October 11, 2001
Sidney M. Wolfe, M.D.
Director, Public Citizen’s Health Research Group
National Academy of Sciences Committee on the Framework for Evaluating the Safety of Dietary Supplements
The goal of this committee must be to delineate a scientific evidence-based decision-making process for setting priorities, but a Catch-22 exists because of the lack of data on the safety and efficacy for most of these drug supplements. Priorities for safety review should ideally be based on pre-existing knowledge of safety problems but the Dietary Supplement Health and Education Act (DSHEA) prevents the FDA from requiring such data. Similarly, since the benefit-risk balancing that should precede a patient’s decision to use drug supplements needs to include a consideration of effectiveness or benefit in order to ascertain whether the benefits outweigh the risks–the kind of logic which eventually led to the 1962 drug efficacy requirement being added to the earlier 1938 drug safety requirement–DSHEA’s failure to allow the FDA to require efficacy data is also a serious hindrance. Safety evaluation is further handicapped by the failure of DSHEA to require manufacturers to submit adverse reaction reports on their products. In summary, unlike the regulation of other drugs or even food additives, wherein the burden of proof lies with the manufacturer to document safety prior to approval, the burden is on the FDA to demonstrate harm for these drug supplements despite these disabling features of DSHEA.
Although the recommendations for how to set priorities within existing statutory/regulatory framework is one outcome of the deliberations of this committee, going outside the box, so to speak, and strongly urging major strengthening changes in DSHEA is also a must. It is irresponsible for the FDA itself, well aware of the serious harm done by the prohibitions on its authority imposed by DSHEA, to have stated, in a most cowardly way, that changes in the law are not needed. During March 25,1999 testimony before the House Government Reform Committee, Chairman Dan Burton asked FDA Commissioner Dr. Jane Henney, “Do you think that the FDA has enough authority right now to deal with dietary supplements?” Her answer was “We believe that we have the appropriate authorities that we need.” More recently, before that committee on March 20th of this year, FDA Center for Food Safety and Applied Nutrition (CFSAN) Director Joe Levitt reaffirmed Dr. Henney’s official FDA policy against asking for more legislative authority and pretended that as long as more financial resources were made available, CFSAN could do its job implementing DSHEA and would “provide consumers with a high level of confidence in the safety, composition and labeling of dietary supplements.”
Thus, I will discuss a short-term strategy for the safety evaluation framework–what can be initiated now–and then summarize some of the legislative changes that must be addressed as soon as possible.
For some of these drug supplements, masquerading as foods, even under existing statutory authority, a ban would be appropriate; for others, a public health-oriented warning of DO NOT USE would be an important way of lessening the damage done by these chemicals. For others, strong warnings about use should be required.
What follows are some principles to guide the setting of priorities, with examples to illustrate each.
1. Chemical similarity to known, dangerous, pharmacologically-active compounds/drugs: case example ephedra The following chart shows the closely related chemical structures of phenylpropanolamine (PPA), amphetamine and ephedrine. Notice that PPA is identical to ephedrine except for the absence of a methyl (CH3) group. In fact, the body metabolizes a small portion of ephedrine to PPA (now banned) which is also called norephedrine (“nor” meaning no methyl group).
(note that PPA is also known as norephedrine–ephedrine without the methyl (CH3)
The well-documented concerns about the cardiac toxicity and brain toxicity of ephedrine (also associated with a large number of strokes due to bleeding in the brain), the known brain toxicity of amphetamine and the use of amphetamine as an appetite suppressant as well as the studies documenting an increased amount of hemmorhagic stroke in users of PPA confirm that there are toxic pharmacological as well as chemical similarities between all of these compounds.
The recently updated review of CFSAN’s Special Nutritionals Adverse Event Monitoring System (SN/AEMS), including data collected from January 1993 until February 2001, shows that ephedrine alkaloid dietary supplements are associated with more reports of deaths, myocardial infarctions, cardiac arrhythmias, hypertension, stroke and seizure events than all other dietary supplements combined. According to the FDA analysis, during this interval there were:
3308 adverse events for all dietary supplements, 1398 of these (42%) for the ephedrine alkaloids (EA)
137 reports of death, 81 deaths (59%) associated with EA
38 reports of myocardial infarction/heart attack, 32 reports (84%) associated with EA
98 reports of cardiac arrhythmias, 62 (63%) associated with EA
144 reports of hypertension, 91 (63%) associated with EA
85 reports of stroke, 69 (81%) associated with EA
121 reports of seizure, 70 (58%) associated with EA
Two earlier FDA-commissioned reviews of a much smaller number of adverse events reported to the FDA involving the use of ephedrine alkaloids (did not include data from 2000 and 2001) confirmed the cardiac toxicity of these chemicals. The first study found that 47% of cases involved the cardiovascular system (17 cases of hypertension, 13 with palpitations or fast heartbeat, 10 strokes). There were also 7 reports of seizures.[i] The second study, by Dr. Woosley found that of the 104 reports in which causation by ephedrine alkaloids was very likely, there were 10 cases of sudden death, 9 cardiac arrhythmias, another 23 possible arrhythmic events, 3 heart attacks, 10 cases of chest pain and 15 severe strokes.[ii]
Randy Sasich, M.D., the son of our colleague Larry Sasich, Pharm D., MPH, was in an internal medicine residency at Barnes-Jewish, the main teaching hospital of Washington University in St. Louis. Within just a 7-month period, he took care of two patients admitted to the coronary care unit because an ephedrine alkaloid dietary supplement (Metabolife) had induced life-threatening cardiac arrhythmias. He is aware of a third patient who used Metabolife and experienced an arrhythmia but was not hospitalized:
Case 1 –April 1999. This patient, a female in her late fifties, presented at the emergency room with a dangerously rapid rate of contractions of one of the large chambers of the heart, or ventricles (ventricular tachycardia or V-tach), after using an ephedrine alkaloid dietary supplement for weight control. She was admitted to the coronary care unit for observation. She was subsequently discharged.
Case 2 –April 1999. This patient, a female in her late thirties, suffered a heart attack (acute anterior myocardiaI infarct) and cardiac arrest while using an ephedrine alkaloid drug supplement for weight control. She was a smoker but had no evidence of previous atherosclerotic disease of any significance. She suffered brain damage due to a lack of circulation.
Case 3 –October 1999. A female nurse, age unknown, experienced a rapid heart rate while using an ephedrine alkaloid drug supplement. The rapid rate was documented by her colleagues using an electrocardiogram (ECG or EKG). She was observed until her rapid rate resolved.
These three cases of cardiac injury from ephedrine alkaloid drug supplements in one hospital in only seven months is a further indication that ephedrine alkaloid toxicity is a much more common problem than the FDA data indicate.
2. Interactions with other drugs: case example St. John’s Wort
Once it is clear that there is p450 enzyme inhibition or other effects on the metabolism of other drugs by these drug supplements, the full scope of this problem should be determined and prompt, appropriate action taken. In the case of St. John’s Wort, we wrote to the FDA on March 2, 2000: [iii]
“British physicians and patients are now being forcefully warned–for many more drugs than American physicians or patients–about potentially serious, clinically important drug interactions between the unregulated herbal St. John’s Wort (Hypericum perforatum) and a large number of prescription drugs. For ten widely-used drugs or classes of drugs, the British government’s Committee on the Safety of Medicines is warning doctors and patients to stop the use of St. John’s Wort in people using any of these drugs and urging that patients be warned not to start the use of St. John’s Wort if they are already using these prescription drugs. For some of these drugs, however, patients are urged to see their pharmacist or doctor before stopping St. John’s Wort as the dose of the prescription medicine may need to be altered to prevent adverse effects.
The United Kingdom’s Committee on Safety of Medicines warned on February 29, 2000 that St. John’s Wort should not be used with the following list of widely used prescription drugs because of the possible serious consequences:
cyclosporin (Sandimmune, Neoral)
theophylline (Theo-Dur and many others)
We are aware from the Food and Drug Administration’s (FDA) February 10, 2000 Public Health Advisory that the agency has contacted manufacturers to add warnings to the professional product labeling of indinavir (Crixivan) and other antiretroviral drugs used to treat AIDS that when these drugs are used in combination with St. John’s Wort the blood concentrations of the AIDS drugs may be significantly decreased. In the same letter, in a short paragraph entitled ‘Other Drugs’, FDA mentioned categories of drugs, but not specific drugs which could have harmful interactions with St. John’s Wort:
Seeking labeling changes only for the antiretroviral drugs as indicated in FDA=s February 10th Advisory is an insufficient response to a serious public health hazard. We strongly urge the FDA to immediately issue a warning to American physicians and patients about all of these drugs and require warnings be included in the labeling for the above listed drugs about the potentially serious consequences that can result when St. John’s Wort is used in combination with any of the drugs listed above.
3. Especially vulnerable populations: inadequate safety tests/evidence of harm: case example drugs for pregnancy
In February 2000, we wrote to the FDA protesting the agency’s decision to categorize “ordinary morning sickness” and “leg edema associated with pregnancy” as common conditions that are not “diseases.” Under the dangerous provisions of DSHEA, that categorization would allow drug supplement manufacturers to promote products as treatments of those conditions without first proving that the products are safe and effective. We strongly disagreed with that categorization.
“Both morning sickness and edema of pregnancy, when uncomfortable enough to cause a woman to use a substance for relief of symptoms, are severe enough to be considered diseases. We urge you immediately to amend the rule explicitly to include morning sickness and edema of pregnancy as diseases. Although these are the only two pregnancy-related conditions which are explicitly mentioned, we are opposed to the idea that any product claims for a pregnancy-related condition–be it structure/function or disease masquerading as non-disease such as nausea/vomiting or edema of pregnancy–be allowed to escape regulation as drugs. The exceptions, of course are vitamins (other than vitamin A supplements) and iron because there is actual evidence of deficiencies of these chemicals in pregnant women.
Moreover, morning sickness and edema of pregnancy and other problems associated with pregnancy, when severe enough to cause a woman to seek treatment, cannot be considered “normal.” Rather, in that circumstance, the condition could very well be one that could cause “significant or permanent harm.” For example, edema of pregnancy could well be an early symptom of pre-eclampsia or other types of toxemia of pregnancy which, if undiagnosed and not properly treated, can jeopardize the health of both the mother and infant. Morning sickness can progress to hyperemesis gravidarum (extreme and persistent vomiting) and severe dehydration and become life-threatening for mother and infant. Thus, even if pregnancy were properly categorized as a “life stage or process” comparable to adolescence or menopause–which it is not–these conditions would be diseases, under the FDA’s own reasoning. See 65 Fed. Reg. 1020.
Even if the FDA decides, based on concerns about maternal and fetal harm, to disallow all pregnancy-related claims, this is not enough. Given that millions of Americans use herbals/dietary supplements, even in the absence of claims for treating problems of pregnancy, pregnant women may continue to use the supplements they started to use before they became pregnant. Thus, all supplements should be required to carry a warning “DO NOT USE IF YOU ARE PREGNANT” unless there is clear evidence from well conducted studies that there are no adverse reproductive effects. Given that three such chemicals, caffeine, ephedra and vitamin A are known to cause birth defects or other adverse effects on reproduction and that few of the others have been tested, the combination of unknown reproductive toxicity and unknown benefit should serve to disallow their sale without the above pregnancy warning. A time limit should be placed for allowing the companies to conduct and submit to the FDA the reproductive toxicity studies necessary to determine these risks.
Since the generation of women who are now in the child-bearing age range are much more likely than their counterparts five or ten years ago to use the Internet as a source of information, it is instructive to look at the confusing, often conflicting information concerning herbals and pregnancy posted on the Web, usually by companies selling herbals/food supplements.
On one website is a list of herbals recommended for use by pregnant women. It includes such substances as black cohosh, blue cohosh (both to be used only during the third trimester), cleavers and horsetail. The company sponsoring this website is Snowbound Herbals. (Sbherbals.com/usefulin pregnancy.html)
On another website, information compiled by an RN and an Ob/Gyn discusses “Herbs to Avoid During Pregnancy and Breast Feeding” Among a list of herbals which are said to be too dangerous to use by pregnant women are several herbals also mentioned on the above list as recommended for use by pregnant women. These are “Black Cohosh: Can cause abortion. Diuretic”; “Blue Cohosh: Can cause abortion, induce contractions, diuretic”; “Cleavers: Strong diuretic–not good for diabetics either”; “Horsetail: Diuretic, astringent”.
Even more confusing is the fact that on another part of Snowbound Herbals website, under a section entitled “Herbs to Avoid in Pregnancy”, two of the herbs to avoid, fennel “uterine stimulant, essential oils” and Lavender “essential oils and bitter principles” are ones recommended as “useful for pregnancy” on the above-mentioned portion of their website.
The cause of most birth defects remains unknown. The best evidence suggests that many birth defects are caused by agents that humans have consumed for hundreds of years. Although we do not have the evidence to identify which dietary supplements have been and continue to cause birth defects, it is reasonable to assume that humans are now consuming such agents. A government regulation that facilitates consumption by pregnant women of such agents, which have not been tested for their adverse effects on the fetus, will unfortunately put embryos and fetuses at risk.
In sharp contrast, chemicals that are classified as drugs must undergo rigorous scrutiny, before marketing approval, for any adverse effects on reproduction, including fetal toxicity and birth defects. As a result, data are available to allow such drugs to be categorized into one of several categories concerning risk of use during pregnancy. Currently, 81 drugs are listed in FDA Pregnancy Category X, defined as: “Studies in animals or humans demonstrate fetal abnormalities or adverse reaction reports indicate evidence of fetal risk. The risk of use in a pregnant woman clearly outweighs any possible benefit.” Included on this list are such chemicals as vitamin A, ephedrine, and caffeine–all of which are found, not infrequently, in herbal preparations or dietary supplements. When sold as herbals or food supplements, these three chemicals sometimes, but not always, have a pregnancy warning. Because DSHEA does not allow the FDA to require the kinds of studies that would produce evidence to categorize other food supplements or herbals into safe or unsafe categories for use in pregnancy, claims for morning sickness or edema of pregnancy or any other pregnancy-related claims will be unaccompanied by any assurance that the products will not cause birth defects or other kinds of fetal toxicity.
The Presidential Executive Order of April 21, 1997, “Protecting Infants and Children from Environmental Health and Safety Hazards” speaks clearly to the recognition of the unique vulnerability of fetuses, infants and children. Because of its recognition of this heightened vulnerability to various chemicals, it requires all agencies of the federal government to take into account the unique vulnerabilities of infants and children in setting standards and issuing regulations. This applies to drug supplements as well as to “traditional” drugs.
4. More rigorous checks for contaminants such as lead, arsenic, digitalis activity and other toxins
Beyond the lack of meticulous evaluation of the safety and effectiveness of the ingredients which are supposed to be in these drug supplements, there is the additional problem, with this dangerously under-regulated industry, of contamination. In a study published in the New England Journal of Medicine (September 17, 1998, volume 239, page 847), scientists from the California Department of Health reported that 32% of 260 Asian herbal products purchased off the shelves in California stores were contaminated with lead, arsenic or undeclared pharmaceuticals such as digitalis. Although this may be partially remedied when the long-overdue FDA Good Manufacturing Practices (GMP) regulations are issued, random checks such as done in the California study will probably continue to yield positive results.
The Need for Legislation to Significantly Strengthen the FDA’s Ability to Properly Regulate Drug Supplements
Since at the heart of this problem is the irrational legal distinction that has been made between those pharmacologically active chemicals which are regulated as prescription or over-the-counter drugs and those which others call dietary supplements which I call drug supplements, eventually the same standards for safety and effectiveness must be adopted. These drug supplements are either safe and effective or they are not and if there is not adequate evidence of their safety and effectiveness, why should they be used?
In addition to standards for safety and effectiveness, other legislative changes should include a mandatory adverse event reporting requirement for all drug supplement manufacturers, mandatory warning labels for risks, requirements for company and product registration, and identification of the raw ingredients and the source (by country) for each of the ingredients in each product. This latter requirement is necessary to ensure that BSE-contaminated recycled cow organs do not appear on the shelves in this country as drug supplements. In addition, mandated funds are necessary to implement and enforce the Good Manufacturing Practices regulation that will hopefully be finalized soon. In addition, the FDA should be appropriated the funds to purchase the entire drug supplement database of the American Association of Poison Control Centers. At present, only the ephedra alkaloid cases have been contracted for by the FDA.
* I will mainly use the phrase “drug supplements” instead of “dietary supplements” because the latter term is misleading and ignores the evidence that all of these chemicals or chemical mixes have pharmacologic and structural properties which are in the realm of drugs, not foods. The American Association of Poison Control Centers (AAPCC) correctly categorizes herbals/dietary supplements as pharmaceutical products because they have pharmacologic activity.
[i] Haller, C. A.; Benowitz, N. L. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000; 343:1833-8
[ii] Woosley, R. Letter to the FDA. August 18,1999
[iii] Public Citizen Health Research Group letter to FDA Commissioner Dr. Jane Henney, February 3, 2000.