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Posted July 22, 2011: by Bill Sardi
New Dietary Ingredient Notifications and Related Issues; Availability
Docket No. FDA-2011-D-0376
Comment Tracking Number: 80ec9da3
Date: July 22, 2011
Food & Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Knowledge of Health, Inc.
457 West Allen Avenue, Suite 117
San Dimas, CA 91773
This comment is submitted to the FDA under 21 CFR 10.115(g)(5)).
The New Dietary Ingredient (NDI) guideline, as drafted by FDA 16 years following the Dietary Supplement Health & Education Act of 1994, is impractical, imposes onerous and incalculable costs upon industry and consumers, would result in withdrawal of many dietary supplements which Americans rely upon for their health, may end up being nothing more than a giant paperwork exercise without improving public health and safety, and represents issuance of yet another document from FDA that unfairly portrays dietary supplements as unsafe and “adulterated” which may result in consumers backing away from use of supplements for no justifiable reason.
No other industry has been similarly challenged to submit virtually all of its product offerings for safety testing retroactively. It is not foreseeable that an entire industry, particularly small business entities, will be capable of conducting safety tests on virtually all of its product offerings and that FDA would even be capable of evaluating NDI applications in a timely way.
The FDA NDI draft guideline claims there are 56,000 dietary supplements currently being sold in the marketplace, for which only 700 have submitted NDI notifications. Assume that NDI compliance efforts produce 40,000 NDI submissions over a 3-year period. Just how would FDA anticipate timely review given such a high volume of NDI submissions?
At 240 workdays per year, not counting re-evaluations, the FDA would have to review and approve/disapprove 55 NDI submissions per day. Anyone can foresee inevitable bureaucratic delays similar to those now experienced by the US Patent Office where over 1 million patent applications are back-logged.
Furthermore, it may take years of testing before a new dietary supplement could be marketed. It would then be impossible for supplement manufacturers to update their products in a timely manner in light of newly published science. For example, if it is determined that inclusion or an increase in the dosage of trace minerals such as iodine, or of essential vitamins such as vitamin D in multivitamins would improve public health, which some current scientific literature suggests, it might take years to make that change under proposed NDI guidelines.
Furthermore, FDA review may cause endless re-review and delays and unlimited expenses that small or large businesses could not possibly incur. For these reasons, the NDI guideline should be deemed to be impractical and often beyond the manpower capabilities of most dietary supplement manufacturers. It is an anti-small business document.
The rationale for declaring dietary supplements manufactured since 1994 as “adulterated” is contrived. Thousands of dietary supplements have been safely introduced to the marketplace since 1994 without a measurable increase in morbidity or mortality. The FDA concedes this fact to some degree, but demands manufacturers submit data showing safe history of a product for more than two decades. Sixteen years (since 1994) is not sufficient for FDA.
Few if any supplement companies have kept adequate safety records (adverse reaction data) over the entire time period beginning in 1994. Some companies keep adverse event records, but they are not expected to be remarkable given the low severity and rate of side effects associated with dietary supplements. Yet the FDA demands long-term safety data be examined to receive NDI status.
The FDA Center for Food Safety and Nutrition (CFSAN) conducted a 1-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Of 275 dietary supplements calls, 41% involved exposures to products that produced symptoms, but only two-thirds were rated as probably or possibly related to supplement use. Eight adverse events required hospital admission. Most supplement-related adverse events were deemed to be minor. Clinically significant toxic effects were most frequently reported with caffeine and yohimbe-containing products.
Then in 2007 the FDA began tabulating adverse events reported by dietary supplement manufacturers directly rather than via poison control centers. There were only 604 adverse event reports received, 368 reports from supplement manufacturers and 236 reports from consumers or health care professionals. This amounts to 1 adverse event report per year for every 600 or so dietary supplements on the market.
These adverse event reports do not necessarily serve as evidence that any reported symptoms or adverse reactions were caused by dietary supplements in question, only that these products were associated with such reports. Five deaths and 85 hospitalizations were reported during this monitoring time period, but again, the deaths may or may not be related to supplement use. An FDA official said: “Some of these deaths were likely due to underlying medical conditions.” For comparison, there were 482,154 adverse-event reports for FDA-approved prescription drugs in 2007.
The prevailing question is, what existing public health problem is being averted by compliance with this proposed guideline?
The DRAFT GUIDANCE document says:
“If the required premarket notification is not submitted to FDA, section 413(a) of the FD&C Act provides that the dietary supplement containing the NDI is deemed to be adulterated under section 402(f) of the FD&C Act (21 U.S.C. 342(f)). Even if the notification is submitted as required, the dietary supplement containing the NDI is adulterated under section 402(f) unless there is a history of use or other evidence of safety establishing that the NDI, when used under the conditions recommended or suggested in the labeling of the dietary supplement, will reasonably be expected to be safe.”
This is technical adulteration (by omission of safety tests), not true adulteration (i.e. potentially toxic impurities) that would pose risk to public health, nor is it intentional adulteration (known but concealed toxins or impurities). There is no dietary supplement in current use that has been identified as a significant risk to public health. So compliance with the new NDI guideline may end up being a paperwork exercise rather than a true advancement in ensuring dietary supplements safety.
Foods do not undergo safety testing in such a manner as this. The FDA is applying a drug standard for dietary supplements. Yet there are far more outbreaks of food poisoning, with some deaths reported from foods. Dietary supplements are legally defined as extensions of foods, not drugs.
The fact that there are no documented outbreaks of toxicity or birth defects that have been attributed to dietary supplements that have been introduced since the passage of the Dietary Supplement Health & Education Act of 1994 suggests this is purely an expensive bureaucratic paperwork exercise that has no meaningful end point in mind.
There is no economic impact statement issued by the FDA in regard to what percentage of existing products on store shelves would be forced to comply with toxicity testing, nor is there any economic impact data regarding how many jobs would be lost, number of products that would disappear from store shelves, and how many products generate sufficient profits to economically justify the cost of testing, and what the impact of these new guidelines would have upon consumer prices.
It is likely that most dietary supplements on store shelves today use newer sources of dietary ingredients or have been reformulated since 1994 and would be subject to safety testing. This is an unprecedented and far-reaching proposal aimed at an industry that has produced relatively safe products and would force manufacturers to submit every product for safety testing under the presumption that their products, which have been sold on store shelves for years, are unsafe until proven otherwise.
According to Joseph F Borzelleca PhD, of the Department of Pharmacology & Toxicology at Virginia Commonwealth University School of Medicine, the safety of a new food ingredient may take up to seven years and cost tens of millions of dollars. Such costs would be expected to result in soaring retail prices for dietary supplements, likely beyond the affordability of most consumers.
According to the American Botanical Council, the top selling herbal product for 2010 was cranberry with $35 million in sales. It would be very difficult to justify the cost of such testing even for the top-selling herbal product category as a whole (not just each cranberry product sold at retail).
The proposed NDI guideline should not proceed until an economic impact document is produced by industry. It appears the NDI guideline would virtually destroy the dietary supplement industry, which is akin to throwing the baby out with the bathwater.
Additionally, dietary supplements are safer than tap water, table salt, aspirin and even food, so how would the proposed testing requirements improve upon what currently exists?
Poison control center data do not confirm that dietary supplements pose significant risk for morbidity or mortality.
In the past there have been reported safety problems (deaths) involving Ephedra (Ma huang), a stimulant used by dieters, and for the amino acid tryptophan used as a sleep and antidepressant aid. But the widely publicized problems with Ephedra were largely produced by crash dieters who overdosed on Ephedra or Ephedra users who had pre-existing cardiac conditions., The tryptophan problem was isolated to a single pharmaceutical source of this molecule in Japan where the manufacturing process had been altered. It is unlikely that toxicity studies would have averted these problems since they are only proposed when manufacturing processes or ingredients change, not for every production batch.
It is noted that Ephedra produced proven weight loss while drugs that produced similar side effects were approved for use by the FDA.
If at all, any application of this proposed guideline should be applied to products from this point in time forward, not backwards to 1994. It took the FDA 16 years to create this proposed guideline and dietary supplements should not be assumed to be toxic or teratogenic (causing birth defects) until proven otherwise. It is the FDA’s responsibility to prove there is a public health problem and then take action.
It should be recognized that the very issuance of a document such as the NDI draft guideline can produce a cloud of suspicion over dietary supplements as a whole and result in a lack of consumer confidence. FDA has a history of irresponsible and unwarranted actions against the dietary supplement industry. These include tactics to unfairly frighten the public away from dietary supplements and to censor statements about dietary supplements that are true and factual.
The very fact that FDA proposes to test all dietary supplements for toxicity and teratogenicity (birth defects) could be interpreted by the public that all dietary supplements are unsafe and this could result in a massive and unjustified downturn in demand for dietary supplements. News headlines could pejoratively say “dietary supplement industry has never subjected its products for safety testing,” or “dietary supplement industry resists safety tests.”
For example, in the past FDA issued a public announcement inviting the public to report any side reactions related to the use of kava, a popular herbal product that has traditionally been used as an antidepressant and anti-anxiety agent. This was based upon poorly substantiated reports of side effects from kava use by pharmaceutical companies in Europe that offered kava as a drug. Those European suppliers apparently skirted around didn’t practice Good Manufacturing Processes and used cultivars of kava that were potentially toxic to the liver. There was no evidence that kava products in the U.S. were a significant problem.
Issuance of that announcement by FDA created an imagined fear that there was some problem with kava and sales of that herb declined to the point where growers of this herb in the South Pacific had to abandon their crops. Again, it was never demonstrated that there was any significant health problem posed by kava supplements in the U.S.
While FDA must issue documents that deal with public safety, documents such as the newly drafted NDI guidelines should include accompanying balanced language which explains dietary supplements are relatively safe when taken in suggested serving size and that there is no present need for undue concern by the public.
This petition to FDA extends beyond the proposed NDI guidance and suggests truthful statements about dietary supplements should be available for consumers to decide the level of evidence for themselves, not for government to decide for them. Court decisions have ruled in favor of more transparency rather than censorship for dietary supplement claims. Let the consumer decide.
The FDA has a long-standing policy to censor truthful facts about dietary supplements, namely to prohibit any mention that a dietary supplement prevents, treats or cures any disease. Yet in fact, dietary supplements do in fact prevent, treat and cure diseases. In fact, such a warning, that dietary supplements are “not intended to prevent, treat or cure disease” must be affixed to every dietary supplement label and accompany advertising materials.
Some obvious examples of dietary supplement that cure diseases are vitamin C for scurvy, vitamin D for rickets, vitamin B1 (thiamin) for beri beri, vitamin B3 (niacin) for pellagra and vitamin B12 (cobalamin) for pernicious anemia.
Industry is so intimidated by FDA it is reticent to say that vitamin C prevents the symptoms of scurvy, namely skin bruising, bleeding gums, fatigue, irritability and eye hemorrhage. The same is true for symptoms of rickets which includes soft bones, poor calcium absorption, weak immunity (abnormally low neutrophil count) and mental depression due to vitamin D deficiency. Ditto for symptoms of vitamin B1 deficiency, which include pain, premature graying of hair, uncontrolled eye twitching (nystagmus), chronic diarrhea that mimics irritable bowel, dermatitis (skin problems) and dementia (mental problems), and for B12 deficiency which produces symptoms of short-term memory loss, fatigue, sore tongue and burning feet.
The public cannot be informed of the link between these symptoms and a nutrient deficiency because the FDA deems these to be “disease claims” that are only appropriate for FDA-approved drugs. But no man-made pharmaceutical alternative to essential vitamins can adequately make up for a vitamin deficiency, leaving a needy population uninformed.
As a suggestion, manufacturers of dietary supplements should be permitted to publish health claims for their products as long as they are clearly categorized as in vitro (lab dish), animal (in vivo) or human studies, and specified as to whether the science is based upon a generic substance or the specific brand of supplement involved, and indicates the equivalent human dosage that was employed. A suggested format for publication of such information is provided below.
Dietary Supplement: ABC Company Vitamin C
Health claim: Prevents symptoms of scurvy: bleeding gums, fatigue, eye hemorrhage, irritability.
|Test-tube(lab dish) data (in vitro)||Animal data (in vivo)||Human data||Equivalent human dose employed|
|Studies conducted on generic vitamin C as ascorbic acid||Resolution of signs of scurvy: aching limbs, eye hemorrhage, skin bruising, bleeding gums, swelling, shortness of breath
Hodges RE, et al, Clinical Manifestations of ascorbic acid deficiency in man, Am J Clin Nut 1971 April; 24: 432-43. PMID: 5090631
|66.5 – 600 mg supplements, 77.5 mg from diet|
|Studies conducted on this specific brand of vitamin C||None|
All that the FDA currently allows to be stated on product labels is that a dietary supplement “supports a healthy heart, skin, liver, brain function, etc.,” which is too nebulous for the public to associate with their symptoms. In many instances, this results in patients being treated with inappropriate drugs for conditions that have a nutritional origin, which also deters self care.
Truthful and transparent dietary supplement labeling is particularly important for health conditions for which there are no approved drugs or effective drugs. For example, there is no FDA-approved drug for fatty liver, a condition that affects some 35% of American adults. There is evidence that some dietary supplements may be effective for this condition, such as rice bran IP6, milk thistle and resveratrol. Consumers should have access to this information closer to the point of sale for their own examination, preferably printed on the product label or accompanying literature.
Truthful and transparent supplement labeling is also important for mortal conditions for which there may only be safety and effectiveness data from animal studies. Since it is unethical to subject at-risk humans to controlled studies where an inactive placebo is used in lieu of standard treatment, animal data may be the only information available for consumer analysis.
An example is resveratrol, a molecule extracted from grapes or other botanical sources that is offered as a dietary supplement. Resveratrol has been shown to reduce the size of experimentally-produced heart attacks in laboratory animals to the point where an animal would survive an otherwise mortal event. Resveratrol is a potential alternative to aspirin, which is commonly used under the assumption that it prevents heart attacks.
However, a baby aspirin (81 mg) has been shown to be too low a dose to avert a heart attack and a standard aspirin tablet (325 mg) places aspirin users at risk for bleeding gastric ulcers which can be mortal. A few thousand people die from this problem annually. So in real terms, aspirin may not prevent mortal heart attacks as alleged. A recent large review involving over 100,000 subjects did not show that aspirin reduces cardiovascular mortality.
In light of the fact aspirin may not always avert a mortal heart attack, and resveratrol may switch on natural internal defenses in the heart (what is called cardioprotection) and turn a mortal heart attack into a non-mortal event, such information should be made available to the public, even though it is based solely upon animal data. Aspirin was initially found to avert heart attacks by retrospective analysis, not by prospective controlled studies.
To leave the public at large with the false assumption that aspirin prevent heart attacks, with no mention of resveratrol’s potential to prevent a mortal heart attack, appears to be unconscionable given that death is the consequence. Furthermore, there is the question, if a dietary supplement prevents death, is mortality a disease? Is a claim that a dietary supplement reduces the risk for death permissible under current guidelines?
It should be noted, even with food fortification programs, widespread deficiencies of essential nutrients are still prevalent, which suggests use of dietary supplements should be expanded, not restricted and overregulated.
We now live in a genomic era where it is recognized that large segments of the population may require greater than RDA (Recommended Daily Allowance) levels of nutrients to protect and maintain their genome (library of genes) based upon their genetic inheritance.
For example, Asians require more vitamin C than the diet provides due to an inherited difficulty in controlling iron. Those of European or East Indian descent require more vitamin B9 (folic acid) and vitamin B12 (cobalamin). These deficiencies cannot be easily met by dietary intake.
There also are large segments of the American population that have health habits which deplete certain vitamins, such as tobacco smoking (40 million American smokers), which depletes vitamin C. Dietary supplementation may be the only practical way of achieving vitamin sufficiency for smokers. More than three times greater intake (200 mg) of vitamin C than the RDA (60 mg) is suggested for smokers to be vitamin C sufficient.  The typical American diet provides around 110 mg of vitamin C per day. Dietary supplements would close this gap.
The time lag in incorporating newly recognized nutrient requirements into food fortification programs also demands expanded use of dietary supplements. Health authorities are typically slow in updating nutrient requirements in foods. Such a time lag in applied science would most certainly dial in a certain level of needless disease in the population at large. Given emerging science and typically slow response by public health authorities, the need for economical and readily available dietary supplements becomes even more apparent.
Additionally, the fact that many Americans now cannot afford health insurance suggests greater emphasis upon self care, for which dietary supplements are an important component. A large percentage of Americans rely upon dietary supplements to stay healthy. An estimated 50% of Americans, greater than 70% of senior Americans, consume dietary supplements.
It should be said that far more Americans die of nutrient deficiencies than of alleged adulteration or misbranding of dietary supplements.
It is ironic, in an era of embarrassing recalls and withdrawals of FDA-approved drugs, that the FDA targets dietary supplements for safety issues. Prescription drugs are approved based upon limited data from a few hundred human subjects and the drug is then allowed to be widely marketed and advertised until safety data is acquired on larger groups of people. Then, as has happened far too often, a drug is recalled by FDA or withdrawn by the manufacturer.,, In some instances, such as Vioxx, FDA was not forthcoming about mortality data involving anti-inflammatory drugs (e.g. Vioxx and other non-steroidal anti-inflammatory drugs), which resulted in thousands of avoidable deaths. A whistle blower had to reveal these facts to the American public by traveling overseas to make a public statement in a foreign medical journal.
Meanwhile, if use of a dietary supplement, even if misused, results in just a few deaths, this is widely reported in the news media and products may be forced to be withdrawn or recalled by FDA, as was the case with Ephedra.
So in essence what we have is a system of oversight that results in drugs having a license to kill, while dietary supplements face bureaucratic overkill by a government agency that claims to be working in the public’s interest.
A criticism is that dietary supplements are often used by the public to treat disease when there is insufficient evidence for such use as there is for drugs. But it should also be said that the FDA more than infrequently approves ineffective prescription drugs., “FDA approved” does not necessarily equate with effectiveness.
Even large classes of FDA are approved by the FDA without proven effectiveness. For example, statin cholesterol-lowering drugs do reduce circulating cholesterol levels but have not been shown to reduce mortality for coronary artery disease. Yielding to pressure from the pharmaceutical industry, cancer drugs are now approved by the FDA without improving overall survival. It cannot be accurately said in all cases that dietary supplements are not proven to be as effective as prescription drugs. They may be equally ineffective.
For these and other reasons, this petition submitted to the FDA strongly advocates dietary supplements be removed from oversight by an agency that has obvious conflicts of interest in the promotion drugs over dietary supplements.
Greater Congressional oversight appears to be the only option to protect the freedom to purchase dietary supplements without onerous regulation and resultant high cost.
It should be said here, as a final note, Congress received more letters regarding the issue of dietary supplement freedom during the time period preceding passage of the Dietary Supplement Health & Education Act of 1994 than any other issue facing federal legislators. Congressional representative who seek re-election will surely take into consideration public demands for unhindered access to affordable dietary supplements and table the proposed new dietary ingredient guidelines indefinitely.
Many foreigners travel to America to purchase dietary supplements in volume because they are more expensive, available only by prescription, or totally unavailable in their native country. These foreign consumers come to America to purchase dietary supplements because this is a land known for free markets and freedom to use dietary supplements without prescription. It would be an embarrassing irony, in “the land of the free,” that under the guise of consumer protection, such health freedoms would be discarded.
Knowledge of Health, Inc.
457 West Allen Avenue, Suite 117
San Dimas, CA 91773
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