JULY 18, 1991
FOR RELEASE ONLY UPON DELIVERY
Mr. Chairman:
Thank you for the opportunity to appear before the Subcommittee today. I am Dr. Douglas Archer, Deputy Director of FDA's Center for Food Safety and Applied Nutrition. With me today are: Ms. Mary Pendergast, Advisor to the Commissioner, Mr. Daniel Michels, Director of Compliance of FDA's Center for Drug Evaluation and Research, Dr. Samuel Page, Chief of CFSAN's Natural Products and Instrumentation Branch, and Mr. Philip Derfler, Associate General Counsel for Foods.
Your letter of invitation asked that we discuss the FDA's regulation of the amino acid, L-tryptophan (LT). We will also discuss the Agency's actions in response to the onset of an illness designated Eosinophilia-Myalgia Syndrome (EMS), which is associated with the consumption of LT. EMS is a multi organ system disorder which is characterized by elevated eosinophil (a type of white blood cell) counts and severe muscle pain. Other symptoms include numbness, weakness, joint pain, swelling, rash, sclerodermiform skin changes, fever, and cough.
Because it is not yet clear whether the illness is associated with a contaminant, L-tryptophan itself, or even due to individual abnormalities in L-tryptophan metabolism, we will also discuss the scientific research to date.
OVERVIEW
The LT/EMS incident that is the focus of this hearing, and especially the suffering and death of those who used the products in question, demonstrate the dangers inherent in the various health fraud schemes that are being perpetrated upon segments of the American Public. As part of Commissioner Kessler's announced program of stepped up enforcement, he has stated unequivocally that the FDA will not tolerate unsubstantiated drug claims being made for foods, including amino acid supplements. But enforcement alone will not solve the problems that led to the EMS epidemic in 1989. Doctors should not be telling patients to take products such as L-tryptophan and L-lysine, for drug purposes. The medical and health claims made for such products have not been established and the risks from the suggested uses of such products may be substantial. This is far different from physicians exercising informed medical Judgment in selecting approved drugs with known risks for unapproved uses.
Another aspect of this problem is that some segments of the supplement industry have been able to capitalize on the confusion created by health claims for foods. We are working to correct that confusion. Health claims may be appropriate as to how the overall diet can be structured to reduce the risk of developing certain diet related diseases, but they cannot be used to claim that a product will cure, mitigate, or prevent disease. Moreover, as long as there is a strong demand for these products, unscrupulous suppliers will continue to appear and count legal fees, FDA seizures and fines as merely a cost of doing business.
We have alerted the public and contacted every U.S. distributor of manufactured LT products subject to this voluntary recall by domestic manufacturers. But we fear not everyone is being open and above-board in responding to this problem; as a result of the recall by manufacturers, some consumers may still be hoarding the product, and unscrupulous merchants may be selling the product. People who are taking hoarded LT product are placing themselves at risk of serious illness. Such self-medication is misdirected, and we warn them that the risk is not worth any alleged benefit -- a benefit which has not been scientifically demonstrated. We urge these consumers to consult with their physician before continuing to take LT. We call on dealers to destroy or return to their distributor any unsold product.
REGULATORY STATUS OF LT
LT is one of the amino acids which are building blocks of all plant and animal proteins. It is an essential amino acid, that is, it must be supplied from the diet because it cannot be manufactured in the body in amounts adequate for normal growth or nutrition. People get all the amino acids they require just by eating an adequate diet.
LT as an entity is regulated by FDA as a food additive and as a drug. Amino acids such as LT are approved for use to enhance the protein quality of food. In addition, amino acids have been approved for addition to foods designed to meet the nutritional requirements of individuals who have impaired digestion or absorption capacity and of individuals who have severe hypersensitivity to intact proteins. Such uses include infant formulas, medical foods and fortified protein supplements. As a drug LT has been approved for use in certain intravenous (parenteral) drug products. It was approved as a drug primarily because of the route of administration rather than its intended uses. These approved uses, however, do not allow marketing of LT as a component of a dietary supplement. LT cannot lawfully be used as an ingredient of such a food until FDA approves a food additive petition based on a showing that LT is safe for use in those products.
Oral dosage forms of LT, marketed as food supplements, have been promoted to treat a variety of medical problems including insomnia, premenstrual tension, stress, and depression. Marketing LT for the treatment, cure, or prevention of any illness, disease, sign, or symptom makes the product a drug under the Federal Food, Drug, and Cosmetic (FDC) Act. However, there is no approved new drug application that allows its marketing in any oral dosage form, nor is there any condition for which LT is generally recognized as safe and effective.
In summary, the only lawfully marketed products with LT are foods in compliance with 21 CFR 172.320, infant formulas, enteral nutrition products, and approved parenteral drug products. Any other product that contains manufactured LT is illegally marketed.
AGENCY ACTIONS IN THE EMS/LT INCIDENT
We think that FDA acted promptly, effectively and responsibly in responding to the EMS/LT incident. Of course we did not act alone. Much credit must be given to the public health network in this country, especially the Centers for Disease Control (CDC), and the State health officials in New Mexico, Minnesota, Oregon, and New York. Let me briefly recount FDA's efforts.
Oral dosage forms of LT have been promoted in magazine and newspaper articles and advertisements to treat a variety of problems, including insomnia, premenstrual tension, stress, pain, weight lose and depression. The products themselves were not labeled for these medical indications but were being sold as food supplements. FDA frowned on consumer purchases for these uses as unnecessary and as a waste of money (FDA Consumer, September 1985, "The Essential Guide to Amino Acids" and "The Confusing World of Health Food"s July/August 1978).
However, for reasons that I will explain later, we felt constrained to tolerate these practices primarily because we had no indications of any adverse effects from these usage. We had even solicited reports of adverse reactions in a 1986 note in the Journal of the American Medical Association.
FDA's first knowledge of any public health concern with LT was a report to FDA headquarter. by a field investigator from New Mexico late Tuesday afternoon, November 7, 1989. We immediately started compiling information, and establishing contacts to evaluate the report. Working through the week and Veteran. Day holiday, FDA staff evaluated the press report, gathered additional information, and conferred with CDC, state officials, and our own medical experts. At the time there were 30 reported cases of EMS and no deaths. FDA issued a strong warning to the public on Saturday morning, November 11, 1989. Our warning advised individuals to discontinue using L-tryptophan and to check with their physician. if they were under a doctor's care. We issued our warning early, for at this time, CDC's scientific Judgment was that there was insufficient epidemiologic information to make a definitive association between LT and the reported illness, later named Eosinophi1ia-Myalgia Syndrome.
One week later on November 17, 1989, acting in consultation with CDC, FDA (under the direction of then-Acting Commissioner James S. Benson) requested a nationwide recall of all over-the-counter dietary supplements in capsule or tablet form providing 100 mg or more of LT in a daily dose. The recall was limited to products providing 100 mg or more per day because, at the time, the lowest daily intake associated with illness was 150 mg. In addition FDA issued an Import Alert to detain all foreign shipments of manufactured LT. We also maintained close contact with all levels of CDC to identify the cause of the syndrome and to coordinate activities.
Subsequent to the recall there was one reported case of EMS associated with consumption of LT in a daily dose level of less than 100 mg. Because of this one case and because some firms took actions to try to circumvent the recall, e.g., reformulating their products to contain just less than 100 mg, on March 23, 1990, Acting Commissioner Benson requested an expansion of the recall to all marketed product. containing added manufactured LT, except those that were permitted to contain added LT by existing food additive regulations. The net effect of the recall and import alert on LT was a ban on the oral dosage form because the raw material was imported. All bulk product was manufactured in Japan by six different firms, the major supplier being Showa Denko, K.K., and distributed in raw powder form. U.S. manufacturers formulated oral dosage forms for distribution from the raw powder. Finally, on February 19, 1991, because of the strong epidemiological relationship between EMS and LT manufactured by Showa Denko, K.K., FDA expanded the recall to include legal products containing Showa Denko LT.
We believe that we have been successful in alerting the distribution system and the public to the problem associated with manufactured LT. FDA field offices conducted over 12,300 visit. to supplement manufacturers, repackers, distributors, wholesalers and retailers to audit the effectiveness of the recall. Although to date 31 deaths and more than 1,500 cases of EMS have been reported to CDC, it is clear from epidemiological data that our decisive action upon learning of the problem averted many additional injuries. The attached chart of the onset of the illness show that less than one percent of the cases had onset after the November 17, 1989 recall requested by FDA.
As I stated earlier, we are concerned there may be unscrupulous merchants still selling the product. We consider marketing of LT after this recall as a very serious violation of the FDC Act. The Agency will vigorously pursue regulatory actions, including criminal prosecution if appropriate.
Until we know more about the etiology of EMS, including the role of contaminants, LT itself and certain predisposing health conditions, FDA cannot allow LT back on the market except for the limited uses covered by existing regulation. Even if all health issues were resolved, a food additive petition on the use of LT in dietary supplements would have to be filed and approved before dietary supplements containing this substance could again be marketed.
REGULATORY HISTORY
A recounting of the history of the regulation of LT will provide perspective on the Agency's posture toward the marketing of the dietary supplement uses of LT and the other amino acids.
In 1945, FDA issued a Trade Correspondence that stated that a food to which an amino acid is added would be regarded as a food for a special dietary use and must be so labeled, but may also in some cases be subject to the drug provisions of the Act. Amino acid preparations offered for parenteral use fall into the category of new drugs.
The 1958 Food Additives Amendment required the premarket approval of any substance whose intended use could reasonably be expected to result in its becoming a component of food unless the substance is generally recognized as safe (GRAS) or prior sanctioned. In 1960, FDA proposed, and in 1961, it decided to list LT as GRAS for use in dietary supplements,
(Title 21, Code of Federal Regulations (CFR) 121.101(d) (5) (1970)).
In 1972, FDA proposed to revoke the GRAS status of the use of LT and other amino acids in dietary supplements because FDA felt that the available data did not allow us to say these uses were safe. Questions concerned: the potential for a free amino acid to produce toxic or other adverse effects; the potential risk to health involving the antagonism of moderate amounts of certain amino acids by relatively high amounts of certain others; and the potential for an amino acid imbalanced diet which affects the body's quantitative need for an amino acid. These questions were based on experimental animal studies cited in the scientific literature. Furthermore, there was an Agency desire to closely regulate the addition of all vitamin, mineral and amino acids used in foods, including dietary supplements.
At the same time that we proposed to revoke the GRAS status of the use of amino acids in dietary supplements, we proposed a food additive regulation setting the conditions under which amino acids could be used to improve the protein quality of foods. The final regulations published in the Federal Register of July 26, 1973, stated that we wanted to prevent the random addition of amino acids to foods, and so limited the approved food additive use of amino acids to foods that contained naturally occurring, primarily intact protein that is considered a significant dietary source. The Agency also addressed the use of amino acids in special formulations for nutritional use in medical conditions.
From 1974 through 1976 LT was listed in the CFR as a food additive. However, because of an error in recodifying FDA' s regulations, LT was listed as GRAS for use as a nutrient and/or dietary supplement in the CFR published March 15, 1977. We corrected this error by a Notice dated October 28, 1977. However this error prejudiced at least one attempt to seize LT supplement products.
In 1977, FDA seized LT tablets on the grounds that the tablets contained an unapproved food additive. The seizure was contested (Schiff case), and the court found for the manufacturer, pointing out that in publishing the new CFR, there had been an inadvertent failure to remove the old GRAS list which included LT. The court found that the manufacturer was entitled to rely on the published regulations even if in error. In another seizure initiated in 1977 against LT as a dietary supplement (the L-tryptophan-Rest case), FDA agreed to dismissal with prejudice against the Government on September 14, 1982. It was clear that the court was inclined to agree with the defendant's position that the product was GRAS. This five-year litigation is indicative of the resource intensive nature of this type of case, requiring expert witnesses with the accompanying depositions and other discovery devices, and has become a significant factor in deciding whether to pursue additional cases.
The so-called Proxmire Amendment to the FDC Act is another factor influencing the atmosphere in which the Agency made its decisions regarding the regulation of amino acids. The Proxmire Amendment was passed in 1976 to prevent FDA from limiting the potency of a vitamin or mineral supplement based on either food misbranding charges or on the grounds that the supplement would be a drug if it exceeded the level of potency that FDA considered to be rational or useful. The amendment was passed in direct response to an FDA rulemaking effort and it seemed to signal Congressional intent that supplement-type products not be regulated without indication. of real danger to health.
While some concerns regarding the safety of LT had been noted, they were based on experiments in animals. And human exposures at the time included a variety of clinical evaluations, particularly in other countries. It was not until the recent incidents that human toxicity was reported. Because of the apparent minimal safety concerns, FDA chose to take no further actions as LT cases were resource intensive and appeared to be not winnable so long as no health problem existed.
FUTURE REGULATORY DIRECTION
The EMS/LT incident has prompted us to reexamine our regulatory posture toward amino acids and dietary supplements. Two studies are underway:
(1) FASEB Report on Amino Acids
FDA has contracted for an objective, up-to-date scientific review of the safety of use of free amino acids to be done by the Federation of American societies for Experimental Biology (FASEB). FDA will use this report to establish its enforcement priorities with regard to these product.
The FASEB study is scheduled to be completed by December 31, 1991, and will: (a) identify current products in the marketplace and describe their active principal ingredients and total nutrient composition; (b) describe current label and labeling information on products identified in the marketplace, including descriptions of recommended intake levels; (c) review dietary exposure data to subject substances by the U.S. population and subgroups; (d) identify animal or clinical studies and cave reports that bear on the safety of these products as currently used; and (e) identify safety end points and provide guidelines for interpretation of data for evaluating safety issues.
In addition' the study report will address: (a) the safe range of intake, if any, for each amino acid and related compounds from special dietary foods; (b) the criteria utilized in evaluating safety of each amino acid; and (c) a critique of strengths and weaknesses of available scientific evidence.
(2) Dietary Supplement Task Force
In addition to the work being done on amino acids by FASEB, Commissioner Kessler has established a FDA Task Force to review the Agency's regulation of dietary supplements and to recommend a course of action with respect to these products. Amino acids are one class of substances being considered by the task force; vitamins and mineral are another class; currently all other dietary supplement products fall into a third general class. The Task Force, which had its first meeting in April 1991, has announced a public hearing for August 29 and 30 to receive comments on how dietary supplements should be regulated. The task force anticipates making it. recommendations in late 1991.
RESEARCH EFFORTS
The Governmental research on the LT/EMS problem is a fully integrated effort of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), CDC and FDA. Showa Denko, K.K. and numerous independent researchers, some funded by Showa Denko, K.K., have also devoted extensive efforts to determining the cause of the disease. The initial chemistry research efforts focused on the screening for contaminants in LT, including searches for toxic elements, heat decomposition products, microbiological agents, and industrial chemical contaminants. An FDA/CDC team developed a chromatographic procedure for profiling LT samples for trace organic components. Using this technique and epidemiologic data, several components could be associated with the illness. FDA/CDC and, independently, researchers at the Mayo Clinic and Showa Denko K.K., identified one of these contaminants as 1,1'-ethylidene-bis-L-tryptophan (EBT). This compound can be readily formed by the reaction of acetaldehyde, a common product of fermentation and other biological processes, and LT. Several other contaminants have been identified. On-going research will determine if these contaminants cause or contribute to EMS.
One of the most significant scientific breakthroughs was the development of an animal model for EMS. Efforts in this area were led by researchers at NIMH. After suspect LT was fed to a special strain of rats, several pathological changes that were comparable to those in the EMS patients were observed. Testing of some of the purified contaminants is in progress.
FDA will continue research planning and coordination with NIMH, NIH, and CDC. Major research efforts by FDA include continuation or expansion of current studies of:
That concludes my prepared remarks. My colleagues and I would be happy to respond to any questions the Subcommittee may have.
This statement was issued on July 18, 1991.
For more recent information on Dietary Supplements
See
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