (the amount of ephedra herb being adjusted on the basis of herb lot analyses so that one tablespoon of product contains a total of 20 mg. of ephedra alkaloids).  No ephedra extracts are used in this product, there is no caffeine or other methylxanthines, and it contains no synthetic ephedrine, pseudoephedrine, or phenylpropanolamine.

     Since whole ground herb is used rather than an instantly soluble ephedra alkaloid extract, blood levels of the alkaloids increase much more slowly as the ground herb slowly releases its alkaloids, thereby providing a time-release effect and reducing the risk of adverse effects in sensitive individuals.

     Products containing real ephedra herb when ingested are pharmacokinetically substantially different from products containing ephedra alkaloid extracts; regulating them in an identical manner is arbitrary, capricious, and contrary to fact.

     With a one tablespoon serving, this product contains approximately 1.8 grams of ephedra herb (adjusted to standardize the amount of ephedra alkaloids) per serving of tea, quite conservative compared to the traditional tea serving of 1.5 to 9 grams (usually 5 to 6 gm.) of ephedra herb referred to on page 20 of the proposed Rule.

     On the basis of the FDA's proposed Rule, we propose the following new label for this product:

NOTICE: CONTAINS EPHEDRA HERB WHICH CONTAINS EPHEDRINE ALKALOIDS.
FDA MANDATED SERVING SIZE:: 1 TEASPOON (contains 6.7 mg. total ephedra alkaloids). The FDA believes that a serving size of 8 mg. or more would present an unreasonable risk of injury or illness.  Taking more than this recommended serving may cause heart attack, stroke, seizure, or death.
TRADITIONAL SERVING SIZE: 1 TABLESPOON (contains 20 mg. total ephedra alkaloids from approximately 1.8 grams of herb). This serving size is NOT approved by the FDA.
DIRECTIONS: Add 4 ounces of hot or cold water to one serving of mix. Stir briskly and drink. DO NOT EXCEED THREE SERVINGS A DAY!      On the first day, drink one-half serving before breakfast. For the next two days, drink one serving before breakfast. For the next three days, drink a second serving before lunch. From then on, drink a third serving one hour before dinner. Do not take more than one serving within a 6 hour period. Keep in a cool, dry place. Keep lid tightly closed when not in use.
FDA MANDATED INSTRUCTIONS: Consult a health care provider before use.  Do not use this product for more than 7 days.  Risk of adverse reactions increases with duration of use.  Starting and stopping use may increase risk of adverse reactions.

WARNING: KEEP OUT OF REACH OF CHILDREN. NOT FOR SALE TO OR USE BY PERSONS UNDER THE AGE OF 18.  DO NOT EXCEED RECOMMENDED SERVING SIZE OR FREQUENCY.   May cause insomnia in sensitive individuals, especially if taken too soon before bedtime. Consult your physician before use if you are taking asthma medications, decongestants, anorectic (appetite suppressing) drugs, antidepressants, or cardiovascular medications. Use of caffeine containing beverages may increase the stimulating effects of this product. Do not use this tea if you are pregnant or lactating, if you have high blood pressure or cardiovascular disease (especially stroke or cardiac arrhythmia) or a family history of these disorders, diabetes, difficulty in urination due to prostrate enlargement, seizure disorder, glaucoma, hyperthyroidism, or psychiatric disease.  Do not drink this tea within 14 days after taking MAO (monoamine oxidase) inhibitor drugs. Stop use and call your health care professional if dizziness, headache, heart palpitations, or tingling sensations occur. Stop use or reduce serving size if sleeplessness, tremors, nausea, or nervousness occurs. Stop use if symptoms of allergy to this product develop.

     Note that these instructions increase the serving size from the initial one-half of 6.7/20. mg. ephedra alkaloids once per day to the final 6.7/20 mg. three times per day over a period of seven days.  This schedule is designed to reduce the incidence of adverse effects by allowing the development of tolerance to the CNS and cardiovascular effects of the ephedra alkaloids.

     The Caution on page 43 of the proposed Rule has been modified in several respects:

     1)   "Warning" is used rather than "Caution," as is tentatively proposed by the FDA.

     2)   Rather than "Seek advice from a health care practitioner if you are pregnant or nursing or if you are at risk or are being treated for high blood pressure, heart, heart, thyroid or psychiatric disease, diabetes, seizure disorder, stroke, or difficulty in urination due to prostrate enlargement." these and other conditions are all listed as "Do not use if..." absolutely contraindicated conditions.  We do not believe that these conditions should be required as absolute contraindications (rather than checking first with your doctor), as we have expressed it, but the stronger form of warning we have used should not be prohibited. It would be arbitrary, capricious, and not in the public interest for the FDA to standardize the warning in such a way as to prevent the listing of additional contraindications or to prevent contraindications from being listed as absolute rather than relative.  FDA should require a minimum list of contraindications but must never prohibit additional or stronger contraindications than their minimum required list.  For example, rather than "Consult your health care professional before use if you are taking an MAO inhibitor or any other prescription drug." we believe that we should be permitted a label warning that taking an MAO inhibitor within the last 14 days is an absolute contraindication.

     3)   "Taking more than the recommended amount will not necessarily increase benefits." has not been used because it is both weak and lacks credibility.  Worse yet, this lack of credibility may tend to reduce the credibility of the other warning statements.  Instead, we have used the FDA's much stronger warning: "The FDA believes that a serving size of 8 mg. or more would present an unreasonable risk of injury or illness.  Taking more than this recommended serving may cause heart attack, stroke, seizure, or death."  We do not believe that this stronger warning should be required, but the FDA should not prohibit a stronger warning than the one that is proposed.

     4)   We have not instructed the user to consult with their health care professional if they are taking any prescription drug.  Such consultations may easily cost $50 or more; people will generally ignore this warning.  It is unreasonable to expect customers to take this action; they simply won't do it.  It is unwise to put a warning on the label that one knows will be generally disregarded, for such warnings promote a general disregard for other far more important warnings.  As an alternative to this ineffective warning, we believe that we should be allowed to say "Consult your physician before use if you are taking asthma medications, decongestants, anorectic (appetite suppressing) drugs, antidepressants, or cardiovascular medications."  If the FDA Rule requires the label to carry "Consult your health care practitioner before use if you are taking an MAO inhibitor or any other prescription drug," this statement will be prefixed with the truthful non-misleading "FDA mandated Warning:", which is protected speech under the First Amendment.

     5)   Users of ephedra dietary supplements should not be instructed to call a physician if "sleeplessness, tremors, nausea, or nervousness occur," since these are not likely to be precursor symptoms of a potentially serious or life-threatening adverse reaction.  Instead, they should be instructed to "stop use or reduce serving size."  If users are instructed to make an expensive call to their doctor because of a minor matter like temporary insomnia, they are less likely to call their doctor when "dizziness, headache, heart palpitations, or tingling sensations occur," which may be symptoms of far more serious problems such as hypertension, stroke, or a potentially serious cardiac arrhythmia.  There is a very real cost to diluting major warnings with minor warnings.  If the FDA's Rule requires the label to carry their preferred warning, it will be prefixed with the truthful non-misleading "FDA mandated Warning:", which is protected speech under the First Amendment.

     6)   The split label:  This label identifies FDA mandated information as such.  This label contains two different serving sizes, one mandated by the FDA and identified as such, and an alternate serving size that provides a traditional amount of ephedra herb per serving.

     Identifying FDA mandated information as such is truthful and non-misleading.  Indeed, without such identification, the customer would be misled into believing that the product manufacturer voluntarily agreed with this information and had voluntarily placed it on the label.  FDA has no constitutional authority to prohibit the truthful identification of the FDA as the source of this information and its mandatory nature.

     The FDA mandated serving size is one teaspoon containing 6.7 mg. ephedra alkaloids.  This serving size is clearly identified as being recommended by the FDA.  Moreover, the FDA's reasons are clearly and forthrightly stated, "The FDA believes that a serving size of 8 mg. or larger would present an unreasonable risk of injury or illness.  Taking more than this recommended serving may cause heart attack, stroke, seizure, or death."  This is the strongest warning regarding serving size that the FDA has proposed in the Rule.  If this were the only serving size described on the label, we believe the FDA would have no objections.

     The traditional serving size is one tablespoon containing 20 mg. of ephedra alkaloids.  It is in fact at the low end of the traditional ephedra herb dosage range.  The statement that this is a traditional serving size is truthful and non-misleading; the FDA has no constitutional authority to prohibit it.  An FDA prohibition of this traditional serving size statement would be a content based prior restraint caused by FDA's not wanting people to know this information.  The FDA doesn't want people to know this information, because if they learn of it, people may not behave the way the FDA wants; customers may choose to take the larger servings rather than the FDA's preferred smaller ones.  The First Amendment prohibits the manipulation of consumer behavior by restricting the communication of truthful, non-misleading information.

Quotes from the U.S. Supreme Court decision in 44 Liquormart v. Rhode Island (1996 WL 241709 (U.S.))
     "...a State's paternalistic assumption that the public will use truthful, non-misleading commercial information unwisely cannot justify a decision to suppress it."  (at 8)
     "It is precisely this kind of choice, between the dangers of suppressing information, and the dangers of its misuse  if it is freely available, that the First Amendment makes for us." (quoting from Pittsburgh Press Co. v. Pittsburgh Comm'n on Human Relations, 413 U.S. 376, 93 S.Ct. 2553, 37 L.Ed.2d. 770 (1973)
     "In case after case following Virginia Pharmacy Bd., the Court, and individual Members of the Court, have continued to stress the importance of ... the impropriety of manipulating consumer choices or public opinion through the suppression of accurate 'commercial' information..." (J. Thomas, concurring, at 21)

     The First Amendment of the US Constitution absolutely prohibits the FDA from banning labeling that is neither misleading nor deceptive.  Indeed, Pearson & Shaw, et. al, have a First Amendment lawsuit against the FDA Commissioner before the U.S. District Court for the District of D.C. at this very moment.  (Civil Action No. 95-1865 (EGS), District Court for the District of Columbia)  If the FDA proceeds with its proposed Rule, it is likely to be sued again.

     Note, too, that this product does not describe any non-traditional uses (or indeed, any uses at all) on the label or labeling.  Nearly all customers of this product use it before meals to help satisfy appetite (the reason most foods are eaten) as an adjunct to their own personal weight loss or weight maintenance program.

     In addition to considering the constitutional issues that an FDA attempt to ban this label would raise, we suggest that the FDA consider the pragmatic public health value of allowing the vendor to provide a maximum serving size that is likely to be heeded.  The FDA's serving size is so small that consumers will generally ignore the FDA's dose limitation.  This is especially likely for the many millions of people who have had prior experience with ephedra herb products.

     Without an alternate serving size that is more likely to be heeded by the consumer, the consumer may take unnecessary risks.  The consumer will know that the FDA has radically reduced the dose of the supplement, so they will take more -- perhaps far too much more than needed to compensate for FDA's dosage reduction.

     For the sake of both liberty and government legitimacy under the constitution, FDA must not attempt to prohibit ephedra dietary supplement labels from displaying truthful non-misleading traditional dose statements.

     For the sake of consumer safety, the manufacturers of existing products must not be prohibited from informing the consumer of both the size of the old dose and the new dose.  If FDA prohibits the publication of this information on the labels and in the labeling of existing products, they will not only be violating the First Amendment ban on content based prior restraint in an unconstitutional attempt to manipulate the public's behavior by denying them information, FDA will be dramatically increasing the risks to the public of accidental overdose. Moreover, the FDA's credibility will drop further as its actions are scrutinized in public fora such as health newsletters and the Internet.

     The alternate serving size provides 20 mg. of ephedra alkaloids, a little more than the 17 mg. median dose and substantially less than the 30 mg. mean dose of products that FDA identified in its market survey, and with which millions of consumers may be familiar.  By providing the customer with an alternate serving size near the low end of the traditional dose range, there is a reduced risk of large accidental overdoses taken by consumers who reject FDA's recommended dose but who otherwise don't know how much to take.  If the FDA continues to arrogantly delude itself by believing that it can control people's behavior by enforcing ignorance through their proposed rule, they will succeed only in violating the constitution, discrediting themselves, and causing greater risk and harm through uninformed and unintentional gross overdoses.

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                   ONE SIZE DOES NOT FIT ALL:

            EPHEDRA HERB IS NOT EPHEDRA HERB EXTRACT

         EPHEDRA HERB EXTRACT IS NOT SYNTHETIC EPHEDRINE

FDA'S PROPOSED RULE ANALYTICAL METHOD WILL NOT PROVIDE ACCURATE MEASUREMENTS OF THE BIOAVAILABLE EPHEDRA HERB ALKALOIDS IN PRODUCTS MADE WITH ACTUAL EPHEDRA HERB  RATHER THAN WITH EXTRACTS

       Food Advisory Committee meeting August 27-28, 1996

     When actual ephedra herb is ingested rather than an instantly soluble ephedra alkaloid extract, blood levels of the alkaloids increase much more slowly as the ground herb slowly releases its alkaloids, thereby providing a time-release effect and reducing the risk of adverse effects in sensitive individuals.

     Products containing actual ephedra herb when ingested are pharmacokinetically substantially different from products containing ephedra alkaloid extracts; regulating them in an identical manner is arbitrary, capricious, and contrary to fact.
 

Vol. I, pg. 146 Dr. Jasinski
"...we already know if you put medications in a certain sort of matrix that's natural may alter this from -- the pharmacology from the pure medication in terms of absorption and rate of limitation [elimination?]."

Vol. I, pg. 146 Dr. Yetley
"We are not aware of data on the botanicals that would answer the questions you have."  "But those are the scientific issues that we're asking this group of experts to discuss and to make some recommendations on."

Vol. I, pg. 147 Dr. Inchiosa
"The herbs themselves might contribute to affecting the alkalinity of the urine, which is going to affect the half-life of the drug, which is going to influence the steady state plasma concentrations."

Vol. I, pg. 157 Dr. Hsieh
"Do you want us to look at the compounds, or do you want us to look at the herb? And the two should not be equated." (emphasis added)

Vol. I, pg. 158 Dr. Yetley
"I understand that the two are not equated, but both could be ingredients in the products that we're seeing. So you need--the botanical is certainly very common, or at least extracts of the botanical, concentrated extracts of the botanical are very common in these products. But it is also possible that some of these products may have synthetic form, so it's really both." (emphasis added)
     Didn't the FDA do any analyses of the products in their market review to determine whether there was synthetic ephedrine added, whether there were any ephedra alkaloids other than ephedrine in them (as would be the case with a genuine ephedra herb extract), and what percentage contained the actual herb rather than an ephedra alkaloid extract?
     Even though the FDA's Dr. Yetley correctly states, "I understand that the two are not equated,..." FDA's proposed Rule does precisely that; it treats ephedra herb products exactly the same as ephedra herb alkaloid extract products.
     Because of this, FDA must withdraw the Rule, re-convene the Committee, reach new conclusions that correct these errors, and re-propose a new Rule.

Vol. I, pg. 180 Dr. Jasinski
"Just a question of Dr. Obermeyer. What is the extraction efficiency? Have you done this? If you take the herb and make a tea, what is the extraction efficacy?" (emphasis added)

Vol. I, pg. 180 Dr. Jasinski
"I'm not talking about your chemical analysis. If somebody makes a tea, what is the extraction efficacy?" (emphasis added)

Vol. I, pg. 180 Dr. Obermeyer
"That depends on brew time. So if you would steep it for one minute versus three minutes versus someone that forgot it in their tea cup for ten minutes, that would be much different."  (emphasis added)

Vol. I, pg. 181 Dr. Jasinski
"What's the maximum extraction efficacy you can do if you make a tea and you put it in the pot and you boil it up?" (emphasis added)

Vol. I, pg. 181 Dr. Obermeyer
"We have not worked on that for the maximum. What we would extract it for would be methanol to be the maximum out of an herb..." (emphasis added)
     The FDA has no idea how much of the ephedra alkaloids would actually be extracted and ingested from a cup of tea made with actual ephedra herb (rather than ephedra extract or synthetic ephedrine HCl).  Furthermore, the FDA has no idea how much of the ephedra alkaloids would be extracted in the human gut from ground ephedra herb consumed as an iced tea which is consumed without brewing.
     The numbers the FDA's Dr. Obermeyer is providing are the results of chemical analysis that have very little if anything to do with how a tea containing actual ephedra herb (rather than ephedra alkaloid extract) is used. There is no hot methanol extraction, either in the consumers' tea pots or in the human GI tract.

Vol. I, pg. 181 Dr. Jasinski
"I mean, the question before the group is, you know, in terms of dose and what you're going to get and what the safe dose is going to be. If you don't know what people get out of the herb when they brew it, there's no way to answer this question." (emphasis added)
     FDA's proposed Rule treats products containing actual ephedra herb exactly the same as products containing ephedra herb extract which is arbitrary, capricious, and contrary to fact.  Because of this, FDA must withdraw the Rule, do its laboratory homework, re-convene the Committee, reach new conclusions that correct these errors, and re-propose a new Rule.

Vol. I, pg. 181 Dr. Obermeyer
"Right. Most of the products really are encapsulated or tablets of the ma huang extract. This is what we are seeing mostly. And very few products are actually the herb root as a tea."  (emphasis added)
     FDA's Dr. Obermeyer here admits that Dr. Jasinski is correct in his concerns that ephedra herb products are not the same as ephedra alkaloid extract products.  Dr. Obermeyer also admits that "very few" of the products that the FDA is considering in this meeting "are actually the herb ... as a tea.".
     If the FDA wishes to proceed with their proposed Rule without gathering the needed new data on actual ephedra herb products, holding new Committee meetings, and making major modifications in the Rule and analytical method, FDA should exempt all products from this Rule that contain actual ephedra herb rather than ephedra herb alkaloid extracts or synthetic ephedrine.  To apply the proposed Rule to products that contain actual ephedra herb (not ephedra herb alkaloid extracts or synthetic ephedrine) would be arbitrary, capricious, and contrary to fact.
     Technical note: Although we have an herbal text which refers to the "twigs and roots" being used in ephedra herb teas, we do not believe that use of the roots is a common commercial practice.  Ephedra Sinica (and related species) is a perennial; leaves (which look rather like green twigs or pine needles) and the stems that bear them are harvested, not the roots.  By leaving the roots and some of the stems and leaves, the plant's stems and leaves grow back next spring, and can be harvested year after year.  This is particularly important since Ephedra Sinica is a slow growing plant.  If grown from seeds or cuttings, several years will pass before the plant can be harvested.  We have seen a lot of the ephedra herb that is imported into the U.S., but we have seen only the needle-like leaves and the stems that bear them; we have never seen any ephedra roots.

Vol. I, pg. 184 Dr. Fong
".... The data as I sit here running through my mind is when you talking about extraction with methanol, and then people taking the capsule with the total extracts or with the herb in there, and what is the bioavailability?  We really don't know what the patient is getting, at least in my mind." (emphasis added)

Vol. I, pg. 184 Dr. Obermeyer
"I believe the literature would probably support your thoughts." (emphasis added)
     This is a member of the FDA staff  here implying that the FDA has not done a search of the literature on the amount of ephedra alkaloids which are bioavailable from the actual herb (as opposed to a methanolic extract), let alone done the research themselves!  Furthermore this is a tacit admission that these are substantive relevant considerations.

Vol. I, pg. 186 Dr. Dentali
"My understanding is that these products that are the industrial supply for what companies are buying and then placing in the capsule mixed with other ingredients are extracts of water and alcohol, not pH manipulated. So you may have high temperature water, alcohol, and that's why the concentrations typically are not higher than 6 percent..."
     This refers to the process currently used to produce the commercially available ephedra herb extracts.  These ephedra herb extracts are clearly made in a different way - with a hot methanol/water mixture - than how a consumer would brew tea (no methanol), which in turn is different than direct ingestion of the actual ground herb, which would not involve the high temperatures used in brewing.  Products made with ephedra herb extract are different from products where the actual herb is brewed in hot water, which in turn are different from products where actual ground ephedra herb is ingested without high temperature brewing.

Vol. I, pg. 186 Dr. Jasinski
"So you just put it into a pot and add alcohol and water and you boil it up?"

Vol. I, pg. 186 Dr. Dentali
"Pretty much."

Vol. I, pg. 186 Dr. Dentali
"Evaporate it off, put it on a carrier."
     There is much faster gut absorption of the alkaloids when on a carrier (from an ephedra herb extract) as compared to the rate of gut absorption when a person swallows actual ground herb.

Vol. I, pg. 152 Dr. Dentali
"I did happen to come across two studies, and I can get the reference to you and possibly a copy of it.  One was conducted in Japan. They had been seeing--they reported seeing a high incidence of adverse effects recently with products containing ephedrine alkaloids. They realized that their data was based on ephedrine and not the extract, and they conducted an animal trial with equivalent amounts of ephedrine alkaloids and comparing the two--in mice, I believe. ... Generally, they found that absorption levels were about half time-wise and the concentrations in the plasma were about half." (emphasis added)
     Ephedra herb extract is not ephedrine, and its pharmacological effects are not the same as ephedrine.  Most of the products producing serious adverse reactions were abused ephedrine containing products, some misbranded as ephedra herb extract products. It is very common to analyze a so-called ephedra product and find nothing but ephedrine; these products do NOT contain either ephedra herb extract or ephedra herb.

Vol. I, pg. 276 Jones
"The available data indicates that though ephedra herb shares some of the properties of ephedrine itself, it also possesses beneficial properties in its own right and is furthermore much better tolerated on an alkaloid equivalence basis." (emphasis added)
 
Vol. II, pg. 80 Mr. Appler
Continues to analyze the Texas reports.  He states "...of the 94 reports in the Poison Control Center for North Texas, there were exactly two that were related to herbal and two others related to ma huang. In every one of those cases, as Dr. Patrick points out, there was no permanent injury of any sort and all the results seen there were mild." (emphasis added)

Vol. II, pg. 257 Dr. Dentali
"The other area that I feel that didn't receive adequate scientific attention was the differences between the herb, the herb extract, and ephedrine." (emphasis added)

     Ephedra herb extract is not ephedrine.  Ephedra herb is not ephedra herb extract; the FDA proposed Rule analytical method LIB No. 4053 may be suited to products containing ephedra alkaloids from ephedra herb extract; we will leave comments on this to those who use ephedra herb extract in their products.  We use only ephedra herb (no alkaloid extract, no synthetic alkaloids). FDA's proposed analytical method is incapable of accurately measuring the amount of bioavailable ephedra alkaloids contained in the actual herb.
     When a consumer drinks a serving of ephedra herb tea - made with the actual herb, not an alkaloid extract - the extraction of the ephedra alkaloids from the herb in the hot water filled teacup is less than when the herb is extracted in a boiling methanol-water solution in an extract factory or in the FDA's proposed Rule analytical method.  No consumer uses a boiling hot methanol-water mixture to make his or her tea.
     When a consumer ingests ground ephedra herb in an iced tea that has never been boiled, the extraction of the ephedra alkaloids occurs slowly in the consumer's gut at 37oC, not in a boiling mixture of methanol and water.  The FDA's proposed Rule analytical method will greatly exaggerate the real deliverable ephedra alkaloid content of actual ephedra herb products.       Remember, the FDA's method was designed to measure the alkaloid content of products made with the alkaloid extract; it has not been validated for products

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