TO:  Dockets Management Branch (HFA-305)
     Food and Drug Administration
     12410 Parklawn Dr., Rm. 1-23
     Rockville, MD 20857
     Comments for Docket No. 95N-0304
 

                           Before the
                  FOOD AND DRUG ADMINISTRATION
                          Rockville, MD
 
 

In re: Proposed rule:           )
Dietary Supplements Containing  )
Ephedrine Alkaloids             )    Docket No. 95N-0304
Fed. Reg. 62(107): 30678-30724  )
June 4, 1997                    )

                                             18 August, 1997

      INTRODUCTION TO COMMENTS OF DURK PEARSON & SANDY SHAW

     Durk Pearson and Sandy Shaw are scientists and authors, maintaining residences in Nevada and California.  Their three best-selling books include the million copy #1 best-seller Life Extension, a Practical Scientific Approach (Warner Books, 1982).
     Their fourth book, Freedom of Informed Choice: FDA v. Nutrient Supplements argues that truthful, non-misleading speech on labels and in labeling is protected by the First Amendment against FDA censorship and discusses the cost to public health of such censorship.
     Pearson and Shaw design dietary supplement formulations and license them to small marketing and manufacturing companies.  The formulations designed by Pearson and Shaw include dietary supplements containing ephedra herb.  Pearson and Shaw and their licensed marketers and manufacturers (all are small businesses) would suffer substantial economic harm if the Proposed Rules regarding the use of ephedra herb in dietary supplements were adopted.  Furthermore, Pearson & Shaw believe that consumers of ephedra herb dietary supplements would actually be endangered by the Proposed Rule.

     Pearson & Shaw do not believe that the FDA has met their burden of proof under DSHEA that ephedra herb dietary supplements are unreasonably unsafe when used as directed; on the contrary, the evidence presented by the FDA shows that extant ephedra herb supplements with extant labeling are generally safer than food in common form.  FDA's labeling proposals, moreover, are an impermissible prior restraint that violate the First Amendment of the U.S. Constitution.  Pearson & Shaw request that FDA withdraw this Proposed Rule, attempt gather evidence that meets their DSHEA burden of proof, and if successful, reconvene the Committee, and develop a new Proposed Rule that, unlike the current Proposed Rule, is not arbitrary, capricious, contrary to fact, and does not violate the First Amendment.  Please see Pearson & Shaw's 107 pages of Comments (attached).
 

                                   Sincerely,
 
 

                                   Durk Pearson
                                   Sandy Shaw
.pa
.pn1
.fo Version of 12 August, 1997 4:10PM PDT;   page #
.lh12
          Pearson & Shaw's Comments to the FDA on         Ephedra Alkaloid Containing Dietary Supplements

All quotes, with page numbers given, are taken from the transcript of the August 27-28 1996 Food Advisory Committee meeting on ephedrine-alkaloid containing dietary supplements.

     1.   The FDA believes that ephedra contains ephedrine, a pharmacological agent, and is therefore a drug, not a food.  As the FDA's Dr. Elizabeth Yetley said (Vol. I pg. 37): "Foods would be used for non-therapeutic purposes."
     This is a very narrow view of foods.  Many foods are used for therapeutic purposes, that is to treat or prevent disease, including garlic, fish oils, prunes, cranberry juice, low fat foods, yogurt, and vegetables and fruits.  The FDA allows a health claim (may reduce the risk of cancer) for fruits and vegetables, as is also true for oat bran and wheat bran.
     Dr. Hui: "It's very difficult to distinguish between what is a food and what is a drug. Think about glucose. Glucose is a drug when somebody is hypoglycemic and glucose is a deadly poison for someone who is very hyperglycemic." (Vol. I pg. 122)
     Dr. Jasinski: "...I was curious in your definition of lack of pharmacologic effect as being a defining factor [of a food]. I have been drinking coffee, and I've got a tachycardia from drinking the coffee right now. So by your definition, coffee beans would not be allowed to be marketed because you can get a pharmacologic effect from coffee beans." (Vol. I pg. 124)
     The notion that foods can be separated from drugs on the basis that drugs have a pharmacological effect and foods do not is false.  At the most basic level, foods have a psychoactive effect by providing a sense of well being and energy following eating and the cascade of profound biochemical effects that result from eating, such as increase in blood glucose levels and alterations in release of neurotransmitters and hormones in various areas of the brain and body.  Carbohydrates, for example, have been shown to increase the passage of the amino acid tryptophan across the blood-brain barrier into the brain, where it is used by the brain in the manufacture of serotonin, a natural calming and sedating agent.  Some people crave carbohydrates when anxious, thus using food as a tranquilizer, a pharmacological effect.  It is well known that a few drops of sugar in water on the tongue of a crying infant often calms it; here sugar water is used as a medicine.  This traditional infant tranquilizer is called a "sugar tit."
     Many components of foods are known to have psychoactive effects and are consumed largely for those psychoactive effects, including coffee, tea, chocolate, and caffeine containing soft drinks.  Recently, in fact, it has been discovered that anandamide (believed to be the natural ligand for brain cannabinoid receptors) and oleylethylamide, an inhibitor of anandamide hydrolase (the enzyme that breaks down anandamide) are found in chocolate, which may account for chocolate's production of a temporary sense of well being in many chocoholics.  The expression "chocoholic" itself implies an intense craving and chocoholics often vie with each other over who has the most extreme chocolate craving.  Paul Rozin of the University of Pennsylvania and his coworkers have found that 23% of premenopausal women crave chocolate in the perimenstruum, the days just before and after the start of menses.  Those women also rate chocolate as being more pleasurable than other people do.  These are pharmacological effects.
     Tea (Camellia sinensis) is one of the most commonly consumed beverages in the world.  In traditional Chinese medicine, tea is recognized to have various health and medicinal effects and is used as a treatment to help digestion, eliminate phlegm, diuresis, reduce sleeping time, improve eyesight, for detoxification, and to eliminate body heat (Han et al, "The Screening of Anticarcinogenic Ingredients in Tea-Polyphenols," Journal of Nutraceuticals, Functional & Medical Foods Vol. 1 No. 2, 1997, pg. 8).  The health effects of tea are becoming known to growing numbers of Westerners as a result of the publication of papers in peer-reviewed scientific journals, which effects include antimicrobial, diuretic, antipyretic and immune function regulation, as well as possible preventive effects in cardiovascular disease and cancer. Traditional Western use of tea was based on tea's tonic and diuretic effects. Indeed, the British craving for tea's stimulating effects was so strong that it led to a severe balance of trade deficit with China, which in turn resulted in the British opium war against China.  Thus, tea is both a food and a medicine and has pharmacological effects.
     Other foods consumed for psychoactive and pharmacological effects include beer and wine. Certainly some of the effects of these beverages are due to their alcohol content, but the same amount of alcohol ingested in the form of different alcoholic beverages provides a significantly different experience due to other active ingredients, such as the hops (an herb with stimulant/sedative effects) in beer and polyphenols in wines.
     The distinction between foods and drugs cannot be made on the basis of the presence or absence of a pharmacological effect, particularly these days when the effects of individual components of foods are being isolated and foods created (for example, by genetic engineering) that contains larger or smaller amounts of selected components (for example, high oleic sunflower oil).  We suggest that the only reasonable way to judge all foods and all drugs is on the basis of the ratio of risks to benefits of their use for individual users, not on the arbitrary and capricious basis of whether there is or is not a pharmacological effect.
     Furthermore, there is an identifiable market of consumers who seek foods that enhance health, based upon such studies in the public domain as Wrick, Gilbert's HealthFocus study, Childs and Poryzees' survey, annual FMI consumer inquiries, and recent Yankelovich research (Childs, "Functional Foods and the Food Industry: Consumer, Economic and Product Development Issues," Journal of Nutraceutical, Functional & Medical Foods, Vol. 1 No. 2 1997, pg. 30).  These individuals are comfortable with self-selection of products for health and subscribe to a health maintenance credo.   Functional foods interests include disease prevention, disease therapy, performance enhancement, and (especially in the U.S.), weight loss.  Wellness is in fact something of a personal philosophy or spiritual element to these consumers.  Hence, the FDA must consider how FDA censorial or prohibitive policies is going to be perceived by these consumers and, thus, the likelihood of such policies being effective for the intended purpose.  It is exceedingly likely that the FDA's attempts to define foods as those substances that are only nutritive and not therapeutic is doomed to failure.  Indeed, this was the message of the DSHEA.  Because of this, 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.
 
     2.   Individuals having heart attacks or strokes while using ephedra herb or ephedrine-containing products is not evidence that the ephedra herb or ephedrine-containing products caused the heart attacks or strokes.  One thing we need to know is how many heart attacks and strokes would be expected in the user population during the period in question.
     Mr. Ford: "...the figure that we have used is about a million and a half doses per day [of ephedra products], and that's just from the health food stores." (Vol. I pg. 250)  Dennis Jones: "...the enormous number of users of this herb. My estimate is 5 to 8 million Americans each year for 10 to 12 weeks, but other people have four times that estimate." (Vol. I pg. 277)  Dr. Bruce M. Chassy: I just wanted to make the point that if millions of people are taking products that contain ephedra alkaloids and we are seeing a very low incidence of these kinds of serious effects, we need to know whether that incidence is any greater than spontaneously occurs." (Vol. II pg. 118, emphasis added)  Dr. E. Wayne Askew (Acting Chairman of the Committee): "And I don't think that we can give you an answer to that." (Vol. II pg. 119)
     But information is available from a number of sources, including public agencies such as the Public Health Service and the Centers for Disease Control, for the heart attack incidence by age.  The FDA did not provide this essential information to the Committee during their two day meeting in which they were evaluating the risks of ephedra alkaloid-containing products.  How, then, could the FDA or the Committee members know whether the incidence of the adverse events were greater for the user population than would have been expected of the general population in the users' age range?
     Scientists at the FDA's Center for Drug Evaluation and Research make the same point in a letter to The Lancet (Vol. 350, July 5, 1997, pg. 69).  In commenting on a study of the possible dangers of using non-sedating adrenergic agonist antihistamines, the scientists state: "...this type of analysis contains inherent flaws and may be subject to biases that could lead to misinterpretation of the data. First, this study does not account for the spontaneous rates of background cardiac events in the untreated population."   These FDA scientists also caution that there may be a bias in reporting when there is heightened awareness of potential adverse events.  The FDA has publicized its concerns about ephedra (see statement by Dr. Lori Love of the FDA, Vol. I pg. 198: "...we have publicized our safety concerns on ephedra-containing products a number of times."), thus creating a potential atmosphere of heightened concern and, hence, a possible reporting bias.  They conclude their letter by noting: "...the FDA has been carefully monitoring spontaneous adverse drug reactions reported in association with the use of these antihistamines. This monitoring is not limited to analysis of crude reporting rates, but includes careful review of individual reports and follow up."  We think that the evidence we present in these comments will show that the FDA has done nothing approaching a "careful review" and "follow up" in the case of adverse reports on ephedra alkaloid containing dietary supplements.  This neglect supports the view of many that FDA has had a long-standing bias in favor of prescription and OTC drugs and against dietary supplements.  Because of this, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     3.   FDA's treatment of the ephedra supplement adverse reaction reports exhibits FDA's infamous bias against dietary supplements.  There have been thousands of complaints received by the FDA from users of aspartame (and MSG) claiming aspartame (or MSG) caused adverse events, including seizures and strokes.
     Strokes and seizures are "consistent" with the known effects of excess excitotoxic amino acid (e.g. aspartic and glutamic acids) activity, but that doesn't mean that aspartame (or MSG) caused them.  FDA has consistently refused to reconsider the wide use of aspartame (and MSG) in foods (and in fact has increased the categories of foods that may contain aspartame) despite the large number of complaints because it is convinced by the scientific studies of aspartame (and MSG) that aspartame (and MSG) use is safe.  However, safety trials of aspartame (and MSG) were done largely on normal people (some aspartame safety studies included individuals with phenylketonuria or non-insulin-dependent diabetes); none of the safety trials on normal individuals would be expected to include individuals with known cardiovascular disease, just as such individuals were excluded in the weight loss clinical trials with ephedrine.  Hence, evidence for aspartame (and MSG) safety may be of no better quality than that for ephedrine, despite thousands of complaints to the FDA of adverse events, some of them serious.  (For information on aspartame safety trials, see, for example, Stegink and Filer, Aspartame Physiology and Biochemistry, Marcel Dekker, 1984)
     The association of the consumption of a substance and the occurrence of an adverse event is not the same as cause and effect.  Dr. Cynthia T. Culmo, of the Texas Department of Health, discussed the state of Texas' recent experience with adverse event reports from users of ephedra-alkaloid containing products.  The FDA has relied heavily on this evidence.  However, note the exchange on Vol. I pp. 81-82 between Dr. Culmo and Dr. Jasinski:
     Dr. Jasinski (Vol. I pg. 81): "But that's associated, and being causal and associated is different."  "A certain percentage of young people are going to die from strokes or some unexplained cardiac event, and it's associated."  "...have you done some sort of analysis on this data?"
     Dr. Culmo (Vol. I pg. 82): "It's tabulated. It hasn't actually been broken down. But, again, we keep saying associated. I don't believe we've ever gone on record and said caused. (emphasis added)  Here, Dr. Culmo backs down under the pressure of tough comments and admits that these associations are just that, associations, and that, to her knowledge, the Texas Department of Health has never publicly called these associations a cause and effect relationship.  Because of bias, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     4.   The FDA argues that even a clear warning will not protect all those in the sensitive population that should not use ephedra-alkaloid containing products because many of them may not know they have the medical conditions in the warning.   However, this is a problem for all those sensitive to food components -- that they may not know they are sensitive.
     Some food sensitivities, such as to peanut protein, can be fatal, while others can cause severe allergic reactions requiring hospitalization.  People generally find out by eating the food and having a reaction. Most such food sensitivity discoveries probably occur in childhood.  But this shows that warning labels only protects those who already know they are sensitive to a food, the same situation as exists with the ephedra herb warnings.  FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     5.   FDA instructed the Committee members not to consider any benefits of ephedra herb use.  In the absence of benefits of use, this makes any risks totally unacceptable.  However, there are benefits described by many users, benefits which consumers are capable of assessing, such as weight loss or energy. A number of peer-reviewed double-blind placebo controlled scientific studies have been published (and some of these cited during the Committee meeting) showing that ephedrine is thermogenic and can be used successfully to help in weight loss.  This was one benefit that the FDA decreed could not be considered.  Several committee members (1996) complained of the problem of considering safety when they were forbidden to consider benefits.
     The FDA describes the Committee's conclusions on determining a safe level (in the rulemaking proposal, pg. 29), "FDA notes that many members of the Food Advisory Committee stated that they were unaware of a basis for determining a safe level."
     Dr. George Ricaurte (Vol. II pg. 222): "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 [by the FDA] 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)
     Dr. Inchiosa (Vol. II pg. 227): "...I could imagine this is going to be very confusing for the consumer, who look at a product that claims nothing, yet has a tremendous list of warnings because the warnings are going to be increased. And, so, really, in an age where we're trying to increase information it's disinformation or no information only a condition of more confusion."  "So, therefore, I agree with Dr. Ricaurte that since you have no claimed benefit, there's no margin of safety that can be calculated." (emphasis added)
     Dr. Croom (Vol I pg. 149) (comments directed to Dr. Yetley)
"...as a scientist, when someone says no risk, I can imagine a spill of this water on this microphone, and when I come to one serious event and I get electrocuted."  "Because no sounds more like why I go to church than a scientific analysis, okay?"
     Because of FDA's incorrect charge to the Committee (that benefits could not be considered) the Committee's risk/benefit analysis could only consider risk, thereby resulting in arbitrary and capricious very low dose recommendations that are not in accord with the scientific evidence.  Because of this, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     6.   Ephedra dietary supplements are already less dangerous than foods in common form.  If you consider food poisoning as a result of bacterial contamination alone, there are 9,000 deaths a year. This does not include the deaths, serious illnesses, and disabilities occurring in many more people from heart attacks and strokes resulting from food-derived excess calories, fat, and cholesterol.  It is not uncommon for a heavy meal to trigger a heart attack in those at risk.  The fat and the noradrenaline released in response to the food increase platelet aggregability, thus increasing the risk of an abnormal blood clot that can cause a heart attack or stroke.
     People think food is much safer than it is and need to be educated so as to be more careful in using and preparing foods.  This is education the FDA could be doing that would be a far better use of limited public funds than attacking the use of ephedra herb products on the basis of poor data.
     John J. Guzewich (Vol. II pg. 238): "...if the CDC has a figure, you know, for infectious disease, which is my area, food-borne disease, that 20 to 30 percent of our population today is at risk for food-borne disease from infectious sources for high-risk population, I don't know if that is a fair number to say for these kinds of compounds [the ephedra alkaloids]."
     Indeed, the CDC estimates that approximately 60,000,000 to 80,000,000 Americans suffer from food poisoning each year -- about one quarter to one third of all food consumers.  How does the incidence of fatalities caused by bacterial food poisoning compare to the incidence of fatalities associated with ephedra dietary supplements?  Nine thousand fatalities per year from bacterial food poisoning in the U.S. is equal to about one food poisoning fatality per 30,000 food consumers.
     The FDA has found 21 deaths associated over three years with the use of ephedra supplements, or about 7 deaths per year. This is the associated-but-not-necessarily-causal numerator.  What is the denominator, the number of people using ephedra supplements on any given day?
     The members of the committee were very concerned that the FDA had not even attempted to supply the essential denominator information.  The transcript of the 1996 Food Advisory Committee expressed grave concern about the FDA's lack of a denominator:
     Dr. Hui, Vol. II pg. 61 "...what you have put together is very useful for us but these are literature written for professionals by scientists and it's used to treat diseases.  There's nothing that's really safe. I think it's all risk-benefit ratio."
     Right. That's why the denominator information is very important.
     Mr. Appler, Vol. II pg. 81  "Your device center of FDA is having a conference on the 21st of September on a topic called Denominator Data.  Since reports of injuries have to be filed under the statute for medical devices, the center is concerned that it can't evaluate the meaning of enumerator ... without knowing what the denominators are."
     Dr. Ricaurte, Vol. II pg. 132  "I don't see Dr. Kessler organizing a meeting to address ephedrine OTC and convening an advisory group seeking advice as to what to do with regard to safety of these compounds, and yet here we are."
"Now the issue then is what is the denominator for--I mean, that's the only way I can try to get at that issue of safety as the agency seeks advice."
     Dr. Jasinski, Vol. I pg. 161  "...yes, we have some serious events, but--I mean, we have a numerator but no denominator in any of this, and coming back to predict safety data, they're asking us to predict safety data without telling people to go out and do a clinical trial to validate the predictions."
     Dr. Kessler, Vol. I pg. 161  "...I ask you to consider [giving] us your best judgment in light of what [data] exists."
     The FDA expects magic, that scientists can make a scientific judgment affecting millions of Americans on the basis of very little and poor quality information provided by the FDA.  The FDA has failed in its duty to provide necessary information, such as the essential denominator data, to the Committee, and should withdraw its proposed Rule until such time that it can hold a properly informed Committee meeting, which can then render an informed decision on which the FDA can base an informed Rule.
     Dr. Marangell, Vol. II pg. 276  "We've been talking about the numerator and denominator, and in my assessment of this I agree the data is very poor..."
     Dickinson, Vol. I pg. 284  "Industry needs more information, needs to be able to come forward with more information on the denominators, as has been mentioned by several speakers here today."
     Some denominator information was provided by industry during the committee meeting:
     Mr. Betz, Vol. II pg. 27  "Over the past five years, Omnitrition has sold approximately 100 million servings of ephedra-based products. We believe that our position in the market is relatively small, probably around 5 percent of the market share.  If you assume it's 10 percent, if you move out on a limb and assume it's 10 percent, that's over the last five years, one billion servings of ephedra-based products."
     Dr. Ziment, Vol. II pg. 29  "Although you say one billion servings have been sold over five years, that means 200 million a year and I would guess that the average consumer takes what, 50 to 100 servings, which may mean one or two million people are taking this drug.  Now, the real question for me is what percentage of one million people who take a drug should be allowed to have adverse reactions before control is taken?"
     Mr. Betz, Vol. II pg. 30  "...our estimates, our understanding of the estimates with respect to the number of people in the United States who are actually using ephedra-based dietary supplements is ... more on the order of perhaps 10 to 20 million people, who have used at some point in the last five years ephedra-based supplements."
     Mr. Ford, Vol. I pg 250: "...the figure that we have used is about a million and a half doses per day [of ephedra products], and that's just from the health food stores."
     Dennis Jones, Vol. II pg. 277: "...the enormous number of users of this herb. My estimate is 5 to 8 million Americans each year for 10 to 12 weeks, but other people have four times that estimate."
     Commenters Pearson and Shaw license a dietary supplement containing whole ground ephedra herb (about 1.8 gram of herb per serving, adjusted to contain 20 mg. total of ephedra alkaloids per serving).  Their experience in the market has led them to conclude that the number of consumers of ephedra alkaloid containing dietary supplements is similar to those given at the Committee meeting by representatives of the industry: 1,000,000 to 8,000,000 Americans consume these supplements on any day.
     If as few as 212,000 people are using ephedra supplements and if the 21 deaths were actually a result of ingestion of ephedra alkaloid containing dietary supplements and if food poisoning were the only cause of deaths from consuming foods in common form, then there would be about the same incidence of deaths from consuming foods in common form as of ephedra alkaloid containing dietary supplements. In actuality, the number of people using these supplements is probably closer to ten times as high, there is no compelling evidence that the 21 deaths were all caused by the ingestion of ephedra alkaloid containing dietary supplements and, of course, there are many other causes (besides bacterial food poisoning) of deaths from consuming foods in common form.
     Let us take the lowest industry estimate, 1,000,000 users on any given day, which would result in a worse case incidence estimate: 7 ephedra associated deaths per year per million ephedra users.
     Compare this to 33 bacterial food poisoning caused deaths per year per million food users.
     Even if all the deaths associated with ephedra were definitely caused by ephedra when used according to the label instructions (which the FDA certainly does not contend), the extant dietary supplements (some of which contain up to 110 mg. ephedrine and most of which also contain caffeine) with the extant labels (15 percent of which provide no warnings) are already 4 to 5 times safer than food in common form.
     Moreover, remember that the food death incidence figure refers to bacterial food poisoning, not anaphylactic reactions, not cardiovascular deaths from excessive doses of calories, fat, and cholesterol, and not other causes.
     Congress has not delegated authority to FDA under DSHEA to require dietary supplements to be safer than food in common form.  In this rulemaking, the FDA exceeds its Congressionally delegated authority by requiring a much higher standard of safety for dietary supplements than for food in common form.  FDA's rulemaking is a clear expression of FDA's bias against dietary supplements.  FDA must withdraw this proposed rulemaking because it is ultra vires and violates the APA.
     The safest way to establish dose when using an ephedra alkaloid containing dietary supplement (or virtually any other kind of supplement) is to begin with a low dose (perhaps 1/4 to 1/2 of the suggested single serving size) and gradually increase the dose to the suggested level of use.  As Adam Gissen noted on Vol. II pg. 38: "If you try to limit its [ephedra alkaloid containing dietary supplements] use, people are certainly not going to take something that you want to build up to the full dose over 10 days to two weeks, that's not possible to do in one week."  FDA's proposed label statement limiting the dose and the use to one week will discourage consumers from building up the dose slowly.  FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     7.   Under DSHEA, FDA cannot regulate dietary supplements more stringently than foods in common form.  FDA has done precisely this, hence it must withdraw the Rule, and re-convene the Committee with instructions to use a standard that does not fly in the face of the will of Congress.

     8.   FDA has not met its burden of proof, to show that ephedra is a significant and unreasonable risk when used according to label instructions, and not misused or abused.  For example, FDA assumed consumers reporting adverse reactions were using the products according to label instructions. They must provide evidence for this, but did not attempt to do so.  The FDA also admitted that it had obtained very few samples of what the consumer was using at the time of the incident in order to analyze them.  Hence, they had no way to know whether those consumers for which adverse reports were made were following label instructions or were abusing the supplements or even whether they were taking drugs such as cocaine at the same time.       Dr. Lori Love (FDA), Vol. II pg. 149 "...we cannot verify in many cases what a consumer used."
     Mr. Israelson, Vol. II pg. 119: "...on the formulas, which cause these serious adverse reactions at low dosage, 1-to-5 milligrams [of ephedra alkaloids], do you have the formulas themselves, so we could identify what else is in there?"
     Dr. Lori Love, Vol. II pg. 119: "I do not have that in hand and we actually were just analyzing that data over the weekend."
     Dr. Love, Vol. II pg. 107: "...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."
     Dr. Georgitis, Vol. II pg. 107: "Dr. Love, I have a question for you, in terms of the serious adverse 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:
     Dr. Love, Vol. II pg. 107: We haven't expressed our data in that form because, of course, we have only 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."  Because of this failure to meet the Congressionally mandated standard of proof, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     9.   People who don't know they have one of the conditions given on ephedra herb labels as contraindications, conditions such as cardiovascular disease, hypertension, diabetes, etc., may still use ephedra herb.  Some misuse due to ignorance, however, is unavoidable no matter what regulations you put in place and the same problem applies to many other common and widely available products. For example, people who are at risk of heart attack may buy a shovel and shovel snow, eat a high fat meal or engage in an intense exercise regimen, and drop dead.  People who don't know they have diabetes may chronically eat high sugar foods and damage themselves via hyperglycemic glycosylation and other mechanisms.  People with one of the medical conditions as those given on a label for which an OTC should not be used (including ephedrine containing OTCs) may not realize they have one of those medical conditions.  Perhaps a warning could be added: "If you are not sure whether you have one or more of these conditions, see a physician before using this product."  However, the list of warnings can be made only so long without type so small you need a magnifying glass to read it.
     There has to be some room for personal responsibility in the sale and use of any product.  That is why we favor education rather than the FDA representing that they shield consumers from the need to consider risks.  It is dangerous for consumers to believe that the FDA has done all their thinking for them, thus excusing them from taking responsibility for their actions.

     10.  The FDA at several points during the 1996 meeting of the Drug Advisory Committee told the participants to ignore the issue of adverse reactions associated with the use of ephedrine alkaloids in OTC drug products, which includes phenylpropanolamine (in OTC products for weight loss), pseudoephedrine, and ephedrine.
     Dr. Harry H.S. Fong (Vol. I pg. 47): "Currently, pseudoephedrine and phenylpropanolamine are used in OTC. So, what would happen if ephedrine is banned from the OTC market? Would pseudoephedrine and phenylpropanolamine follow up in also being removed from the market? They are, after all, similar alkaloids, and they are also derived from ephedra?"
     Dr. Elizabeth Yetley (Vol. I pg. 47): "I think that what we're really focusing on today is not the drug issues, but the dietary supplement issues."
     This response of Dr. Yetley of the FDA evades the important fact that anyone can walk into a supermarket or drug store and buy these OTC products containing ephedra alkaloids. If the FDA is going to restrict the dose or length of use of ephedrine containing products on the basis of safety, it is a reasonable question why these others, with similar effects, would not also be restricted. (Note, too, that some OTC products contain 24 mg. of ephedrine plus 120 mg. of theophylline, a caffeine like drug. Moreover, the OTC pseudoephedrine and phenylpropanolamine containing products contain about 3 to 6 times as much of pseudoephedrine or phenylpropanolamine alkaloids as the total ephedra alkaloid content of a typical ephedra dietary supplement.)  This again brings up the question of bias on the part of the FDA. Moreover, if ephedrine containing dietary supplements used for weight loss or energy have FDA set doses that do not provide the benefits sought by consumers, many such consumers may turn to available OTC products containing pseudoephedrine or phenylpropanolamine or ephedrine plus theophylline at higher dosages, with the perverse result that some consumers may end up using higher doses of ephedrine alkaloids than they did in the dietary supplements.
     Dr. Irwin Ziment, Vol. II pg. 115: "...I feel that there is a disconnect in that we are hearing a lot about the dangers of ma huang and ephedrine without knowing the dangers of comparable orthodox drugs." Dr. Ziment, Vol. II pg. 116: "...Dr. Love, perhaps can give us a little bit more information on the side effects that are actually recorded, even on a year-to-year basis in adverse drug reports on the legitimate ephedrine products."
     Dr. Lori Love (FDA), Vol. II pg. 116 "I don't have that data and I will defer to people from Drugs [FDA] on that."  Unfortunately, there were no data on this essential subject supplied by Drugs (Branch of FDA) at the meeting.
     There are political issues in whether the FDA regulates the OTC ephedra alkaloids or the ephedra alkaloid containing dietary supplements.
     Dr. Jasinski (Vol. I pg. 99): "What I don't understand is if you look at the DAWN data that you quoted, pseudoephedrine was much greater a public health problem, two to three times by my estimate, as ephedrine, yet you control, you exempted pseudoephedrine when the DAWN data which was used for the basis shows it's two or three times the incidents and emergency rooms and deaths. Could you go through that?"
     Frank Wickham (Texas Department of Health)(Vol. I pg. 99): "Yes, Dr. Jasinski, that was a result of a political decision and based upon pressure brought upon the sponsor of the original legislation." (emphasis added)
     (Such political pressure can and will be brought to bear upon the FDA.  Placing different standards upon the safety of ephedra alkaloids in OTC products and in DSHEA dietary supplement products would be arbitrary and capricious.)
     Then, Dr. Jasinski said (Vol. I pg. 99): "...the health food stores make money selling ephedrine-containing products. The drug stores with the pharmacists make their money by selling pseudoephedrine-containing cold products, if you want to look at this cynically. Is this politics?"
     Mr. Wickham, Vol. I pg. 100:  "...I think that is part of the politics as far as the market is concerned, yes."
     Here we see a clear conflict of interest between the marketers of ephedra alkaloid containing dietary supplements and the drug stores offering an ephedra alkaloid in OTC pseudoephedrine-containing cold products. We must carefully examine FDA policies to be sure that there is no FDA bias toward the OTC trade of ephedra alkaloid containing products. In the recent past the FDA has stated explicitly its concerns that the sale of dietary supplements might impinge upon the sales of pharmaceutical drugs.
     FDA must withdraw the Rule and re-convene the Committee without suppressing extremely relevant information, make a new decision which considers this essential data, and issue a new rule.

     11.  Reducing the dose below an effective level (for weight loss or energy) will result in increased risks for those people who will take more to try to get the results they seek (not knowing how much they should take as one serving or the daily limits they should respect) and, perceiving the use instructions as "fake" or government propaganda, may also ignore the safety warnings, perceiving them to be equally "fake" or not useful as well.
     Many consumers already using ephedra herb products will be familiar with doses above the dose suggested by FDA and may consider the entire label a misleading government message, with potentially lethal consequences, especially if the contraindications are perceived to be, like the dose and maximum use period disinformation, something to be ignored.
     Setting dosages to arbitrarily low levels will not "fool" consumers and is not the answer to ignorance among consumers about safety considerations.  Better education and more information is the best answer. It is not a perfect answer but, in a free society, it is far better than the alternative of FDA attempting to impose choices on millions of people.  The FDA's credibility to dietary supplement consumers rests on whether consumers consider them a reliable source of information.  If not, the FDA's "advice" will surely fall on deaf ears.  Because of this, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     12.  Caffeine toxicity:  Oral doses of greater than 1 gram of caffeine may be toxic in adults.  That is about the same as is found in ten cups of coffee or in 10 No-Doz tablets.  (Pentel, "Toxicity of Over-the-Counter Stimulants," JAMA 252:pg. 1902, 1984)  The theophylline in OTC ephedrine products (120 mg. per tablet) is even more toxic in overdose than is caffeine.  Because of this, FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that is free from arbitrary and capricious bias against dietary supplements and in favor of OTC drugs, and re-propose a new Rule.

     13.  We have examined published reports of adverse events with ephedrine, phenylpropanolamine, and pseudoephedrine that are exhibits to the FDA's proposed rulemaking, including 56, 60, 62, 63, 67, 68, 69, 70, 71, 73, 100, and 128.
     We concluded that most of the adverse events were associated with abuse:
     Reference 68 concerns a 28 year old woman with a three week history of progressing shortness of breath, dry cough, fatigue, and orthopnea. She admitted to taking 25 mg. ephedrine tablets for 8 years to try to lose weight.  One week before the onset of symptoms she reduced her daily intake from 80 tablets to 3 tablets, after which her symptoms rapidly worsened.  80 tablets of 25 mg. of ephedrine is 2000 mg. (!) a day. This is an immense overdose; it is possible that the tolerance experienced by users of ephedrine explains at least in part why this woman didn't die from taking so much.
     Reference 67 concerns a 32 year old housewife who developed congestive heart failure after ten years of taking large quantities of ephedrine containing compounds for energy. It is not clear exactly what dose she was using but it appears to have been an immense overdose, as she was taking three bottles of an ephedrine containing cough medicine daily at the time of psychiatric referral.
     Reference 66 concerns a 36 year old insurance agent who was taking a cough medication containing ephedrine. He had progressively increased his ephedrine intake until he was drinking more than a bottle a day, each of which contained 400 mg. of ephedrine.
     Reference 69 concerned a 20 year old man who suffered an intracerebral hemorrhage after taking an unknown quantity of "speed," containing ephedrine. It was clearly used as a substitute for illicit drugs, such as amphetamine.  The patient had used "speed" in the past but did not know the exact composition of the pills, though urine drug screen on admission revealed no amphetamine, methamphetamine, phenylpropanolamine, or caffeine.
     Reference 70 concerned three case reports. Cases one and two had both used large quantities of the same ephedrine containing pills (each pill contained 15.3 mg. of ephedrine). Case 1 consumed 10 of the pills (150 mg. of ephedrine) all at once and Case 2 had consumed 10-20 of the pills (153 to 306 mg.) daily for 23 years!  Case 3 suffered a ruptured berry aneurysm which, unfortunately for its victims, can result from many commonplace events, including exercise and emotional excitement.
     Reference 86 concerned a 54 year old Polish woman who had become psychotic.  She admitted under questioning to have taken increasing quantities of ephedrine over the past 20 years, to her most recent dosage of up to 15 tablets, each containing 30 mg. of ephedrine (450 mg. of ephedrine) five times a day (a total of 2,250 mg. of ephedrine!) during exacerbations of her asthma.
     Reference 82 concerned a 26 year old man who developed psychosis. Three days before admission to the hospital, he started taking ephedrine (30 mg. five tablets twice a night) to keep awake while holding a job in a bakery.  The total amount of ephedrine he had ingested in the three days before admission was 750 mg.
     Reference 100 concerned a 45 year old man who had been taking a daily herbal diet supplement for weight loss.  After several weeks of using "greater amounts," he began to get restless and couldn't sleep.  At that time, he experienced personality changes and mania.  The amount of ephedrine he was using is not clear, but the "greater amounts" suggests that it may have been an excessive amount and substantially greater than that recommended in the label instructions.
     Reference 128 concerns a 33 year old woman who developed acute hepatitis in association with the use of ma huang.  Unfortunately, this is not a problem uniquely associated with ma huang or even herbs in general. Any plant matter may have the problem. Ma huang from Asia may be grown in fields fertilized with fresh human feces. Commenters Pearson and Shaw (and many other dietary supplement formulators) require that the raw herb be sterilized with heat, ethylene oxide, or ionizing radiation before used in the manufacture of their licensed products. Most reputable herb suppliers do this before sale, even if it is not specified in the purchase order.
     A number of Americans were recently reported in national newspapers as having developed hepatitis as a result of eating imported strawberries, causing something of a public relations problem at the FDA, since the public blamed the FDA for the problem.
     Reference 56 concerns a 14 year old girl who took 15 to 18 capsules of a product containing (per tablet) 25 mg. of ephedrine, 200 mg. of caffeine, and 50 mg. of phenylpropanolamine, in a suicide gesture. She developed cardiac arrhythmias as a result, from which she recovered.  If she took 15 capsules, her total dose was 375 mg. of ephedrine, 3000 mg. of caffeine (doses of caffeine alone of 1000 mg. or more may be toxic), and 750 mg. of phenylpropanolamine.
     Reference 122 concerns potential risks to medically controlled hypertensive patients taking sustained-release pseudoephedrine for nasal congestion.  The authors found that "pseudoephedrine administration did not result in statistically significant changes in any cardiovascular parameter.  Mild disturbances in sleeping pattern and urinary retention in some male subjects were the only significant symptoms detected.  The authors concluded that "while sustained release pseudoephedrine appears safe for the majority of medically controlled hypertensive patients without statistically significant effects on blood pressure or heart rates, our studies did show an upward trend in these parameters which, in a larger population of hypertensive patients, may prove to be clinically significant."
     Reference 71 concerns a 17 year old girl who had made an attempt at self-poisoning 12 months previously but was said not to be a drug abuser.  She was admitted to hospital after taking 20 tablets containing pseudoephedrine 60 mg. (a total of 1200 mg. of pseudoephedrine) and was diagnosed with an intracranial hemorrhage.  The authors note at the end of the letter that "Pseudoephedrine has only rarely produced neurological complications. Because it is a very weak sympathomimetic amine, which has not achieved status as a drug of abuse or addiction. The present case, however, serves to illustrate its potential dangers."  If ephedrine becomes available only in low dosages, pseudoephedrine might be abused more frequently.
     Reference 62 concerns three patients that developed clinical evidence of heart injury after acute ingestion of phenylpropanolamine.  The first case, a 24 year old woman had chest pains three hours after ingesting a single capsule containing 50 mg. of phenylpropanolamine, 4 mg. of chlorpheniramine, and 0.2 mg. of belladonna alkaloids. It ought to be considered that the combination of these substances, rather than the phenylpropanolamine, was responsible for her injuries.  Cases two and three were clearly cases of abuse.  Patient two had taken eight capsules each containing 50 mg. of phenylpropanolamine, 8 mg. of chlorpheniramine, and 2.5 mg. of isopropamide.  Patient three was a 31 year old schizophrenic woman who ingested approximately 40 tablets, each containing 50 mg. of phenylpropanolamine and 200 mg. of caffeine. This is clearly abuse.
     Reference 63 concerns a 43 year old black woman who was brought to the hospital after two episodes of palpitations associated with shortness of breath, tinnitus, dizziness, diaphoresis, and inability to stand.  She had no prior history of heart disease, but had a history of hypertension, which was controlled without medication.  She was taking capsules that contained 75 mg. of phenylpropanolamine and 200 mg. of caffeine.  The total amount she was taking was not specified.  This woman should not have been taking a sympathomimetic with her history of hypertension.
     Reference 65 concerns three patients. One, an 18 year old obese woman, was admitted to the hospital with neurological symptoms after taking two tablets of ComtrexR for "congestion."  The patient experienced a grand mal seizure at the hospital.  No drug scan was done, so we do not know whether she might have been using any drugs along with the Comtrex.  The second patient, a 26 year old man, drank three to six ounces of whiskey eight hours prior to admission. He had taken two black capsules three to four hours prior to admission. Each capsule contained 200 mg. of caffeine, 25 mg. of ephedrine, and 50 mg. of phenylpropanolamine.  His blood alcohol was 5 mg% (5 times the legally drunk level). This man eventually died in the hospital.  This combination of high dose alcohol, along with high doses of caffeine, ephedrine, and phenylpropanolamine is clearly drug abuse.  The third patient was a 17 year old man who ingested two black capsules, later identified as "pick-me-up" capsules containing 200 mg. of caffeine, 200 mg. of ephedrine, and 50 mg. of phenylpropanolamine. This man had a large stroke and died.
     Reference 73 is a 1990 review of reported adverse drug reactions (ADRs) for phenylpropanolamine since 1965. "Since 1965, 142 ADRs have been reported in 85 studies, 69% of these in North America. Many such cases may go unrecognized. Of ADRs attributed to legitimately [OTC or prescription] sold PPA products, 85% occurred after consumption of OTC products versus only 15% after prescription drugs. The PPA product often contained combination ingredients, or PPA was consumed along with additional drugs. An overdose of PPA was taken in about a third of the cases.  After ingestion of non-overdose amounts, 82% of the [reported] ADRs were severe. The most frequent side effects involved symptoms compatible with acute hypertension, with severe headache the most common complaint. Twenty-four intracranial hemorrhages, eight seizures, and eight deaths (mostly due to stroke) were associated with PPA ingestion."  While the discussed adverse reactions are serious, 142 ADRs (though possibly underreported) should be compared to the tens of millions of consumers using PPA products during this 25 year period.  In fact, this paper mentions that in 1981, a marketing research company reported that 9.5 million adults were using OTC diet aids, making PPA the fifth most used drug in the U.S. At the time of the publication of this paper (1990), three FDA advisory panels had judged PPA to be safe.  In another study cited here, a review of over 200,000 prescriptions for PPA-containing products found no increased incidence of hospitalization for hypertension, arrhythmias, or stroke.
     Reference 60 concerns a 28 year old man with no known cardiac risk factors and no history of smoking, drinking alcohol, or using reacreational drugs, or family history of heart disease, who had a heart attack after taking 60 mg. of pseudoephedrine. Subsequent examination showed that he had normal coronary arteries. The authors suggest that "pseudoephedrine, a sympathomimetic agent, may be implicated in the initiation of coronary spasm..."  FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this lack of consideration for the information in the adverse reaction cases that FDA claims to depend upon, and re-propose a new Rule.
 
     14.  We have considered the data presented by the FDA in light of the paper on how to evaluate adverse drug reactions in Reference 43 (Jones, "Approaches to Evaluating Causation of Suspected Drug Reactions" in Strom, Velo (eds): Drug Epidemiology and Post-Marketing Surveillance, New York: Plenum Press, 1992, pp. 103-113:
     The limitations of the FDA data make it very difficult to assess the degree of cause and effect versus mere association.  For example, Table 3, the Naranjo Algorithm and Types of Data Requiring Judgement provides a series of 10 questions about the adverse event that can be used to assess cause and effect versus association.  Question 5 is: "Are there alternative causes which could have caused event?" This question refers to confounders. For example, there is a background incidence of such events as heart attacks and strokes in the population of probably millions of individuals using the ephedra alkaloid containing products.  The FDA did not provide information to the Food Advisory Committee on this background level of these types of events, making it virtually impossible to know whether the incidence of adverse events reported was higher or lower or about the same as the background incidence.  As Dr. Bruce M. Chassy noted at the Food Advisory Committee meeting (Vol. II pg. 119): "...we need to know whether that incidence is any greater than spontaneously occurs." (Such data exist. For example, G. Michael Vincent, a cardiologist at the University of Utah School of Medicine in Salt Lake City says that there are 8,000 sudden, unexplained deaths among children and adults each year.)
     The FDA has admitted that it has little information on what the consumer actually took.  A consumer who is abusing a substance (by, for example, taking inappropriately large doses) may not be perfectly truthful about this stupid behavior when asked what they took.  The FDA simply assumed that the consumer used the product according to the label instructions.  For example, Dr. Love (Vol. I pg. 210) said "And the adverse events are reported when the product was apparently used according to label instructions, which appears to be in the majority of the individuals where we have evaluable data."  (emphasis added) Then on Vol. II pg. 120, Dr. Love says "Are you asking if we can verify that or any other information that our patients give us? I mean that's a very difficult question. If the patient told you that they took an over-the-counter product at X value [dosage], you would believe them."
     There is a need to verify the dose the consumer claimed to take.  However, Dr. Lori Love of the FDA noted (Vol. II pg. 149): "...we cannot verify in many cases what a consumer used."  Then on pg. Vol. II 107, Dr. Love says "...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."  Dr. Love admitted (Vol. II pg. 107) that the FDA could not provide information on the dose-response relationship (as, for example, how many of the adverse events took place at dosages below the median value of 20 milligrams per serving).  This is important for answering question 8 of the Naranjo Algorithm: "Was reaction dose-related?"  A median amount does not provide any information on the distribution of doses, eg., do the doses fall in a narrow range about the average or do they have a very broad range or is there a bimodal distribution.  A small percentage of very high dosages could have had a large effect on the median. This is particularly important with respect to the deaths. Did they occur at especially high dose levels?  It would have been much more useful if the FDA had supplied the average dose and the standard deviation.
     Moreover, Dennis Jones reported to the committee (Vol. I pg. 275) that "...a fixed ephedrine/caffeine combination based mainly on the work by Astrup and his colleagues has been approved for weight loss indications in Europe and is being touted by many as the safest and most effective treatment available. Danish data indicated only 86 reportable adverse reactions, which were defined as reactions which necessitate stopping the therapy, out of 9.6 million daily doses during a two-year period..."  The FDA should have followed up on this information before issuing their proposed new rules. We suspect that the FDA was in a big rush to get their rules out because of political, not scientific or public health, considerations.
     The FDA did not prepare a ma huang tea in the usual manner (heated in a pot) to determine how much of the ephedra alkaloids are extracted so as to know how much the consumer might  have actually ingested in the case of ma huang products used as a traditional tea.  Instead, the FDA put the ma huang into a pot and added methanol and water, boiled it, evaporated it, and put it on a carrier.  That is not how a tea is prepared for human consumption!  Plus you get much faster absorption when in the form of a concentrated extract on a carrier as compared to the absorption when a person swallows ground whole ephedra herb.
     Question #4 of the Naranjo Algorithm asks: "Did reaction reappear when drug re-administered?"  But Dr. Love (Vol. I pg. 202) stated at the Food Advisory Committee meeting that the FDA has reports on rechallenges in only 4 percent of the reported adverse events.  FDA has done an extremely poor job of discriminating between causality and mere association without proof of causality, hence FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that corrects this error, and re-propose a new Rule.

     15.  The FDA seems to be in an awful rush to get these proposed rules issued, when the poor quality of the data available at the Drug Advisory Committee meeting would strongly suggest the collection of additional information, as we have suggested in these comments.
     For example, on Vol. II pg. 158 Dr. Jasinski asks Dr. Love: "...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?"  Dr. Love answered (Vol. II pg. 158): "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."  Then on Vol. II pg. 196, Dr. Kessler says "I have promised a number of people that the agency will work hard to get to a decision soon after this advisory committee."  (emphasis added)
     What about the report and the peer review that Dr. Love said the FDA "intend[s]" to do? That report and peer review were not a part of the record for public comment. Apparently, the FDA does not "intend" to do it. One suspects that at least some of the rush here is due to political considerations.  FDA has behaved in a grossly arbitrary and capricious manner, using the Committee as little more than a fig leaf to cover their politically influenced decision.  Perhaps now that David Kessler is no longer FDA Commissioner, FDA can take whatever amount of time is required to do the job correctly.  FDA must withdraw the Rule, re-convene the Committee, reach a new conclusion that is based on science, not political considerations, and re-propose a new Rule.  Congress, not FDA, is supposed to be the judge of political considerations.

                     Michael Davidson, M.D.
               Analysis of Adverse Events Reports

     16.  There was inadequate time at the meeting to consider the report of  Michael Davidson, M.D., a physician and fellow of the American College of Cardiology, assistant professor of medicine at Rush Presbyterian-St. Luke's Medical Center, and medical director of the Chicago Center for Clinical Research.
     Dr. Davidson was commissioned by the NNFA to review the case files underlying 191 adverse event summaries (see Adverse Event Clinical Summaries at Tab F).  He gave detailed analyses of all these events at the Food Advisory Committee meeting.  Of the 191 events, he categorized 84 as serious. Of the 84 serious events, he determined that 13 were not related to ephedra, 8 were unknown for lack of information, 34 were remotely related, 22 were possibly related, and 7 were probably related.  Dr. Davidson's report to the Committee is on Vol. I pp. 59-69 of the meeting transcripts. Unfortun