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Meetings and Workshops |
U.S. Food and Drug Administration • Center for Drug Evaluation and Research |
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Meetings and Workshops |
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Food and Drug Administration Meeting on Safety Issues Associated with DIETARY SUPPLEMENT USE DURING PREGNANCY Thursday, March 30, 2000 Ballroom Gaithersburg Hilton 620 Perry Parkway Gaithersburg, Maryland 20877 Proceedings By: CASET Associates, Ltd. 10201 Lee Highway, Suite 160 Fairfax, VA 22030 (703) 352-0091 PARTICIPANTS: Rose Cunningham, Project Manager FDA Panel Members: Margaret Dotzel, JD Michael Greene, MD Bonnie Lee Joe Levitt, JD Louisa Nickerson, JD Bernard Schwetz, DVM, PhD Janet Woodcock, MD Morning Public Panel Members: Josef Brinckmann Annette Dickinson Jan Friedman Donald Mattison, MD Michael McGuffin Allen Mitchell Dr. William Soller Afternoon Public Panel Members: Marietta Anthony Dr. David Erickson Juliette Kendrick Godfrey Oakley, Jr., MD, MSPM Dr. Susan Panny Sidney Wolfe, MD TABLE OF CONTENTS Page Administrative Announcements 1 Rose Cunningham Opening Remarks and Introductions 2 Bernard Schwetz Overview of Legal Background 7 Louisa Nickerson Morning Public Panel Presentations Dr. R. William Soller, Sr. Vice President 17 Consumer Healthcare Products Association Allen A. Mitchell, Director 27 Slone Epidemiology Unit Boston University School of Public Medicine Michael McGuffin, President 33 American Herbal Products Association Questions from FDA Panel 44 Discussion from Floor 67 Morning Public Panel Presentations (Continued) Annette Dickinson, Vice President for Scientific and 77 Regulatory Affairs, The Council for Responsible Nutrition Donald R. Mattison, MD, Medical Director 85 March of Dimes Birth Defects Foundation Joseph A. Brinckmann, Research and Development Manager 95 Traditional Medicinals Jan M. Friedman, Professor 103 Medical Genetics, University of British Columbia Questions from FDA Panel 111 Introduction of Afternoon Public Panel Members 128 Bernard Schwetz Afternoon Public Panel Presentations Sidney M. Wolfe, MD, Director, 128 Public Citizen's Health Research Group Dr. Susan Panny 137 American Academy of Pediatrics Juliette S. Kendrick, Medical Epidemiologist 142 Centers for Disease Control and Prevention Dr. J. David Erickson 149 Centers for Disease Control and Prevention Questions from FDA Panel 154 Discussion from Floor 166 Afternoon Public Panel Presentations (Continued) Marietta Anthony, Director of Women's Health 170 Department of Pharmacology, Georgetown University Godfrey P. Oakley, Jr., MD, M.S.P.M. 177 Visiting Professor, Epidemiology Rollins School of Public Health of Emory University Questions from FDA Panel 183 P R O C E E D I N G S (9:05 a.m.) Agenda Item: Administrative Announcements MS. CUNNINGHAM: Good morning, ladies and gentlemen. I am Rose Cunningham. I am the project manager for this meeting. The Public Meeting on Safety Issues Associated With Dietary Supplement Use During Pregnancy is about to begin. Before turning the meeting over to Dr._Schwetz, I would like to go over a few administrative items with you, sort of the important things. The telephones and the restrooms are located beside the elevators. You take a left out of the salon and a left down the hall. In case of an emergency and we need to evacuate the building, please go out the doors, and there are double doors right in front of you, and it will take you to a parking lot. Unless specified as an emergency, any messages that we receive will be held at the desk outside the meeting room for you. Please check there during break and lunch. We will be taking a short break around 10;45 and another around 2:45, and we hope to adjourn for lunch at 12:15. Since each public speaker has been allotted his or her requested time, we ask that you respect our schedule. This will help us stay on track and give everyone an opportunity to present. I will be operating a timer that will give you a two-minute wrap-up warning with a flashing yellow light. At the end of your allotted time, you will see a flashing red light and the buzzer will sound. Hopefully we will not have to open the floors at the end of your allotted time, and then we can go on. The FDA panel members will ask questions after every three or four presentations as noted on the schedule. After that, if time permits, we will allow for questions from the floor. There are microphones set up, and we ask that you speak directly into the mike. Identify yourself because this meeting is being transcribed. A transcript is being made of the meeting. If we stick to the agenda, we will have time around 4:00 p.m. for any unscheduled presentations. If you would like to make an unscheduled presentation, please sign up at the desk outside the door, and we will give you two to three minutes. I would like to introduce our chairperson for the day, Bern Schwetz, the Acting Deputy Commissioner for Food and Drug Administration. Agenda Item: Opening Remarks and Introductions. DR. SCHWETZ: Good morning to all of you. As you can tell, Rose is always very well organized, but Rose, when you talk about the possibility of an evacuation, do you know something that the rest of us do not? [Laughter.] Let me introduce the FDA panel before I make some opening comments. First, Dr. Janet Woodcock, the Director of the Center for Drug Evaluation and Research; Mr. Joe Levitt, Director of the Center for Food safety and Applied Nutrition; Margaret Peggy Dotzel, the Acting Associate Commissioner for Policy; Ms. Louisa Nickerson, Associate Chief Council for Foods; Dr. Michael Greene, Chair of our Reproductive Drugs Advisory Committee and the Pregnancy Labeling Subcommittee; and Ms. Bonnie Lee from the FDA Office of Regulatory Affairs. I welcome you both from the standpoint of taking your time to be here but also to participate in what I am sure will be an important and productive discussion. We have today in front of us a very complex set of questions. As you are aware and as will be discussed in more detail by Ms._Nickerson in just a few minutes, the Dietary Supplement Health and Education Act provides the legal framework under which manufacturers of supplements are permitted to make structure/function claims for their products. Not surprisingly, given the complexity of the issues, with promulgation of the final rule last January that described the distinction between structure/function claims and disease claims, many of you raised questions. One subject in particular appeared most urgent, and that was the use of supplements during pregnancy. What prompted our discussion today was the explicit statement in the preamble to the rule that dietary supplements could make claims about mild conditions that caused no permanent harm and are commonly associated with particular stages of life, and that such claims would not be considered disease claims. The rule provided examples of conditions associated with such states including the menstrual cycle, menopause, aging and pregnancy and included example of conditions such as morning sickness and leg edema associated with pregnancy. The rule did specifically identify as disease claims and therefore excluded under DSHEA claims about abnormal conditions associated with the natural state or process if the abnormal condition were uncommon or could cause significant or permanent harm. Examples provided included hyperemesis privaderum or toxemia associated with pregnancy. It should be noted that the rule did not change a fundamental fact. The use of supplements during pregnancy has never been restricted. Indeed, there are structure/function claims for use during pregnancy that have been traditionally included on dietary supplements such as the claim "for nutritional support during pregnancy" that are not impacted by the final rule. Promulgation of the rule and the ensuing discussion did, however, serve to bring this fact to the forefront of the discussion. It also highlighted our awareness that there is extremely little known about the effect of these products on embryos and fetuses exposed to them during a pregnancy with notable exceptions, of course, such as the vitamins. One reason for this lack of knowledge is that the regulatory paradigm embodied in DSHEA contains an implicit general assumption of safety for dietary supplements unless contrary evidence emerges. After we published that rule, we received comments opposed to classifying morning sickness and leg edema associated with pregnancy as appropriate for structure/function claims. These comments expressed concern that use of dietary supplements during pregnancy may adversely affect the embryo or the fetus. Some urged revising the rule so that it does not allow these claims to be made in the absence of evidence of safety to the unborn. Some argued that FDA should determine that all conditions associated with pregnancy are diseases so that dietary supplements could not make any claims for conditions associated with pregnancy unless the manufacturer submitted data to FDA and met the standard for new drug approval or authorization of a health claim. The common thread of these comments, although not explicitly expressed, seems to be that structure/function claims should be low risk whereas pregnancy claims should be high risk, a concept not well articulated in DSHEA. We all share the goals of wanting to protect and promote public health and have a particular concern for the safety of pregnant women and their unborn children. The purpose of today's meeting is to solicit your insight and comments on exposure of pregnant women to dietary supplements, the level of risk involved, the acceptability of that risk, the actions you believe we should take, and the legal options available to us. Although FDA will consider all reasonable options that we can implement under current law, we will be deliberating on them after this meeting and will not be articulating a specific agency direction today. As I mentioned, our first presentation today will outline the legal rules under which dietary supplements are marketed. Please keep this information and these issues in the forefront of your mind during your presentations and your questions. We are interested in hearing you address in particular the following questions: What are the risks and to whom? What are our options under the current legal framework? What actions should we consider? I am looking for a particularly productive day. With that, I will turn it over to Louisa Nickerson to talk about the overview of the legal background. Louisa. Agenda Item: Overview of Legal Background. MS. NICKERSON: Good morning. The source of legal requirements governing dietary supplements is the Federal Food, Drug and Cosmetic Act as amended by the Dietary Supplement Health and Education Act of 1994 or DSHEA. In addition, there are implementing regulations in parts 101, 111 and 190 of the Code of Federal Regulations. This morning, I am going to give just a brief overview of the legal framework governing dietary supplements starting with the definition of a dietary supplement. A dietary supplement is a product other than tobacco that is intended to supplement the diet, that contains one or more dietary ingredients, and the dietary ingredient is any one of the following: a vitamin, mineral, herb or other botanical, amino acid, dietary substance by use for man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract or combination of any of the other types of dietary ingredient. A dietary supplement must be intended for ingestion. For example, topical products like lotions and ointments are not covered. A dietary supplement must not be represented for use as a conventional food or as a sole item of a meal or the diet. It must be labeled as a dietary supplement. Generally, the dietary supplement category does not include articles approved as new drugs, licensed as biologics, or authorized for clinical investigation under an IMD unless the product was previously marketed as a dietary supplement or is a food. The next topic is safety. FDA regulation of dietary supplement safety generally is post-market unlike with drugs and devices where it is generally pre-market. Like conventional foods, dietary supplements may be freely sold without prior approval from FDA. Unlike with drugs and food additives, FDA has no authority to require pre-market safety testing or pre-market submission of safety information for a dietary supplement with one exception. If the dietary supplement contains a new dietary ingredient, that is an ingredient not marketed in the U.S. before the passage of DSHEA on October 15, 1994, and the new dietary ingredient has not been present in the food supply without chemical alteration, a manufacturer must notify FDA at least 75 days before marketing the product. The manufacturer must include in the notification the information on which the manufacturer based its conclusion that a dietary supplement containing the new dietary ingredient will reasonably be expected to be safe. However, the nature of the safety information on which the manufacturer may rely is not specified in the law, and there is no requirement that a manufacturer wait for a safety determination from FDA before marketing the product. Once on the market, a dietary supplement is adulterated if it or one of its ingredients presents a significant or unreasonable risk of illness or injury when used as directed on the label or under normal conditions of use if there are no directions. A dietary supplement is also adulterated if it contains a poisonous or deleterious substance that may render it injurious to health. In addition, the Secretary of HHS may declare that a dietary supplement or dietary ingredient poses an imminent hazard to public health or safety. In enforcement proceedings, FDA has the burden of proof to show that a dietary supplement is adulterated. The difference between the safety standard for dietary supplements and the safety standard for most other FDA-regulated products such as drugs is that for most other products, lack of safety information works in the agency's favor. That is, if a product has not been affirmatively shown to be safe, it cannot be marketed. For dietary supplements, it is just the reverse. Unless there is affirmative evidence that a supplement is unsafe, it can be marketed. Lack of information is not enough to keep a product off of the market. DSHEA provides for the use of claims to affect the structure or function of the body as well as to other types of claims that we will not be discussing here today. Structure/function claims do not require FDA authorization. However, claims may not be made about the use of a dietary supplement to diagnose, prevent, mitigate, treat or cure a disease unless, prior to marketing, the claim has been authorized as a health claim or the product has been approved as a drug. For example, a product may not carry the claim "cures cancer" or "treats arthritis" without prior FDA review and authorization. Structure/function claims, as previously noted, do not require prior authorization from FDA, but they do require notification to FDA within 30 days of marketing and must be accompanied by the disclaimer, "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease." In addition, the manufacturer must have substantiation of the claim as truthful and not misleading. All claims authorized by FDA such as the claim linking folic acid and reduced risk of neural tube birth defects and the claim that calcium may reduce the risk of osteoporosis may be made in supplement labeling if the product qualifies to bear the claim. In the final rule that gave rise to this meeting, FDA issued criteria for determining when a statement about a dietary supplement is a structure/function claim and when it is a claim to diagnose, mitigate, treat, cure or prevent disease. As Dr. Schwetz has explained, the rule classifies certain claims about common, mild conditions associated with pregnancy such as morning sickness and leg edema as structure/function claims. The rule classifies claims about other, more serious, conditions associated with pregnancy such as hyperemesis gravidarum and toxemia of pregnancy as disease claims. With regard to ingredient and nutrition labeling, for purposes of this meeting, it is probably sufficient just to note that dietary supplements do have to have ingredient and nutrition labeling. Nutrition labeling for dietary supplements is broader than for conventional foods in that it includes all dietary ingredients that are present in significant amounts whereas for conventional foods, only certain macronutrients such as protein and various types of fat and some of the traditional vitamins and minerals must be listed. In addition to ingredient and nutrition labeling, FDA also has authority to require other kinds of information in the labeling of dietary supplements. As is true for any food, the labeling of a dietary supplement is misleading if it fails to reveal facts that are material in light of representations made about the product or consequences that may result from its use under the conditions prescribed in labeling or advertising or under such conditions as are customary or usual. Representations that might be relevant for purposes of today's topic might be claims about conditions that are common during pregnancy or direct claims of usefulness during pregnancy. Consequences from use of the product that would be relevant might include a variety of adverse effects on the fetus or the pregnant woman. Under this authority, to prevent dietary supplement labeling from being misleading, FDA may require dietary supplements to bear warnings, directions for use and other material information. Thank you. DR. SCHWETZ: Thank you, Louisa. I think it would be helpful if there are questions by either the morning panelists or the afternoon panelists about what Louisa has just said that we would talk about them now rather than ongoing throughout the day. Louisa, would you be willing to take questions for clarification and expansion. MS. NICKERSON: I will try. I thought that we were not having question and answer today. DR. SCHWETZ: I thought just in terms of clarification of any of the information that you have already presented. If there is anything that would be said that could clarify it, I think it might help. DR. WOLFE: Do you have a rough estimate as to how many times the FDA has taken any enforcement action concerning dietary supplements just on the issue of misleading labels? I imagine this happened, is it like 10 times or 100 times or what? MS. NICKERSON: It depends on how you define enforcement action. If you mean a court case_- DR. WOLFE: No, just any kind of communication. MS. NICKERSON: Warning letter? DR. WOLFE: Warning letter, notice of violation, anything like that, all of the above. MS. NICKERSON: I am sorry. I think we would have to have somebody from the Center for Food Safety and Applied Nutrition to answer that question. Fortunately, we do. MR. LEVITT: There have been_- I cannot give you exact numbers but there are, in the probably several hundred letters that have gone to companies that say that "The claim that you are making on your product is not appropriate. It is a structure/function claim. Company is required to submit to us with your products new structure/function claims they are making." In about ten percent of those cases we have written back to say no, that is not an appropriate structure/function claim. A smaller subset of those have been followed up by warning letters that come either from our center or from the_- DR. WOLFE: So the 300 are the ones where you have written saying that it is not okay, it is a structure/function claim? MR. LEVITT: Right. DR. WOLFE: Is that the main category in which you have found misleading violations or whatever? MR. LEVITT: Yes. DR. WOLFE: Okay, thank you. DR. SCHWETZ: Don. Dr. Mattison. MS. CUNNINGHAM: Excuse me. Once again, I would like to remind people that when you come to the microphone, please identify yourself for the transcript. DR. WOLFE: The person who just spoke was Sidney Wolfe. DR. MATTISON: Don Mattison. Two questions. Under the dietary supplements act, what kind of exclusionary labeling is permitted? Then with respect to the ruling about new structure/function claims or not being used as a dietary supplement prior to 1994, does that relate to the type of claim that was made with respect to structure/function? For example, if no structure/function claims related to pregnancy were used for a dietary supplement prior to 1994, could they be used subsequent to 1994 with those kind of claims? MS. NICKERSON: What do you mean by "exclusionary labeling"? DR. MATTISON: Not to be used in pregnancy. Not to be used without consulting a physician if you are pregnant or lactating. MS. NICKERSON: You are asking what kind of labeling of that type is required? DR. MATTISON: Would it be permitted? MS. NICKERSON: Would it be permitted? DR. MATTISON: Could it be required? MS. NICKERSON: It is always permitted as long as it is truthful. Yes, I think that we can require it under the authority that I was describing to prevent misleading labeling. As for your second question, there is no connection between the new dietary ingredient provision of DSHEA that I was describing that defines new dietary ingredients as those that were not marketed in the United States before passage of DSHEA and the structure/function provision of DSHEA. Those are just two completely different things. The new dietary ingredient provision has to do with whether an ingredient can be marketed in a dietary supplement without first submitting safety information to FDA, and the structure/function provision has to do with what claims may be made. DR. ERICKSON: Dave Erickson from CDC. Ms._Nickerson, you just made some comments about the need for a label to reveal all material facts. Is that in the act or is that some sort of an FDA operational definition? Could you just tell us a little bit more about that, please? MS. NICKERSON: Certainly. It is in the Federal Food, Drug and Cosmetic Act. It is Section 403(A) of the act and Section 201 of the Act. Section 403(A) says that a food which includes a dietary supplement may not bear labeling which is false or misleading. Then Section 201, that is 21 U.S.C. 321(M) says that in determining whether labeling is misleading, you take into account representations that are made about the product and consequences that may result from its use. DR. SCHWETZ: Thank you very much. We do not want to take time away from any of the presenters, and it is 9:30, so I think we should move to the first part of the morning panel that includes three speakers, and then we will have time for questions and discussion. The first one is Dr._William Soller, Senior Vice President, Consumer Health Care Products Association. Dr. Soller. Agenda Item: Morning Public Panel Presentations. DR. SOLLER: Thank you and good morning. I am Dr._Bill Soller, Senior Vice President and Director of Science and Technology for the Consumer Healthcare Products Association. CHPA is the 119-year old trade organization representing the manufacturers and distributors of national and store brand dietary supplements and non-prescription medicines. CHPA membership includes over 200 companies involved in the manufacture and distribution of these self-care products and their affiliated services. Thank you for the opportunity to convey our perspective on how to address the issue of pregnancy, nursing as it relates to the structure/function rule, and specifically our perspective on our recent announcement of a voluntary industry labeling program to address concerns in this area. To address the issues that were set forth in the February 24 Federal Register announcement of the meeting, I will make brief background comments, elaborate the points to consider on the safety and benefits of dietary supplements, explain the rationale for our recently-adopted voluntary program, and the program itself, and make brief concluding remarks. By way of background, FDA issued its final rule on structure/function claims for dietary supplements and quite appropriately made a distinction between diseases such as heart disease and natural states such as simple, non-cystic acne, simple constipation, the menstrual period and others. I emphasize it was unexpected to many in the industry that FDA included symptoms like edema associated with pregnancy as a potential condition that would be amenable to structure/function claims. In response, CHPA undertook a situation analysis looking at the safety of dietary supplements in pregnancy as well as the uses, the intended uses, of dietary supplements in pregnancy. I would like to take a look at each in its turn. First, it is important to recall in any potential safety or efficacy issue that FDA has a longstanding policy that label statements must be scientifically documented, clinically significant and important to the safe and effective use of the product by the consumer. This policy has stood up very well over time as a framework for working through public health issues relating to labeling of self-care products. It is a three-part standard with credible scientific documentation as the first hurdle. Without adequate scientific documentation, there is really no need to determine whether the effect under scrutiny has clinical significance let alone importance to the consumer use situation when considering most safety issues relating to self-care products. Second, unlike an ingredient-specific safety issue that is scientifically documented, this issue related to pregnancy and nursing has a unique situation relative to FDA's longstanding policy since the potential dangers of specific dietary supplement use in pregnancy are not uniformly documented scientifically. While a number of self-care products such as prenatal dietary supplements have good safety profiles for use in pregnancy, there are also a number of these self-care products for which the scientific documentation in pregnancy/nursing may not be fully developed. Hence, any approach that would be based in substantial part on an absence of scientific documentation. This is the uniqueness of this situation. Further, pregnancy and nursing are particularly vulnerable periods for the unborn with unknowns making this into a unique situation relative to ingredient-specific safety issues. I cannot overemphasize this point enough that pregnancy/nursing are unique regulatory matters. We typically make label decisions based on scientific data and adequate documentation, yet here we have little published documentation across many dietary supplement products, and we have a particularly vulnerable population under consideration. Hence, this situation should be viewed as it was when the pregnancy/nursing statements were placed on OTC drug products in December, 1982, that is as unique. Therefore, in other situations involving possible label changes to dietary supplements, we would expect that FDA's longstanding policy would remain intact. A third point that we considered in our situation analysis was the finding that many of our members already include pregnancy and nursing statements on their product labels. As a final point relating to our assessment of the safety aspects of the current situation is the fact that under the Dietary Supplement Health Education Act of 1994, for dietary supplements as well as for foods, it is the manufacturer's responsibility to insure that dietary supplement products are safe and properly labeled prior to marketing. As stated earlier, we feel very strongly about the fact that the uniqueness of the pregnancy/nursing issue and our response to it should not be seen as a signal of erosion of our commitment to DSHEA, or our members' confidence in the safety of their products, nor an erosion of our support for the substantial enforcement powers that FDA and FTC already have over dietary supplements. To underscore this point, I quote Commissioner Haney on March 25th before the House Committee on Government Reform last year when she said that FDA has the tools at its disposal to take enforcement actions against dietary supplements found to have safety labeling or other violations of the act. Thus, in determining our response to FDA's ruling that conditions associated with pregnancy may be areas of structure/function claims, we considered current FDA policy finding pregnancy/nursing to be unique among potential labeling issues; determined that many of our members had already stepped forward with specific labeling in this regard; and recalled the fundamental premise of the law that it is the manufacturer's responsibility to insure dietary supplements are safe and properly labeled prior to marketing. All of these points had to be a part of our response to this issue. As part of our situation analysis, we also considered how dietary supplements are intended to be used. Some are intended for use in pregnancy/nursing while some are not. A balanced diet and adequate intake of essential nutrients is important for a full-term, normal pregnancy. Adequate intake of such micronutrients as folate, zinc, iron and other ingredients are important in the prenatal period. For example, supplementation with iron is generally recommended in pregnancy to meet the energy demands both of the mother as well as the rapidly-growing fetus. Inadequate intake of zinc or folate or both potentially leads to impaired cell division and alterations in protein synthesis. Such alterations are most notable and have the greatest potential to do harm during periods of rapid tissue growth. Of course, folate is the subject of an authorized health claim for the prevention of neural tube defects. Thus, if certain dietary supplements are important for use in pregnancy, and if there is no concern about their safety in those such situations, there would seem to be little need for a statement to consult a health professional before use of such a product. Such a statement, indeed, might frighten a consumer away from use. On the other hand, certain dietary supplements are intended for use in subpopulations not likely to become pregnant including young children, post-menopausal women and men. Here, a pregnancy and nursing statement would not be logical. Therefore, from our situation analysis looking at the safety and at matters pertaining to intended use, our approach was to create a workable program that would be consistent with the law, the Dietary Supplement Health Education Act; be logical, that is it would not call pregnancy or refer to pregnancy as a disease even for the purpose of the final rule; be consistent with past rulings in this area such as the OTC rule adopted in December 1982; encompass past scientific determinations in this area. For example, if there are compendia that would list products which should not be used in pregnancy or should only be used under a health professional's supervision in pregnancy, that would be encompassed in this. Be medically appropriate; recognize and not interfere with important benefits of certain dietary supplements in pregnancy and nursing; place important information into the hands of the consumer; and importantly, be reasonably flexible in the wording to encompass current labeling that is already out there. I would like to now briefly describe our voluntary pregnancy/nursing labeling program for dietary supplements. The basic statement is, "If pregnant or nursing, ask a health professional before using this product," or alternatively worded statements that are the substantial equivalent. For example, instead of "health professional," it might be "doctor, pharmacist or other health professional." It might put, "Before using this product..." as the first part of that statement, that kind of flexibility that creates the substantial equivalent of what is intended here. We include the following exemptions that are based on considerations of our situation analysis. Dietary supplements with recognized nutrient value that have recommended daily intake values and are labeled at or below the RDI. Dietary supplements with recognized nutrient values which are intended for prenatal use and/or for use during nursing and which solely contain vitamins and minerals with RDIs at levels safe for these intended uses. Dietary supplements that may be used during pregnancy or by nursing mothers based on recognized compendia or based on determinations or pending recommendations of other authoritative bodies such as the National Academy of science, United States Pharmacopoeia, or based on company-generated research or information. On this particular point, the height of the bar created by the CHPA voluntary program is consistent with the CRN view that structure/function statements for dietary supplement use in pregnancy must meet a rigorous standard of evidence regarding safety and benefit. The additional exemptions include dietary supplements that are labeled exclusively for pediatric use, for post-menopausal women, and for men. In addition, the programs stays use of edema associated with pregnancy from a structure/function claim during pregnancy. We are unaware of any dietary supplements making such claims during pregnancy, although reviewing one of the submissions, I noticed that there may be some websites that are doing that. I can at least say that for our members. CHPA's program was adopted on March 22, 2000, with a compliance date of the next label printing but no later than April 2, 2001. I will note that this one-year compliance date is similar to the one-year date given in the final rule for pregnancy/nursing label statements for OTC drugs adopted in December 1982. Furthermore, we plan to soon petition the agency to adopt our voluntary program into regulation. CHPA has a long history of highly-successful voluntary labeling programs that have been supported by FDA even including FDA's urging that all manufacturers adopt our programs as we have promulgated them. Further, many of our programs have been adopted into regulation by FDA in a form that maintains virtually all of the essential elements of our program including, for example, the packaging and labeling of prenatal iron-containing vitamin-mineral products to help reduce accidental childhood poisonings several years ago, solid OTC dosage form identification, and many ingredient-specific labeling recommendations for self-care products. By adopting our program into regulation, there would be consistency across the industry on a labeling matter of importance to a vulnerable subpopulation of consumers. In conclusion, CHPA's approach formalizes existing practice by many of our members, addresses FDA's questions relating to safety, acknowledges the benefits of certain dietary supplements in pregnancy and nursing. There is a rapid response by responsible manufacturers. It is consistent with past consumer products of rulings in this area and ultimately, indeed primarily, meets consumers' needs. Thank you. I would be pleased to answer any questions. MS. CUNNINGHAM: [Comment off microphone.] DR. SOLLER: Thank you, Rose. That sounds good to me. DR. SCHWETZ: Thank you, Dr. Soller. We will proceed directly to Allen Mitchell, Director of the Sloan Epidemiology Unit. DR. MITCHELL: Thank you. I very much appreciate having the opportunity to be here today to give my perspective on the safety issues associated with diet supplement use during pregnancy. For the record, I am Director of the Sloan Epidemiology Unit of Boston University Schools of Public Health and Medicine where I am professor of public health and pediatrics. I was trained in pediatrics and for more than three decades have devoted my career to studying the risks and safety of medications used in pregnancy. I have come here to ask that you immediately reconsider the final rule regarding uses of dietary supplements during pregnancy published in January 6 of this year. This rule, as has been stated, allows dietary supplement manufacturers to promote their products for treatment of pregnancy-related conditions without first proving that the products are safe and effective. To allow such claims to be made in the absence of evidence of fetal safety is to ignore the very history that made the FDA the world's most highly-regarded regulatory agency, a reputation, which I might add, is well deserved. Until 40 years ago, the scientific community and public alike viewed the placenta as an effective barrier to exogenous drugs and chemicals. However, the Thalidomide catastrophe in which over 10,000 babies worldwide suffered terrible birth defects following their mother's use of that drug changed that view dramatically, instantly, and we would hope forever. The similarities to the current situation are both ironic and, I would argue, frightening. First, as would be permitted for supplements, Thalidomide was promoted specifically for the treatment of nausea and vomiting in pregnancy. Second, just as dietary supplements are viewed as safe, so, too, was Thalidomide promoted as a safe alternative to then current treatments, primarily barbiturates. The U.S. escaped the brunt of the Thalidomide disaster because the FDA, as a result of Dr. Kelsey's careful review of safety data, demanded more information before it would approve the drug for marketing. Though the U.S. population was spared, other countries were far less fortunate. The lesson was not lost on Americans, however. Indeed, it was specifically the Thalidomide disaster in the early 1960s and the public's demand to be protected from unsafe drugs that led to strengthening of the FDA's regulatory authority and responsibilities. These changes have created public confidence in the general safety of regulated drug products. This confidence has, I believe, spilled over to include unregulated dietary supplements. The notion that dietary supplements are safe may be debated, but when it comes to the fetus, assumptions of safety are without foundation. The truth is that we simply do not know the fetal effects of the vast majority of dietary supplements, and we certainly do not know that they are safe, that is that they carry no risk to the fetus. The few studies that have been conducted do not offer reassurance. On the other hand, evidence is emerging that argues for caution. I will briefly cite just three examples. In 1999, researchers studying donor human sperm in hamster oocytes reported that "St. John's Wort, Gingko and Echinacea in high concentrations damage reproductive cells" and that "St. John's Wort was mutogenic to sperm cells." Vitamins taken in large doses also have raised concerns. Some studies suggest that high dose Vitamin_A causes birth defects. Though these results are not universally accepted, there is biologic reason to worry about high dose Vitamin_A since it is a congener or close cousin of the acne drug isotretinoin, Acutane(?), which is a classic and very potent human teratogen. Finally, we and others have raised questions about whether pseudoephedrine may be responsible for an increased risk of a rare but serious birth defect called gastroschisis. Most will recognize pseudoephedrine as a common ingredient in over-the-counter medications sold for he treatment of colds, allergies and sinus congestion. However, it is critically important to recognize that pseudoephedrine, which is derived from ephedra, is a natural plant product. It is also found in a number of herbal supplements that are promoted for the treatment of colds, allergies and sinus congestion. If the concern were proven real and OTC pseudoephedrine did indeed cause birth defects in humans, wouldn't herbal pseudoephedrine similarly cause birth defects? If this natural product caused birth defects, what fetal harm might be caused by other dietary supplements? In its long history of concern about the fetal risks that might result from medications used by pregnant women, FDA just yesterday completed another meeting of a subcommittee that is assisting the agency in seeking ways to apply pregnancy registries and other approaches to learn, as rapidly as possible, about the teratogenic effects of new medications. This is part of a remarkable effort focused on drug products that have already passed FDA-mandated animal testing for fetal safety before they are approved for marketing. Without the benefit of similar testing before human use and based on existing information about certain vitamins and plant-derived agents and dietary supplements, there is indeed reason for concern that some dietary supplements carry the strong potential to be human teratogens. Allowing their promotion for the treatment of a disease directly associated with the early stages of pregnancy serves to encourage their use, particularly since pregnant women will be led to believe that dietary supplements represent a safe alternative to other medications. The fact that FDA retains the ability to remove a product if it finds it to be unsafe, in this case teratogenic, provides little comfort. Unlike most risks, definitive evidence of human teratogenesis comes only after there have been human exposures and human tragedies. Given our ignorance at this time, can we honestly judge that the benefits of dietary supplements to pregnant women are so compelling and unique that we should allow their promotion even at the risk of permitting another Thalidomide. Because of the FDA, the population of this country escaped the Thalidomide disaster. We must not forget the lessons of that defining episode. To maintain the current rule is almost certainly to invite medical, moral and public health disasters that could, with simple revision of that rule, be averted. I thank you for this opportunity. DR. SCHWETZ: Thank you, Dr. Mitchell, and thank you for your nice words about the FDA as well. The third speaker in this set, Michael McGuffin, President of the American Herbal Products Association. MR. MC GUFFIN: Good morning, and thank you for the opportunity to participate in this forum. The American Herbal Products Association or AHPA was founded in 1983 by a group of companies active in the trade in botanicals and is now the national trade association and voice of the herbal products industry. AHPA has always served its members by promoting the responsible commerce of products that contain herbs and their use to enhance health and quality of life. As announced in the Federal Register notice of February 24, this meeting provides an opportunity to comment on safety concerns regarding structure/function claims for dietary supplements used during pregnancy and on other safety issues associated with dietary supplements used during pregnancy. The primary focus of my comments will be on issues related to the use during pregnancy of botanical products that do not bear statements about the effects of the products on conditions associated with pregnancy. The agency seeks information on, among other things: one, potential for harm associated with dietary supplement use during pregnancy; two, means to address safety concerns associated with dietary supplement use during pregnancy; and three, specific warnings for dietary supplements used during pregnancy. The American Herbal Products Association has long understood that its responsibility includes the organization and dissemination of accurate information related to the use of botanicals. In relation to this role, AHPA published in 1997 The Botanical Safety Handbook, a publication on which I was proud to serve as the managing editor. As state in the preface of that work, the goals was "to find a rational platform for the evaluation of herb safety neither assuming that all natural substances are inherently safe as some popular references suggest nor blindly accepting reports of toxicity from uncritical sources." The handbook is organized into a rating system wherein each of the over 600 herbal substances listed in the book are assigned a safety classification. If we could see the slide. Here are our safety classifications. The one most relevant to today's discussion is Class II-B, herbs that are not to be used during pregnancy unless otherwise directed by an expert qualified in the use of the described substance. Of interest to the matter that is the subject of today's meeting, just over 200 of the 644 botanicals listed in the handbook are classified in our Class II-B. So, these are the herbs that are not for use in pregnancy unless otherwise directed by a qualified expert and includes, in reference to Dr._Mitchell's concern, the botanical ephedra. Ephedra is, in our guidance, to be labeled, "Not for use in pregnancy." In July 1998, AHPA's Board of Trustees adopted as a trade recommendation a policy that calls upon its members to label any products that contain herbs classified in Class IIB or C, according to the labeling classifications for those classes. The adoption of a trade recommendation establishes a condition of membership so that all AHPA members are expected to conform to this policy. At the risk of sounding like this is an infomercial for our book, I would like to spend a few minutes discussing the process by which its editors arrived at their classifications as this work serves as a model for assessing existing expert information. As the first stage of preparing this work, several experts in the field of botanicals convened in 1993 to discuss the concept of compiling existing knowledge about the safety issues associated with the herbs that we use. This group included three of the editors, Christopher Hobbs, Roy Upton and myself; Mark Blumenthal, Founder and Director of the American Botanical Council and editor of the English translation of Commission_E; Stephen Foster, the well-known and well-respected writer and lecturer; representatives from the Natural Path community and some of the country's most established and knowledgeable herbalists including Ed_Smith and David Winston. One of our earliest tasks was to define the resources that could serve as the basis for our compilation. We arrived at a list of 29 references from several related disciplines that we identified as our primary sources for authoritative information. These included seven books specifically about poisonous plants, actual and pending regulations related to the use and/or labeling of botanicals in Canada, Australia, Belgium and Britain. We also had an early edition of the translated Commission-E which provided us access to the German regulatory framework. We used classical texts that record the use of botanicals as therapeutic agents such as King's American Dispensatory, Hogger's(?) Handbook, the 11-Volume Wealth of India. These publications are quite different in their formats and in the specific range of plants that they treat. They are, however, similar in that each of them was written by experts who were devoted to the use of plants in the promotion of health and to the preservation of all of the knowledge that has been acquired about these plants. Also, each of them includes toxicological information if any such information is relevant to the plant's historical use. We had contemporary authoritative herb usage texts such as Lee, Young and Foster's Encyclopedia of Common Natural Ingredients, Vice's Herbal Medicine, von_Hallimont's Compendium of Phytotherapy, and Victal's Herbal Drugs and Phytopharmaceuticals. These last three were specifically written to inform practicing pharmacists and naturopaths on the identification and use of botanicals. All four of these works also include contraindications and cautions where any are known. We used Dr. Peter Dismet's first two volumes of his Adverse Effects of Herbal Drugs which provided an in-depth analysis of 42 herbs or classes of herbs with a special emphasis on examining appropriate use during pregnancy and lactation. Finally, five texts that discuss different aspects of the traditional use of Chinese herbs including known contraindications. As you have just heard, we did not skimp in gathering together the existing authoritative references that record information on the use and relevant cautions and contraindications for the botanicals in trade in this country. We did this by identifying the references that we believed to have the same goals that we had defined for ourselves, that is the dissemination of accurate and material information regarding the safe use of botanicals. The process of establishing classifications for each of the botanicals consisted of a review by the editors of all 29 of the identified primary references for each of the botanicals listed. The agreement that we made was that if any of the primary references listed any safety concern, that fact would have to be identified in the plant's listing. Usage history was also determined as relevant to contraindicating a specific herb in pregnancy so that any herb with an established history of use as an amenogogue(?) or an abortifacient was automatically placed in our II-B category. In the course of this review of the data contained in the primary references, if there existed a preponderance of data suggesting a specific caution, the editors established the appropriate restrictive classification. If a single reference was alone in stating a concern or if there was contradictory information, the editors were obliged to identify the concern in the text and to find additional references to either support or refute the reference and thereby make an appropriate classification. This additional requirement resulted in the development of an extensive bibliography of over 250 books and citations. The training and professional experience of certain of the editors was also essential to the creation of an accurate reference. Roy Upton is the Founder of the American Herbal Pharmacopoeia and one of the founders of the American Herbalist Guild. Christopher Hobbs holds a California license as an acupuncturist. Both Chris and Roy have significant experience and training in the hands-on use of therapeutic herbs, and this experience was of tremendous value in qualifying the safety concerns of the botanicals with which they are familiar. Finally, the entire document was reviewed by internationally-recognized experts such as Doctors John_Staba and Dennis Awang. As noted earlier, the agency has posed questions regarding the use of dietary supplements during pregnancy to obtain public comment: one, regarding potential harm from use of supplements during pregnancy; two, to identify means to address any safety concerns for such use; and three, to examine the use of specific wordings on dietary supplement labels regarding their use in pregnancy. For botanical ingredients in dietary supplements, AHPA has provided authoritative answer to these three questions with the 644 plants that are examined in our Botanical Safety Handbook. As is obvious from our extensive references, this is not the only resource for accessing material information about safety issues and specifically pregnancy concerns relating to these herbs. AHPA does not, therefore, represent this work as the only valuable reference for such information nor do we suggest that the information in the Botanical Safety Handbook is not subject to challenge. We do, however, strongly recommend that manufacturers use some accurate resources when designing a label that discloses all material facts related to the use of a dietary supplement. AHPA is aware that there is some interest in recommending that there be a requirement for providing a pregnancy caution on all non-RDI dietary ingredients which, of course, includes all botanical ingredients unless these are specifically marketed to men, children, or women who are not of childbearing age. AHPA strongly opposes such an approach as inappropriate for botanical dietary ingredients. Our concern to this approach is twofold. To begin with, such a requirement would essentially ignore the information that is already known, documented and available to companies that manufacture and label herbal products. At four different points in the commentary that accompanied the final rule for structure/function claims published in January 2000, FDA identified its position that dietary supplements are required to include all facts that are material in light of the consequences that may result from the use of the product. The material facts as they relate to the use of a botanical supplement during pregnancy cannot be generalized and, in fact, are absolutely dependent upon the identify of the botanical ingredient in the supplement. AHPA believes that in order to satisfy the need to provide material facts to a consumer, the manufacturer must access material information about the product's ingredients. Secondly, reliance on a broad pregnancy caution on essentially all herbal supplements would so dilute the message that it would become meaningless where it is actually material. A pregnant woman encountering cautions to seek professional advice prior to use of both mother wort extract and peppermint tea is just as likely to ignore both warnings as to somehow determine that the first is an important health message while the second is frivolous. I would like to also just pass by and discuss in the context of historical use of herbs in enhancing health and quality of life in pregnant women the agency's question regarding the potential hazards that may be associated with botanical substances, supplements used for conditions associated with pregnancy. Various herbs have been used for centuries and beyond to promote the health and comfort of a pregnant woman. Certain of these botanicals have generally been considered as appropriate for use in pregnancy with no need of expert supervision. Other botanicals with a long history of safe use in pregnancy have most often been advised to be used only with expert supervision, for example from a midwife, a naturopathic physician or a qualified herbalist. The agency has asked what are the potential hazards associated with the use of dietary supplements for conditions associated with pregnancy both to the pregnant woman and to the fetus. With regard to botanical supplements, AHPA again believes that this question can only be answered on a specific rather than a general basis. In developing further guidance to address this question, AHPA believes that the agency should utilize the exiting body of knowledge about the historical safe use of herbs to promote health and comfort of a pregnant woman so that whatever the outcome of any such guidance, women will continue to have access to botanicals that can be safely used during pregnancy. I am aware that another presenter this morning, Josef Brinckmann of Traditional Medicinals will discuss herbal products traditionally indicated for use in pregnancy. I will therefore defer to Josef for further comments on the use of botanicals for these conditions. In summary, AHPA shares the concerns that were communicated to FDA regarding the use of supplements during pregnancy. AHPA's members are in the business of promoting health, and we are committed to providing products that are properly labeled and evaluated to assure their safe use by all consumers. As is evident by the fact that nearly one out of three of the botanicals examined in our Botanical Safety Handbook is classified as not for use in pregnancy unless otherwise directed by an expert, we, too, and the botanical traditions upon which our recommendations were made, consider pregnant women to be an especially protected population. We reiterate here today the commitment that we made with the publication of this work in 1997, a commitment to provide appropriate cautions that accurately represent the material facts that are relevant to the use of herbal products during pregnancy. We further recommend that in whatever regulations come to govern the botanical products that have traditionally been used for specific conditions associated with pregnancy there be not only a tolerance for but a recognition of the value that safely-used botanicals can play in promoting health and comfort at this cherished phase in a woman's life. Thank you very much. Agenda Item: Questions from FDA Panel. DR. SCHWETZ: Thank you to all three of you for your comments and for staying well within the time allocation. That helps everybody who follows. We are now ready to have discussion and questions. We will start with anybody from the FDA panel if you have questions for any of the three speakers. DR. WOODCOCK: My question is for Bill Soller and has to do with the selected exemptions that you proposed in your program. The third selected exemption was dietary supplements that can be used in pregnancy and nursing would be exempted from your proposed disclaimer statement or exemption statement based on recognized compendia, authoritative determinations/recommendations, and/or company research and information. You said that you felt that a fairly high bar had been set there, but there is no really bar in there. Do you have further thoughts? DR. SOLLER: I think it is important to recognize the program in its totality and as it is being set up with the first two provisions in terms of defining, for those products where there should be no warning, or label statement rather, that there is a bar set in terms of what is a recognized safe use. Within 2-C, if there is a compendia that has come forward and determined that in fact a particular ingredient might be used safely, and it was a recognized compendia, that would make sense, would you not agree? I mean, if it was_- DR. WOODCOCK: I am here to listen. DR. SOLLER: Yes, okay, thank you. I tried, Janet. [Laughter.] Now I know my boundaries. The second, if there is an authoritative body such as the National Academy of Science that may change the RDI in a pending recommendation, that might be a reason for also exempting out a particular product. The addition of the piece on company-generated research or information, I think in terms of the context of the overall program and what this is saying in terms of the expectation that these products should be safe and properly labeled prior to marketing per DSHEA, that that creates effectively a very high bar for companies in thinking about whether they would take a label statement and not put it on its particular product. I think it is in the environment, the litigative environment that we have as well as in the intent and spirit of this program as our members have conceived it and as they are going to use it. I do not imagine this is going to be a commonly-used provision by our members based on what I have seen in terms of their labeling. DR. WOODCOCK: Yes, I would just like to state that I think researcher information can vary anywhere from anecdotal reports all the way to formal reproductive toxicology studies, and so there is a big range of possibilities there. DR. SOLLER: I think the discussion that we have had internally in looking at this, the members recognize that there was a bar that was set higher, and that a company that would go forward would have to do it in the context of DSHEA, that it is the manufacturer's responsibility to determine that the ingredient, the product, is safe and properly labeled. MR. LEVITT: Dr. Mitchell put squarely on the table the issue of Thalidomide which everybody here is obviously familiar with, and so I would ask both Dr._Soller and Dr._McGuffin, in each of your proposals, do you envision a claim on dietary supplements under any circumstances being allowed to be directly promoted for morning sickness, and if so, how would the public be assured of its safety? DR. MC GUFFIN: I am willing to_- I will give that an attempt, although I think that Josef Brinckmann will get a little more into it. I certainly believe that if we have a historical use and comfort with a pregnant woman using peppermint tea or a tea of fresh ginger root to diminish her nausea, I would like to figure out how to make that still available to her. Now, whether or not that means that we would have a mommy's tea, I do not know. I really do not have a recommendation. All I am saying is that I would sure like to see the rules be written in a way where these products that have a century's long history of providing comfort to a pregnant woman should be allowed to continue to provide comfort to a pregnant woman. DR. SOLLER: Our particular view is that as we were thinking about Section II-C which I referred to earlier was that there may be instances and take a particular condition associated with pregnancy, although our program would put a stay on edema, for example, that there may be a reason. I thought this question might come up, and I took the peppermint that was outside where it might be important and appropriate that we think about the kinds of remedies that might be available for pregnant women who are experiencing that discomfort. The II-C was put in there in terms of company research and information to account for that. The expectation is, in agreement with remarks I know, and I do not mean to preempt Dr._Dickinson's remarks from CRN, but there, she will make a statement, I believe from her statement, that it is the expectation, and we agree with this, that there would be a rigorous standard of evidence regarding the safety of those products that might be used in this particular condition. What Mr._McGuffin is saying, what Dr._Dickinson is saying and what I am saying is that in trying to sort through this, it is important to try to find a way where we can appropriately find a way to allow products like that to be available. MR. LEVITT: Could I just follow up on Dr._Woodcock's question just as squarely here, which is again looking at your selected exemptions, which include company research or information based on its own. That could be interpreted to be anything that any company decides. I guess I would ask again, what assurance do you feel the public has based on a company-by-company, self-defined standard of safety for this population which, you already put up on the screen, is a highly vulnerable population and probably the world's most visible safety tragedy in the past? DR. SOLLER: From our particular standpoint, I can speak for our members that I believe that standard and that bar might be quite high. At the point in time when you adopt this into regulation, as we hope you would, if there was an articulation of the kind of information that would be appropriate for that, then I think that would be something that would be very well worth discussion and possible further elaboration. MS. DOTZEL: I would just like to follow up on that a little bit, Bill. When you talk about a very high standard for this, are we saying that we want a higher standard for pregnant and lactating women than for the general population? Would the standard for safety be higher than for the general population? What is the difference between the standards that you would propose and the standard that already exists under DSHEA? DR. SOLLER: The standard that exists under DSHEA would require_- it requires that manufacturers insure that their products are safe before they are marketed. I will speak for our members, and I believe that they are able to withstand that particular standard under the law, and they are marketing safe products. It is from that base that manufacturers from which this particular program is coming. When you are looking at the particular safety standard for a vulnerable population as if you are looking at it for the larger population, yes, you might have a general warning or label statement, and the label statement that we are suggesting is a general one with exceptions, not unlike the way that the OTC review warning was set up in pregnancy/nursing where there were exemptions. It was only intended for those products intended for systemic absorption with a very large category exemption of all topicals by way of example. In those particular instances where there might be specific concerns on specific ingredients, and there is scientific documentation to then engage a discussion as to whether there should be an additional safety statement that would be tied to a particular ingredient, that would be appropriate. It is consistent with FDA's longstanding policy and the one that I put up earlier in the slide that the label statement at that point would be scientifically documented, clinically significant, important to the safe and effective use of the product by the consumer. It is not really a different standard, but it is invoking the kind of policy that you have used in this unique area in the past. DR. SCHWETZ: Dr. Soller, I have a question of you also about a voluntary labeling program. What level of participation would you expect among manufacturers, and what level of participation would you have to have before a voluntary program provides the safety net that we would all like to see? DR. SOLLER: Well, we have our members that will undertake this particular voluntary labeling program. There are about 30 dietary supplement manufacturers/distributors among our membership. They are large companies. A number of them have a basic pharmaceutical base but also dietary supplement interest. The interest that we have is to have a program that is consistent across the industry, and that is the reason that we will be petitioning the agency to adopt this program into regulation. DR. SCHWETZ: I have a question about the Botanical Safety Handbook, whether it is primarily designed to be useful to the end consumer or is it most valuable to organizations like those that Dr._Friedman represents, an information service to physicians and to consumers? MR. MC GUFFIN: It was actually designed to be readable by consumers so that our goal is to put it at the point of sale so that a consumer is informed about the ingredients in that product. The primary use that we have seen to date, though, is that at the manufacturing level, manufacturers are using it in the design of their label, which is ultimately, in my vision, the best way to use it. You would prefer to give the consumer the information on the package. I always think that is the best way to communicate with the consumer. We were excited, frankly, to see the emphasis in the final rule on this material facts_- when I read the final rule on January 6 and the emphasis and the repetition about providing material facts. Our work contains facts that are material to the consumption of the products as they are meant to be used. That is really the best place, it is to put the information on the label of the package. The reason that we came up with this simple classification was to make it readable all the way down the chain of distribution. MR. LEVITT: If I could ask Dr. Mitchell for his reaction to the proposals that were made both before and afterwards. I do want to say, notwithstanding the tone of our questions, that I think CHPA is to be commended for coming up so quickly with a program that seeks to address the issue that is being raised. Clearly, I think we are also very interested in the AHPA handbook and some of the research that has been conducted in specific areas that, again, try to address this issue. My question is, somebody from your point of view, Dr. Mitchell, do you see either of these proposals as being satisfactory for what you feel needs to be achieved? DR. MITCHELL: Without having had the opportunity to really look at them carefully, I have just seen them as many of the people in the room have just seen them this morning. I think it is a step in the right direction, but I think that there are a couple of issues of concern. One is, are they all encompassing. First of all, are they only voluntary, are they_- will it oblige all members of the industry, responsible and cowboys alike, to follow those guidelines. That is one issue. I think the other issue that is of concern to me is I have yet to hear a compelling argument for why products need to be promoted. If peppermint tea is a traditional approach to treating nausea and vomiting of pregnancy and people want to use it for that purpose, I do not see anything being discussed that would prohibit or interfere with that use. Rather, what we are talking about is avoiding the promotion of that use. It seems to me that on a risk-benefit basis, public health basis, the lack of potential benefit to pregnant women that may result from there not being active commercial promotion of peppermint tea is trivial compared to the potential risk that would be involved in allowing the promotion of other very untested and potentially teratogenic products for the same purpose. DR. SOLLER: Yes, I had a comment, actually two sets of comments if I could address what Dr._Mitchell mentioned second and then first go into some comments that were made earlier. From our perspective, the CHPA membership, the fact that evidence exists on some products, that they have been reviewed and that a particular list has been created, a negative list for use in pregnancy, for example, does not necessarily mean that we have confidence that non-listed products have also been studied and adequately studied. That is one of the founding premises of where we are coming from on this. Second, the program that we put forward does not ignore those compilations where negative lists have been developed because if they are there, then of course the labeling program would encompass them. Third, the issue of dilution of warnings and the frivolousness of having warnings on many products, I think, reflect back on the success of the OTC pregnancy/nursing label statement that went on in 1982. That is generally regarded as a success and something that I think the agency rightfully should take some pride in. The industry came behind that as well. The point that was made by Dr._Mitchell that says yet to hear why promoted in pregnancy. I think we will be hearing more about that as we go through the morning. I would say that if there is safety documentation for a product, and it can be used safely, and it is providing benefits, then the reason a company might want to market it is because that is potentially a successful business venture. For it to be a successful business venture, you do need to promote that particular use. That is fundamental to any consumer product, any health professional-directed product. That would be the reason why, if a particular claim for a product that is found to be safe_- it is why you would want to promote it. For vitamins and minerals, folic acid, we want to promote that kind of usage. MR. MC GUFFIN: If I could comment on both of those points. We are certainly not opposed to the Botanical Safety Handbook or other compendium data coming to be incorporated by reference into regulations. We are at a stage of the process_- a lot of industries, I think, try to gather together the expertise that is inherent in the industry and put it into a readable format. The phase we are at right now is that we have asked our members to conform to it. I understand that there is already some interest at FDA in adopting some of the recommendations that we have made in terms of communicating to marketers of dietary supplements that contain the botanicals upon which we have stated restrictions. Then I think that your question about the promotion of substances, it is very rational. I like what you said about the risk inherent in the promotion of things other than peppermint tea may outweigh the benefit of promoting peppermint tea. There is some rationale in that, certainly. The position that I keep taking is, is there a solution that preserves access to the ones that we already believe to be safe, that are already established in long-term use. I do not want to have a pregnant woman have to somehow get it by osmosis that the peppermint tea is good for her nausea. Somehow, we have to inform her, so I am looking for a means by which we can inform her of that even if there is some_- and in respect of your broader concern. I did not show up here saying that I think that I know what the solution is. I am really just trying to protect a woman's access to these products that have a long history of safe use in promoting health and comfort in pregnancy. MR. LEVITT: Could I just ask because I am not as familiar with all of the product lines as you are. Is your concern and other industry representatives' concern what I will call the peppermint tea exception? Is this all about preserving some ability to promote peppermint tea? The reason I ask, if that is so, then that is useful to know, but I am also worried or concerned about other ingredients that preexisted 1994, so they would not fall under the new dietary ingredient pre-review by us, but new data on an older ingredient for structure/function claim, as I believe what is described does not hook into the prior approval. I am still stuck on what is the public's assurance if it is not in an established compendium or gone through a process. I am trying to figure out what claims are we really_- are we trying to establish a principle? Are we trying to protect peppermint tea? Or are we trying to figure out how we are going to get the data out in the open before it gets into the consumer promotion issue? MR. MC GUFFIN: It is not only peppermint tea that I am talking about, but it is a finite list. It is a list that we could work with you and generate essentially a positive list, where it is peppermint tea, it is raspberry, it is nettle leaf. Again, Josef Brinckmann will present later_- PARTICIPANT: Prenatal vitamins. MR. MC GUFFIN: It is prenatal vitamins, right. In the non-botanical arena, it is prenatal vitamins. I believe we could create a positive list in a meaningful manner and look at some of the history of use and do a thorough search on toxicity data that exists for that. It is not only peppermint, but it is not 2000 botanicals by any means. DR. MITCHELL: Would you be willing to subject them to study? MR. MC GUFFIN: Absolutely. DR. MITCHELL: It seems to me that if a woman has nausea and vomiting of pregnancy sufficient to warrant some treatment, there is actually a product available that used to be called Bendectin(?). Ironically, we have learned from years of research that took tremendous amounts of effort and tremendous amounts of controversy that the scientific community, I think, can now demonstrate that that product, which was used by as many as 25 percent of pregnant women, actually has as good a profile of safety as far as the fetus is concerned as anything. The issue that I raised, and I meant it to be somewhat provocative, is that_- do we want to use products that have a "tradition" of safety, or do we want to use products or promote products that actually have documented scientific evidence of lack of harm. I am not asking you to answer that question specifically, but it seems to me that given the vulnerability of the population, given that I think both of you have indicated that you wish to be quite responsible, it seems to me that the products ought to be held to a very high standard. DR. SOLLER: Dr. Mitchell, if I could just comment on that. There is a principle to be retained here. Step back, look at our program, and you will see I am trying to create the exemptions. How that was created is not unlike_- it is in parallel fashion to how the OTC pregnancy-nursing label statement was created with specific exemptions. There is a desire to think about the kind of label program that would logically say that there were certain categories for which a label statement might not be put on. If that also includes the creation of a positive list, products that have the substantiation for safety, that would be encompassed into the kind of approach that we are trying to put forward. DR. SCHWETZ: Dr. Mattison. DR. MATTISON: I would like to push the safety questions a little bit further. Ms. Dickerson indicated the unique disparity with respect to dietary supplements in comparison to pharmaceutical products where the absence of data demonstrating safety in one allows the agency to prohibit marketing whereas in the other the absence of safety data is of no benefit. Dr. Mitchell indicated that essentially for many of these products, if not for all of them, data demonstrating safety during pregnancy was absent. Within the United States, about half of women become pregnant in an unanticipated fashion. We know that many of the vulnerable periods to fetal development occur prior to the recognition of pregnancy. From that perspective, then, let me go back to the question that Dr._Mitchell raised. My sense from hearing the three previous presentations is that the industry is enthusiastic in endorsing demonstration of safety using currently acceptable clinical study techniques before products be marketed to pregnant women or women of reproductive age given the fact that half of pregnancies are unintended or unanticipated and that much of pregnancy occurs prior to the recognition of pregnancy. Am I accurately summarizing your position? Dr. Mitchell, you might want to comment on your perspective of what the bar should contain, that is to say what should adequate demonstration of safety for women of reproductive age be? MR. MC GUFFIN: We are certainly open to and in fact relish the additional information for the products that we have been using for these hundreds and thousands of years. We have not tried to stop the science on the study of botanicals. It helps us move forward to continue to utilize the contemporary scientific methods for testing and evaluating both efficacy and safety. I would not propose that we take the botanicals off of the market until such time as a safety study is done on_- I will keep with my silly example, peppermint tea. I do not think that we have a_- the work that we did in the Botanical Safety Handbook and the reason that we arrived at one-third of the botanicals listed as not for use in pregnancy is because the body of knowledge that came before us. We are not the first to be sensitive to this stage of life. Our society has been sensitive to this stage of life for a long time, and we have recorded the concerns that have been associated with the use of botanicals in pregnancy and its impact on the health of the pregnant woman and the fetus. Certainly the science has moved forward. Certainly we want to utilize the science and its contemporary incarnation to evaluate this, but I do not believe that that means that we assume that any information that is more than 15 years old is irrelevant. I know that_- I understand the discomfort. I understand that it is a_- that to characterize the difference between the_- and I am specifically talking about botanical dietary supplements and drugs. It sounds like a blatant differentiation. I think as good a question would be we do not know much about the impact of any of the foods that we eat on the health of pregnancy or the fetus either. I do not see the call for evaluating the impact of broccoli on the fetus, or meat on the fetus, or any of the foods. I do not want to go too far there. I do not believe that we need to do that for the foods, but I do think that we need to remember that we have been using the botanicals in much the same manner as we have used the foods for centuries and centuries and centuries. I know that I am not able to give you a yes/no answer. It is a complex issue with regard to botanicals, and I think that we do have to be respectful of their historical use. DR. SOLLER: Just to comment on that, from our standpoint, we took a program approach that was parallel to the OTC situation some years ago. In today's world and as we think about it, the promotion of dietary supplements for use in pregnancy or nursing has a safety bar which we think must be high, and we think that our program, at least for our members and how they are looking at that, creates that high standard. In the absence of scientific documentation, we think that our labeling program, with the suitable, defensible exemptions, is the appropriate solution. DR. MITCHELL: I certainly do not mean to suggest that dietary supplements represent an imminent hazard and that they ought to be withdrawn. It seems to me that the entire focus of these proceedings was on whether they ought to be promoted for use in pregnancy, and that is a very, very different issue. Birth defects are relatively rare events. As an aggregate, major defects affect two to three percent of a normal population of pregnant women. Specific birth defects which are typically the kinds of outcomes that are found in relationship to drug exposures or environmental exposures occur individually at a baseline rate of about 1_per 1,000 and as infrequently as 1 per 10,000. Over the past two days, the FDA Subcommittee on Pregnancy Labeling has been struggling with exactly the kinds of questions that Don has posed which is where should the bar be. I think every reasonable person will argue that we never know enough about safety in pregnancy. That applies as well to prescription and OTC pharmaceuticals as environmental agents or dietary supplements. I do not mean to suggest that there is a magic formula for claiming safety. On the other hand, it does seem reasonable to appreciate that increased risk of birth defects may be occurring historically with various products and escape detection. That has certainly been_- with the exception of something like Thalidomide, that has really been the experience. I think we have learned from the studying of prescription pharmaceuticals that, for example, valproic acid, which increases the risk of neural tube defects perhaps 20 to 30-fold escaped detection in any anecdotal or other sort of case report format. It took a formal study to identify that risk, and that is an appreciable risk. I think there is no difference in the science that needs to be applied to herbal and dietary supplements. I think that there are procedures in place, there are various studies in place, where information on these products could be included in the inquiries. A number of us have had interest in this. It is a difficult area of research because it is hard to identify exactly what women are taking. I think that at least that would represent a step in the right direction, and it seems to me that it would provide some level of assurance. I do not think that we can, from a scientific standpoint, ever assure anybody that any product is absolutely safe. That is certainly the case for birth defects which are rare events, but I think that there are ways to approach the issue that provides some degree of assurance. DR. SCHWETZ: Let me comment on Thalidomide as an example. A lot of us talk about Thalidomide as the epitome of what we want to prevent from getting to the public. If all we do as a regulatory agency and as manufacturers, if all we do is keep Thalidomides off the market, we are falling far short of the mark. Thalidomide-type compounds are relatively uncommon. Fortunately, they are rare. But, there are a lot of compounds that cause subtle damage that is harder to detect. There might be changes in mental acuity. It might be changes in stature. It might be changes in a lot of other behavioral or other functional entities that are much more difficult to detect, and a compound that would cause those kinds of changes is much more likely to go undetected as a cause. It is entirely possible that decades of human experience would fail to identify that a compound is causing a subtle change that is still dangerous to the well-being of the unborn. I think our goal should not just be to keep Thalidomides out of the public use. There are a lot of other things that we need to worry about beyond that. DR. MITCHELL: At the risk of undermining my own argument, I disagree with you just slightly. The just slightly is that I think that the subtle deficiencies in, let's say IQ to use a simple measure, are likely to continue to escape detection. We simply do not have the resolution available in epidemiologic methods and certainly not in clinical trials to identify those outcomes. I think that is a bar that would be set too high even for prescription or OTC pharmaceuticals. I think the point you raise is a critical one in that there is a wide range of outcomes between Thalidomides and, let's say, a five point IQ loss measured at age seven that really bear study. I think valporic acid and neural tube defects is a good example where you have a very definitive outcome that is appreciably increased but would not be picked up by decades of simple observation. I take your point. DR. SOLLER: If I could add a comment, and again in looking at our program, we wanted to encompass the kind of work that has been done to define scientific documentation for why a particular ingredient might not be used in pregnancy or might be used only under the supervision of a health professional. On the same token, we wanted to take a medical perspective that I am building on now from your comment. That is where we can create appropriate exemptions, maybe not a label statement, but in the absence of that information and before the research is developed to insure that there is an appropriate label statement on products. DR. SCHWETZ: Are there any other questions from the panel before we go to Doctor_- Godfrey? Agenda Item: Discussion from Floor. DR. OAKLEY: Godfrey Oakley from Emory University. I just wanted to add onto Dr._Mitchell's comments, and it seems to me one thing that we need to remember, you need_- exposures must already be in place in order to do those kind of studies. If there are products, peppermint tea or whatever, that have been out there for a long time and you can document in some way their exposure history, then you might do studies that would do the sort of thing that Allen is talking about. I can think the case control formats that many people are doing for birth defects would be one way to look at that. You could do it with prematurity. You could do other things, but to have industry put some money into actually doing some case control studies to examine these issues. I also understand that it is the bit of a discussion going on within the government right now, about another large cohort study of pregnant women. If, in fact, you had one percent of all women entering our cohort study on an ongoing basis, and systematically looked at their outcomes and their exposures would be another place to get information not only on these kind of products but almost any kind of product or exposure that you could think about. It would be helpful to the FDA, the EPA, to industry and everybody else. That is not going to happen until there is some political will brought forth. It might be helpful, bringing the political will forth to get a $100_million a year study funded so that we find out not only about these issues but about the 75 percent of birth defects that we do not know the cause for. DR. WOLFE: Sidney Wolfe. I would like to add a little bit onto Dr._Woodcock's important question which has been partly but I do not think satisfactorily answered, which is, what is the standard of evidence in questioning the bar as in saying that it really was not much of a bar? She was referring to the fact that the manufacturers, on their own, could determine what kind of study constituted proof of safety. In Mr._McGuffin's presentation, he said that if anything came up in the existing literature that raised the question about safety, that was sort of put off the charts, so there are 200 compounds that were judged not to be safe for use in pregnancy. The question is really for you, Mr._McGuffin. We are left with then 444 that implicitly are thought to be safe in pregnancy. Getting back to Dr._Woodcock's question, what is the standard of evidence? You reviewed that there was something ranging from centuries of safe use to inclusion in books on toxicity, but how would you characterize the standard of evidence that those 444 compounds had to go through in order to be deemed okay or safe for use in pregnancy? I think that is the major issue. It is important that Dr._Woodcock is here because particularly for this vulnerable population, a standard that is equal to if not_- close to if not equal to that for drugs, reproductive toxicity studies in animals, case control studies as Allen Mitchell has mentioned, really needs to be put in place. I would just like to ask you, of those 444 compounds, how many of them have had animal reproductive toxicity studies that would be judged by people expert in the field to be adequately done and do not show any problem, and/or how many of them have had formal case control or other kinds of epidemiological studies? MR. MC GUFFIN: How do I_- I cannot give you a number. I do not exactly know how many of those, but the_- DR. WOLFE: Roughly. MR. MC GUFFIN: -_minority. DR. WOLFE: The minority. MR. MC GUFFIN: Right. In fact, when Christopher and Roy and I and others in our community got together to do this work, over and over and over, we looked at each other, and we said, What are we doing. Here we have devoted our entire careers, and it is more than our careers, it is a commitment to reestablish botanical options in health care, safe, properly used botanical options. Here we are expending significant resources of our own time with no compensation to tell the world every bad thing that we can find out about these botanicals. But we did not see it that way. We saw it as a distillation of_- we did not have this terminology at that time but the material facts. We wanted a central resource for the material facts. In direct response to your question, there is the fact that none of our 29 references said not for use in pregnancy, proof that it is safe for_- proof for use in pregnancy, no, it is not. We included, though, in the editors and in the review, people who used these botanicals. We deliberately chose our resources to include those who had seriously considered the same perspective that we did, that we want to use these things well, we want to use them safely, we want to use them. We consider them valuable, health-promoting options, and we want to use them responsibly. Very few of them have been subjected to the kind of studies that you are talking about. Nonetheless, we think that the 444_- actually, I think it is 441 that are not classified in II-B. Actually, several dozen of those are classified in the more restrictive class which further implies that it not be used in pregnancy because that classification is not for use at all except under an expert's supervision. Still, we end up with whatever it is, nearly half of the plants as in our Classification_I. Have we proven for any of those_- have we proven for peppermint tea that it has no cause for concern in pregnancy? We have not. Have there been epidemiological studies or animal studies or lab studies, NTP studies? No, there have not. Actually, I know that there have been on some of them, but I do not have those in my head. I do not believe that that is the same as saying there is no evidence of safe use. Because of the nature of our references and our review process, our goal was to really identify every single bit of evidence that we could find that gave us any cause for concern. DR. WOLFE: Just to rephrase what you said, hopefully accurately. Dr._Mitchell is pointing out that the history of safe use itself, given the limitations of case reporting and so forth, really does not mean that much nor does centuries of use. Essentially what you are saying is that the overwhelming majority of the 441 chemicals that your handbook deem to be safe for use in pregnancy have never undergone either formal reproductive toxicity studies in animals or have been subject to a formal epidemiological study, is that correct? MR. MC GUFFIN: That is correct. DR. WOLFE: Okay, thank you. DR. SCHWETZ: One last, quick question from Mr._Levitt, and then we will break. MR. LEVITT: I have just been sitting here trying to figure out to what there is a degree of commonality among the different speakers. I will just throw something out as a test to see kind of yes or no, but I think maybe I am hearing from everyone so far that you would support an evidence-based process that would precede what I would call targeted claims for pregnancy like morning sickness. DR. SOLLER: CHPA would. MR. MC GUFFIN: I believe AHPA would. DR. DICKINSON: CRN would also, and you will hear that in our statement. DR. SCHWETZ: One other question if it is quick. DR. O'CONNOR: Tanya O'Connor. I am from the press, but I do have a personal stake in this issue. I have a question for Dr._Soller and Mr._McGuffin. There is a wealth of information already available on the toxicity of herbs and contraindicated herbs of pregnancy. I have a book here with 250 listed. Among them are both peppermint tea and ginger. One source is the Journal of Pharmacological Sciences, and the other source is the Toxicology of Botanical Medicines. One is listed as an amenogogue, and another is an abortifacient. There is a lot of information out there currently, but yet the consumer is not getting that information. For example, I have gone in twice to a health food store to find herbal remedies, one for flu and another for nausea. I was handed remedies that neither contained a warning or notice as well as no indication from the herbalist on staff that they were dangerous for pregnancy. When I got home, I looked at this book_- and most people I know do not own this book. I found that both_- all of the substances in both of the products were contraindicated with pregnancy. Without official label regulation, how do you expect consumers to get accurate information? DR. SOLLER: From the CHPA standpoint, I mentioned that we would be petitioning the agency for a regulation to adopt our program so that there would be a consistent message across products in the industry. MR. MC GUFFIN: From our perspective, as I said, we are at that stage where we have requested compliance from our members. We think that the next step is a stricter regulatory enforcement. I am familiar with Frances Brunker's work, and I believe that_- I cannot look at the references right now. We have looked at ginger quite extensively. The concern for dried ginger, our book classifies dry ginger as not for use in pregnancy, fresh ginger as appropriate for use in pregnancy, due to the different concentrations of the compounds contained in it. I think Frances missed a detail in that. He had an earlier book that we had hoped to make one of our references because he has been focused on herb toxicity for some time. We checked some of his references and found that he was not accurately representing what his references had said. I would recommend that you go find those two references. In his original book, he had hundreds and hundreds of botanicals just in a list that said not for use in pregnancy. Two-thirds of them were from a single reference, a list that Dr._Norman Farnsworth had compiled in a general article from 1978 or something, that was a compilation of any botanical that had ever been reported any one single time in any culture to have ever been used for any condition of pregnancy. Frances called that not for use in pregnancy. We did not think that that was an accurate representation of the journal article that he identified as serving for the basis of his recommendation. appreciate his work. I think this volume is much more expert than the last one, especially with the details that he gives about whether or not the classification is based on a contemporary scientific basis or observation or empiricism. I think that does help to clarify. There are questions about the accuracy of the information in his work. MS. O'CONNER: Get in the nuances of the research is the differences. Again, with the publication of your handbook, how are consumers supposed to get accurate information given that most do not consult research journals? DR. SCHWETZ: May I ask that we hold this question. We will come back to it after other speakers. We are into the break time, and I do not want to take the time away from the other speakers. Let's come back to that question as we follow up with other speakers. Thank you very much. MR. MC GUFFIN: Can I restate one thing that I said earlier. The best place for a consumer to get the information is on the label of the goods. DR. SCHWETZ: Thank you. Let us reconvene at 11:05. [Brief recess.] DR. SCHWETZ: If we could start. Our next speaker is Dr. Annette Dickinson, the Vice President for Scientific and Regulatory Affairs, the Council for Responsible Nutrition. Dr._Dickinson. DR. DICKINSON: Thank you. I am pleased to be here to address this important issue on behalf of the Council for Responsible Nutrition, which is a trade association of dietary supplement manufacturers. We represent approximately 100 manufacturers of dietary supplements and ingredients of dietary supplements. I have provided copies of our statement at the desk, and I hope many of you will have that. Although pregnancy is a natural state as that term is used in FDA's final rule on structure/function statements, we recognize that it is a state to be treated with the utmost respect and caution. This applies to the marketing of dietary supplements as well as to many other products and practices. CRN recognizes the need to assure that all dietary supplements are safe and beneficial but also recognizes an increased need for prudence when dealing with products intended for use by pregnant or nursing women. In the interest of extreme prudence, CRN members would support an FDA finding that statements relating to morning sickness or edema of pregnancy or other conditions of pregnancy must meet a rigorous standard of evidence regarding safety as well as benefit. We believe DSHEA provides ample authority for FDA to use to establish criteria for safety that must be met before products can be offered for use during pregnancy. Criteria could also be established for determining the adequacy of a company's substantiation for any statement of nutritional support related to pregnancy. However, in discussing dietary supplements in pregnancy, we believe it is very important to recognize the extent and importance of current dietary supplement use, especially vitamin and mineral supplement use, by women of childbearing age. According to NHANES-III, dietary supplements are used by almost 30 percent of teenage girls and by over 40 percent of women of childbearing age in the United States. Among women of 20-39, the overwhelming use of products is of a multivitamin type of product. Sixty-five percent of those women in that age group who use a supplement use only one product, and 83 percent of the time, that one product is a multivitamin with or without minerals. I have attached some tables to my statement which provide additional detail from NHANES-III regarding supplement pattern practices in women of childbearing age. Prenatal vitamin and mineral supplements are almost universally recommended by physicians and are used, according to surveys, by more than 80 percent of pregnant women. Prescription prenatal products are generally specified by physicians and are usually reimbursable by healthcare systems, but dietary supplement prenatal products with similar formulations are also available and are selected by many women. CRN believes it is important to be clear about the benefits of appropriate nutritional supplementation for women who may become pregnant as well as for women who are already pregnant or nursing. While we recognize the basis of the concerns that led to this public meeting, we are anxious to assure that women do not get the wrong message and turn away from multivitamins, calcium products and prenatal supplements known to be beneficial. Nutritional supplements such as these may or may not bear structure/function statements or health claims. They may simply be labeled for use by all adults, or they may be labeled specifically for use by women, or perhaps directly intended for use by pregnant and lactating women. All of these methods of labeling are permissible under existing regs and have been for many decades. FDA has established reference daily intakes to be used in labeling vitamin and mineral products for use by adults generally and a separate set of values to be used in labeling products for use by pregnant or lactating women. Dietary supplements containing calcium or folic acid, as we all know, may also be labeled with an FDA-authorized health claim, and these claims are distinct from claims of nutritional support that are the subject of this proceeding. In 1994, when Congress passed the Dietary Supplement Health and Education Act, they permitted dietary supplements to use label statements referred to as statements of nutritional support which includes statements describing the effect of any product on the structure or any function of the body. For more than five years, the industry has been making label statements under these provisions including some statements relating to women's health uses. CRN recently had the opportunity to review a database which was compiled by the tan sheet covering 3600 statements of nutritional support which had been submitted to FDA at the time the database was complete. Those included approximately 200 statements relating to women's health. There were only a few statements, four in particular, relating to pregnancy in any way. These involved unsaturated fatty acids including DHA and EPA. One was a multivitamin, and one was a calcium product. There is substantial evidence on the benefits of these kinds of ingredients for the mother, the fetus and the newborn infant. Most of the structure/function statements that have been submitted to FDA relating to women's health issues are focused on PMS or on menopause or on general well-being for women. In 1998, in FDA's proposed structure/function rules for dietary supplements, the agency took a rather narrow view of permissible statements about natural states such as aging, menopause and pregnancy. Numerous comments were submitted to the agency, which complained that FDA was wrong in considering many symptoms commonly associated with natural states to be disease conditions. In the final rule, FDA published on January 6th. FDA reversed its position in part by acknowledging that some of these statements about natural conditions could be made and specifically mentioning mornings sickness and leg edema of pregnancy. As we all know, well-respected physicians immediately expressed concern to FDA about the potential risk to pregnant women and unborn babies if a wide variety of supplements were suddenly to be offered for use in morning sickness or edema of pregnancy. The degree of concern was triggered, as we have heard this morning, in part by the tragic history of pharmaceutical products offered for treatment of these conditions in the past, and FDA issued an advisory calling for a hold on any claims relating to these issues. CRN is, in fact, not aware that anyone in the industry has expressed interest in making label statements about these particular conditions prior to the origin of this discussion or that any of our member companies are now making label statements about these conditions. We are not aware of any dietary supplement at all that might potentially be labeled for uses relating to edema of pregnancy based on our review of pharmacological texts that we have available in our office. However, there are a few botanicals that are commonly considered in these texts to have uses in morning sickness. Many women are well aware of these potential uses whether or not the product is labeled with a specific indication for morning sickness. For example, a recent article in the lay press discussed the benefits of a variety of supplements including raspberry leaf tea and ginger for the relief of morning sickness, and we found that these botanicals were affirmatively recommended for these uses in some pharmacopoeias and other professional references. CRN and its members have no wish to see inappropriate products offered for use for morning sickness or edema of pregnancy or for any other use that could be detrimental to pregnant or nursing women or to women who may become pregnant. At the same time, we do not believe that it would be reasonable for FDA to respond to this situation by classifying pregnancy as a disease as a matter of legal fact or to classify such common pregnancy-related conditions as morning sickness as diseases. We believe the key issue in the present controversy is in fact not related directly to claims but is rather a concern about the safety of any product specifically marketed for use by pregnant or nursing women or perhaps even by women generally of childbearing age. CRN believes as a matter of policy it would be preferable to address these safety concerns directly rather than choose the indirect route of prohibiting particular claims. We believe DSHEA permits FDA to establish a rigorous requirement for evidence of safety for products bearing pregnancy-related statements as well as a rigorous requirement for substantiation of any claims. CRN specifically recommends that FDA should issue a guidance document possibly to be followed at some later date by a regulation, but that always takes a very long time. That FDA should issue a guidance document setting for the data that FDA would consider to be necessary to substantiate a label statement about morning sickness or edema of pregnancy or other conditions relating to pregnancy. DSHEA requires that manufacturers have substantiation for any statements of nutritional support. DSHEA, however, does not establish criteria for that substantiation, and FDA has not established any criteria by regulation. The Commission on Dietary Supplement Labels of which I was a member set forth several recommendations regarding the quality and quantity of substantiation that would be appropriate and emphasized that substantiation should cover safety as well as effectiveness. The Commission recommendations, I believe, could provide a model that FDA could consider incorporating into a guidance document on this issue. Secondly, CRN recommends that FDA issue a guidance document setting forth the conditions under which FDA would consider a product bearing a pregnancy-related statement to be adulterated. In such a document, FDA could indicate that a product intended for use in pregnancy would be considered to present a significant or unreasonable risk under DSHEA if it is not recognized, affirmatively recognized, as safe for use during pregnancy or if there is not sufficient evidence to support such a finding. In summary, CRN recognizes the obligation of the industry to provide safe products to the consumer and to substantiate label claims. These obligations take on special significance when they are applied to products intended for use during pregnancy. We believe DSHEA provides ample authority for FDA and the industry to deal with the product safety and with label substantiation, and we believe that authority can be used to resolve the concerns that have been expressed regarding pregnancy-related products and claims. In our prepared statement, we also provide responses to the questions posed by FDA for this hearing. Thank you very much. DR. SCHWETZ: Thank you, Dr._Dickinson. Dr._Mattison, before we have you start, we are going to set the timer, not just because of you, because it was not working right before. DR. DICKINSON: I was wondering why it was flashing at me the whole time. [Laughter.] DR. SCHWETZ: Dr. Don Mattison, Medical Director, March of Dimes Birth Defects Foundation. Don. DR. MATTISON: Thank you. Thank you for the opportunity to comment on FDA interpretation of how structure/function claims related to pregnancy will be dealt with under DSHEA. The March of Dimes Birth Defects Foundation is one of the oldest public health, non-governmental agencies in the United States with a mission devoted to improving the outcome of pregnancy. In accomplishing this mission, the foundation considers its activities against the continuum of reproductive health which begins prior to conception. The foundation is a volunteer-led organization with more than three million volunteers with all ranges of background, from physicians and scientists at highly-specialized academic health centers to health care professionals at community centers to non-professionals of all types. The common theme linking all of these diverse volunteers is the March of Dimes mission to improve pregnancy outcome. From that perspective, this legislation and how structure/function claims are interpreted in relationship to pregnancy are critical to our foundation especially because we believe it is essential to prohibit pregnancy-related structure/function claims under DSHEA. My comments will focus on the following topics: successful adaptation to and completion of pregnancy requires a set of complex physiological changes in the mother as well as dynamic adaptations by the placenta and fetus. One of the most obvious changes is increase in maternal bodyweight. Over the course of pregnancy, the fetus grows to approximately eight pounds, the placenta about a pound and a half. The uterus increases to about two pounds. The weight of the breasts increase about a pound, and blood weight increases about three pounds. Subcutaneous adipose tissue also increases about eight pounds. In addition, there are changes in the physiology of the mother with cardiac output increasing approximately 50 percent, pulmonary function increasing about 40 percent, renal blood flow and glomerular filtration rate both increase about 50 percent, and the motility of the intestines decrease. These are just some of the changes that occur across the course of pregnancy. Indeed, if these changes do not occur, the outcome of pregnancy is typically worse than when they do occur. These changes associated with pregnancy create conditions in which a young, healthy woman would be considered signs and symptoms associated with disease. For example, as a consequence of pulmonary and cardiovascular changes, it is common for a healthy pregnant woman to have leg edema and shortness of breath. In the young, healthy woman who is not pregnant, those symptoms would suggest the need for further evaluation for potential cardiovascular disease. During pregnancy, these are expected, and the healthcare provider teaches the woman that these will occur. Nausea and vomiting of pregnancy and leg edema of pregnancy are also conditions that usually represent normal adaptations of pregnancy but are also symptoms of disease and cannot be distinguished between normal and disease states by the lay person. Nausea and vomiting is generally thought to represent the hormonal changes which take place over the first half of pregnancy, explaining why it typically resolves after the first trimester. Leg edema is thought to be produced by a series of maternal physiological changes including increased vascular permeability, decreased serum protein concentrations, pressure on the uterus, pressure of the uterus on the veins leading from the legs toward the heart, and increased intravascular volume. As I indicated earlier, these are normal adaptations of pregnancy and are more frequently found in those pregnancies that have a healthier outcome. Pregnancy then is a dynamic and evolving physiological state with both maternal as well as fetal changes necessary for a successful outcome. Indeed, as a recognition of this evolving state and the potential for rapid development of disease in either the mother or the fetus, authoritative bodies like the American College of Obstetricians and Gynecologists have established clinical guidelines on the frequency of visits and the types of evaluations recommended. These visits for women with an uncomplicated pregnancy generally occur monthly over the first 28 weeks of pregnancy and then increase every two to three weeks until 36 weeks, and then advance to at least weekly visits until the end of pregnancy. In no other situation are healthy adults seen as frequently by highly trained and specialized health care providers. This frequency of visits has been established by expert clinicians because of the rapidity with which disease can develop during pregnancy. Unlike the normal adult, the physiological status of the mother, the placenta and the fetus are continually changing. From this perspective, we find the binary categorization of DSHEA disease or structure/function claims to be inadequate. During the early part of pregnancy, unlikely stimulated by hormonal changes associated with early pregnancy, there is a characteristic pattern of nausea and vomiting. Nausea and vomiting associated with pregnancy typically begins at about 4 to 8 weeks and persists until 15 to 20 weeks of gestation. Among many women, the symptoms are annoying, uncomfortable but manageable with changes in eating habits. Unfortunately, however, for some women, the nausea and vomiting of pregnancy is worse than annoying or uncomfortable and is certainly not time limited. This continuing and unrelenting vomiting is severe and life-threatening and is termed by clinicians hyperemesis gravidarum, loosely translated as excess of vomiting in pregnancy. This condition produces morbidity because it prevents sufficient nutrients from being ingested by the mother and also leads to dehydration and electrolyte imbalance. Together, these conditions represent physiological stressors for the mother and fetus. What is excess vomiting in pregnancy. Is it vomiting three, four or more times per day. How is the impact on the mother assessed or characterized. I wish the definition were as simple as counting. Unfortunately, that is not the case, and typically the physician will assess blood and urine chemistry to determine the impact of nausea and vomiting on the course of pregnancy. That being the case, allowing or encouraging women to use dietary supplements on the premise that they can be used to manage nausea or vomiting during pregnancy is totally inappropriate because it assumes that the woman can distinguish the normal from abnormal conditions of pregnancy. As described previously, one of the other common symptoms of pregnancy is leg edema produced by increased intravascular volume and so on. Unfortunately, edema is also associated with the development of hypertension or preeclampsia during pregnancy, both diseases that should be carefully followed and treated by a physician experienced in the care of these high risk patients. It is also unfortunate that like nausea and vomiting of pregnancy, it is difficult for a non-health professional to determine if leg edema associated with pregnancy is also associated with other serious changes as these require assessment of the pattern of blood pressure change over the course of pregnancy as well as the measurement of protein and other chemicals in blood and urine. In the Federal Register, it was noted that the FDA specifically seeks comments on the following questions, and I would like to briefly address them in turn. I hope I have provided convincing evidence that pregnancy is a dynamic and evolving physiological state with the potential for rapid development of disease. As others have previously commented, we believe that the use of dietary supplements may produce a false sense of security with respect to symptoms which may signal the development of more severe conditions among pregnant women and so delay the needed diagnosis and treatment. Consider, for example, the two structure/function examples cited. Leg edema may represent normal adaptation to pregnancy or a symptom of preeclampsia, renal impairment, hepatic impairment, nutritional impairment or other conditions which can rapidly progress to disease which impairs the life of the mother of the fetus. Similarly, the nausea and vomiting in the first trimester, while commonly self-limiting, may represent the early signal of hyperemesis gravidarum. Unfortunately, hyperemesis gravidarum with altered carbohydrate or electrolyte status impairing maternal adaptation to pregnancy or fetal growth and development may also produce maternal and fetal dehydration with increased blood viscosity and, as a result, impaired intravillus profusion and increased propensity for blood clotting. Are these different than hazards to other potential users. Yes, because of the complex maternal adaptations to pregnancy necessary for its successful completion. If so, why and on what basis under DSHEA. Unfortunately, the foundation believes that the two state nature of the Dietary Supplement Health Education Act, that is disease or structure/function claims, is not well suited to the dynamic state which occurs over the nine months of pregnancy. Therefore, we argue that all pregnancy-related structure/function claims should be prohibited. Note, however, that there are health claims that we believe should be left intact. These relate to deficiency states which are associated with abnormal pregnancy outcome. One notable example is the benefit derived from folic acid in decreasing the risk of neural tube defects. With respect to the second question, we believe that structure/function claims should not be permitted at all during pregnancy because both the mother and fetus are continuously changing to adapt to pregnancy and to grow and develop. As I previously noted, there is a set schedule of visits which occur over the course of pregnancy and which have been designed by the American College of OB/GYNs to address changing risks with respect to pregnancy. Women who are pregnant may also have other diseases that are unrelated to pregnancy. Unfortunately, it has been shown that the interaction between pregnancy and other diseases found in women are complex and, in some cases, may act to modify adaptations to pregnancy. As a result, these diseases increase maternal morbidity and produce stress for the fetus. These preexisting diseases may therefore act during pregnancy to increase risk for the development and decrease the time needed to develop maternal or fetal diseases. We believe that with the exception of vitamins and minerals that are used in preventing deficiency states, dietary supplements should not be used during pregnancy. For that reason, we will not comment directly about safety_- the ways of addressing safety. We believe that all dietary supplements marketed to women of childbearing age should contain the following warning. "Women of childbearing age should consult with a physician before taking this product because dietary supplements are exempt from any aspects of Food and Drug Administration oversight." However, as noted above, there are classes of products which are used in preventing deficiency states that have been shown to be beneficial during pregnancy. These should be exempted from or excluded from this advisory statement. Thank you for the opportunity to participate in this analysis of DSHEA and present the views of the March of Dimes on how structure/function claims related to pregnancy will be interpreted. In closing, let me briefly reiterate the perspective of the foundation. I hope the material that I have summarized provides the information needed to conclude that the complex set of changes which occur over the course of pregnancy can represent either normal adaptations or disease processes and that the distinction can be difficult and require the evaluation of a trained health professional. In addition, as described by ACOG, the risk for development of disease in the mother of the fetus increases as pregnancy progresses. This is reflected in the increasing frequency of visits suggested by this authoritative body. As a result, pregnancy does not fit neatly within the framework of DSHEA. For these reasons, the March of Dimes requests that FDA prohibit pregnancy-related structure/function claims under DSHEA. Thank you. DR. SCHWETZ: Thank you, Dr._Mattison. The next speaker is Josef Brinckmann, Research and Development Manager, Traditional Medicinals. MR. BRINCKMANN: My name is Josef Brinckmann. I am the Research and Development Manager of Traditional Medicinals in Sebastopol, California. We are a manufacturer of herbal dietary supplement products for preparation in the traditional aqueous infusion dosage form. Many of our products have also been registered for over 15 years within the traditional herbal medicine class of drugs in Canada by the Health Canada Therapeutic Products Program. As a preface to my comments, I would like to state that I have a 20-year old daughter who was born at home in 1979 and that we are expecting another daughter in May of 2000. It is relevant to state that my own family relies mainly on traditional herbal medicine particularly as prescribed from licensed acupuncturists trained in traditional Chinese herbal medicine for our primary healthcare needs. My wife is also currently under the prenatal care of a certified nurse midwife who recommends and/or dispenses certain commercially-available herbal dietary supplement products for common pregnancy-related conditions. My wife has been using certain appropriate herbal dietary supplements and herbal tea, tincture and fluid extract forms throughout her pregnancy with satisfactory effect. For over 25 years, our company has been providing a range of traditional women's herbal formulas including pregnancy and lactation products. Our herbal dietary supplement products are widely recommended by licensed health care professionals who have direct experience in pre- and perinatal care including registered nurses, certified nurse midwives, certified professional midwives, licensed midwives, certified childbirth educators, certified lactation educators, certified dulahs(?) and naturopathic physicians. Our women's herbal products are, in fact, served in hospital maternity wards and community health centers and clinics. Advice with regard to retail stores where our products can be purchased is also given to patients by pre- and perinatal consultants working in hospitals such as Kaiser and women's health centers. It is important that our ability to communicate appropriate indications for use for these dietary supplement products with the licensed practitioners and their patients who rely on them is not interrupted. Based on sales statistics, approximately 1,366,300 individual servings of our pregnancy tea, which has been on the market for over 25 years, are ingested annually. In the last six years, only two non-serious adverse events have been reported to our customer service department for this product. Six years ago was when we began our pharmaco-village program in house. These statistics demonstrate significant evidence of human safety from our perspective. With that being said, there are other manufacturers of ethical herbal products who share some of the serious concerns that are being raised in this public meeting, and we wish to be distinguished from the manufacturers of non-traditional, modern and/or novel phytopharmaceutical dietary supplement products that may be marketed to pregnant women under the provisions of DSHEA though they cannot demonstrate a long extent of safe use among pregnant women. There needs to be a clear differentiation made between modern, non-traditional products with no safety record from those herbal products that have been used traditionally and continue to be used successfully by a significant population of pregnant women for common, non-serious conditions related to supporting a healthy pregnancy. Our recommendation is that such differentiation can be determined by an expert panel that could advise FDA on what sort of requirement should be in a substantiation file or reviewed before marketing a product. The panel would be composed of our colleagues who are trained in the herbal medical arts and sciences such as licensed acupuncturists and naturopathic physicians as well as practicing members of the National Institute of Medical Herbalists of Great Britain, as well as medical doctors from the European countries such as France and Germany where traditional phytomedicine remains an integral part of their curriculum and within their scope of practice. We believe that responsibly formulated traditional herbal products manufactured under good manufacturing practice conditions from companies who have produced the requisite substantiation files and support of an allowable structure/function statement and have had those files reviewed by a qualified expert should be allowed to market their products to the women who rely on them and to communicate the product's specific indications for use during pregnancy. Licensed practitioners rely on the availability of these dietary supplement products in local pharmacies and/or natural foods markets if their own clinics do not have an associated herbal dispensary. I will now point to just a few examples. In 1999, the World Health Organization reported that the medicinal use of ginger preparations to treat pernicious vomiting of pregnancy is supported by clinical data. Naturopathic physicians report that mild nausea as well as hyperemesis gravidarum are effectively treated with ginger. According to the British association which represents practicing medical herbalists and pharmacists, ginger preparations are specifically indicated for vomiting of pregnancy. In a double blind placebo_- a double randomized crossover clinical trial, ginger effectively treated pernicious vomiting of pregnancy. Not teratogenic aberrations were observed in infants born during the study, and all newborn babies had Apgar scores of nine or ten after five minutes. This is the study that the World Health Organization referred to in their ginger monograph published in 1999. It is also apropos to mention, on my flight here, yesterday, I was reading in a current issue of a medical journal from Germany, Zytro-4(?) Phytotherapy. They were actually discussing in the article what pharmacists should be recommending to pregnant or lactating women for conditions of the common cold such as key-tarrah(?) of the upper respiratory tract with cough. This is a journal that is read by pharmacists and doctors, and they are recommending that you can safely recommend English ivy leaf extracts as heterohelix. Just with regard to other comments earlier that there is no information available, there are other well-defined systems of medical herbalism in European countries where there is information available. It just needs to be translated. Another common example is the use of raspberry leaf tea during pregnancy. According to the British Herbal Medical Medicine Association, raspberry leaf is used as a partice(?) preparatory. It has been used consistently in Europe since ancient times for nourishment during pregnancy and preparation for delivery. In a recent national survey of herbal preparation use by certified nurse midwives, 63 percent of the respondents who used herbal preparations in their practice reported recommending raspberry leaf. Raspberry leaf tea is traditionally used during pregnancy for morning sickness, to prevent miscarriage, and to shorten and ease labor. In North American and European systems of medical herbalism, raspberry leaf has a long tradition of use in pregnancy to strengthen and tone the tissue of the womb, assist contractions and check hemorrhage during labor. Additionally, in North American Aboriginal medicine, raspberry tea has a long history of human use as a birthing aide to treat labor pains, particularly among the Cherokee, Jerboas, Iroquois and Mohawk nations. In 1999, Professor of Pharamacognicy Dr._Varo_Tyler, wrote that while he believes that there is insufficient scientific evidence of benefit at the present time, if pregnant women believe that raspberry leaf tea provides relief from various unpleasant effects associated with their condition, no harm is done. In the traditional Chinese medical system of herbalism, traditional herbal formulas that are appropriate for use during pregnancy, for example, to prevent miscarriage, to treat non-severe cramping and pain in the abdomen, or for the treatment of morning sickness, are clearly differentiated in the formularies from those formulas that may be used only with caution during pregnancy and from those formulas that are specifically contraindicated during pregnancy based on the multi-thousand year history of clinical use among a large portion of the world's population, which is well documented. Though pregnant women should first seek the advice of an LAC specializing in gynecology if they are using traditional Chinese medicine for their primary health care before using certain TCM products, the availability and accurate labeling of such traditional herbal dietary supplement products is important to the practitioners and their patients who rely on them for healthcare during pregnancy. In closing, I want to reiterate that the concerns are certainly valid. Therefore, a distinction must be made between those herbal dietary supplements that have a long history of use and are currently used within the medical system, conventional and alternative, versus any new or novel products that do not have sufficient evidence of safe use by pregnant women over a significant extent of time. I would like to thank FDA for creating this forum and for allowing me the opportunity to address the panel on the long history of safe use of certain appropriate traditional herbal dietary supplement products during pregnancy. Thank you. DR. SCHWETZ: Thank you, Mr. Brinckmann. The last speaker of this panel makes this an international panel. Dr. Jan Friedman, Professor of Medical Genetics, University of British Columbia. Jan. DR. FRIEDMAN: Thank you. I appreciate the opportunity to address the panel. As the Chairman just said, I am Professor of Medical Genetics at the University of British Columbia, but more importantly, from the point of view of this morning's discussion is the fact that I am a clinical teratologist which is a person, a physician, in my case, who sees pregnant women who are concerned about the effects of drugs and other chemicals on their developing pregnancy. The lot of my professional life has been devoted to this. I am also the director of a test project which is a computer-based database that provides information that has been peer reviewed on the effects of drugs and other chemicals on the human pregnancy, embryo and fetus. This is used throughout the world, this database. I am also a member of the Council of Teratology Society. Although the agenda does not say so, the statements that I will be making this morning, at least the recommendations that I will be making at the end, are being made on behalf of the Teratology Society's Council on Public Affairs Committee as well as myself. The Teratology Society is a professional organization devoted to preventing birth defects through research, information and education. The main point that I want to make this morning is that the use of dietary supplements in pregnancy cannot be assumed to be safe for the embryo or fetus, but the final rule that the FDA adopted in January makes this assumption. As far as I can tell, the assumption is based on a couple of premises. One premise is that if it is natural, it is likely to be safe. As we have heard repeatedly this morning, this is not always true. Sometimes, it is true, and sometimes it is not. The other premise is that if it has been used for many years that it is safe. This premise is also not true. There are a number of natural products that have been used for many years and are clearly not safe in pregnancy. I will just give you three obvious examples: tobacco, cocaine and heroin. Those are all natural products, and none of them are safe for use in pregnancy. Now, we are not talking about those as dietary supplements, but they are natural products, and they have been used for a long time in pregnancy. Among dietary supplements, there is reason for concern in some cases. I have given the panel a little spreadsheet here that lists these four dietary supplements, blue cohosh, false unicorn root, and hellebore, hemlock and tregicanth(?) as substances that are listed in various places, either in books or on the internet, for human use but about which there is potential concern about the risk in pregnancy. I am sorry this picture is not showing very well, but one of them is hemlock or poison hemlock, which has been advocated for use in treating neuralgia and rheumatism, things that women of reproductive age may have. This has been associated in pigs, cows, sheep and goats with producing cleft palate and limb defects, arthrographosis or congenital contractures of the limbs that you can maybe imagine in that picture. Hellebore, which has been advocated for use of vomiting and cramps, two things that do occur in pregnancy, has been associated in sheep with producing serious brain malformations and cyclopea. This is actually a baby sheep, a lamb, I guess, that has just one eye and these serious brain malformations. Although this particular species, velotrum californicum(?), is not, as far as I know, recommended for use in humans, other members of this genus, including hellebore, are. The presumption turns out to be, in many cases, that there is no effect, but the reason that there is no effect may be that there is inadequate study. I go back to a personal experience on this one. When I was a medical student, I was taught that there was no evidence that alcoholic beverages ingested by the pregnant mother, even in a moderate amount, had any deleterious effect upon the fetus. In fact, we were taught to give pregnant women alcohol, to tell them to drink wine if they were upset or unusually anxious during pregnancy, to relax them. The justification for this was that it had been used for thousands of years, it was a natural product, and no one knew it caused any problems. Well, obviously we know that immoderate use of alcohol during pregnancy can cause fetal alcohol syndrome. The reason that we did not know it at that time was that it had not been studied adequately or in the right way. The traditional knowledge about dietary supplements often may be right, but in some cases, it may be wrong. It often differs in different traditions and cultures. Some cultures make very different claims and use the same substances for very different reasons. Some substances that are considered safe in one tradition are not considered safe in other traditions. One cannot adjudicate these claims. One cannot verify them without doing proper scientific testing. It is true that there is traditional knowledge about dietary supplements that is widely available. In fact, I would argue that it is too widely available. It is available on the internet. It is very easy to find recommendations for what to use in pregnancy and what not to use in pregnancy. It is available in a number of books that you can buy in any bookstore. But if you look at more than one, or if you look at the labels, what you find is often inconsistent. On the second page of the handout that I have given you, I have listed the information provided in five or six different internet and just commonly-available books on black cohosh, ginger root and peppermint, which we talked about at some length this morning. You will see that the recommendations in these various sources range from recommending their use to contraindicating their use for each of these agents during pregnancy. In some cases, they are even said to be severely toxic. This inconsistent information provokes anxiety, as we heard, and this anxiety often is especially important in pregnant women because they are very concerned. They are more concerned about harming their baby than they are about harming themselves, in many cases, at least. Because of this anxiety, some women may actually have abortions. They may decide that the risk_- or the anxiety is too great for them to continue the pregnancy when they get conflicting information on whether or not these substances are safe. We have certainly seen patients who, despite having reassurance from healthcare professionals that as far as we know the information is_- the exposure is safe, because they cannot get definitive information and because they have been upset, will decide to terminate a pregnancy. I am sure that is not what the FDA intended, but it may sometimes be the result. I do not think that "ask your doctor" or "ask your healthcare professional" or "ask your midwife" is really the answer either. The reason is that in many of these cases, although there is lots of information, and it may be authoritative, it is not necessarily scientifically valid. It has not been proven. There is not a way to say that this_- the consumer certainly has no way of knowing which book, which website, which authority knows what he or she is talking about and which one is just making it up as they go along. This leads us to our recommendations. Once again, these are my recommendations as well as those of the Teratology Society. The first one is that dietary supplements cannot be assumed to be safe for the embryo or fetus, and dietary supplements should not be labeled for use in pregnancy unless they have been shown to be safe by standard scientific methods. There are certainly dietary supplements that have been shown to be safe and even beneficial, folic acid being the example, by standard scientific methods. These should be promoted and used appropriately. Absent those kinds of reassurances, those kinds of studies, they should not be labeled for use in pregnancy. We believe that all dietary supplements should carry a warning that their safety in pregnancy is unknown. Most people assume that if something is on the market in the United States, it is safe, that the FDA in particular has assured its safety. In these cases, that safety is unknown. I think that these agents should simply say that their safety in pregnancy is unknown unless the safety has been established by standard scientific means. We also believe that the FDA should consider all pregnancy-related conditions to be potential illnesses under the 1994 Dietary Supplement Health and Education Act for the reasons that I think Dr._Mattison explained. Now, I notice that many members of the panel here are lawyers. This clearly is an issue that is not just a scientific issue; it is a policy issue. It is an issue that is important to many people for many reasons. Because I have no legal expertise at all, I do not know whether this law provides you the authority to enforce our recommendations as we propose. If it does not, we think that the FDA should work with Congress to amend this act to assure appropriate protection for the embryo or fetus. Clearly, no one on this panel, none of the speakers today or this afternoon, no one in Congress, wants to endanger the embryo or fetus. I think that failure to recognize that there is a special population who is at particular risk and for whom the rules that may be acceptable for adults to make decisions about themselves regarding these supplements do not really apply to needs to be recognized. If that can be done within the context of the regulations, that is great, but if in the judgment of the appropriate legal authorities that cannot be done within the context of the regulations, we think that the law needs to be amended so that it is done. Thank you. Agenda Item: Questions from the Panel. DR. SCHWETZ: Thank you, Dr. Friedman. We have about 20 minutes for questions and discussion. Any questions from the FDA panel? DR. GREENE: I would like to ask a question, just a point of clarification from Mr. Brinckmann. Your title is the Manager of Research and Development. For those of us who are not familiar with your company, I wonder if you could describe for us your program of research and development, please. DR. BRINCKMANN: Our program of research and development encompasses work with practicing medical herbalists and licensed acupuncturists, other qualified individuals, researching the medical herbalism literature. For example, a new product may be an already existing traditional formula. I will give you an example, We are putting out new products this fall that are formulas that are already in commerce in Germany and have been for years available in the pharmacies there. The available literature with regard to safety and toxicology and appropriate indications for use is available to us. We do phytochemical studies, bioassays, and in some cases our products have been the subject of human studies. DR. SCHWETZ: Dr. Woodcock. DR. WOODCOCK: I wanted to ask Dr. Dickinson a question. I think you said, and I am not sure, perhaps you can clarify it, that you felt that the effectiveness as well as the safety of products intended for use in pregnancy should be demonstrated? DR. DICKINSON: Yes. DR. WOODCOCK: So you did say that? DR. DICKINSON: Yes. DR. WOODCOCK: When you were talking about the fact that there should be adequate evidence, would that again, as I asked earlier, would that be in your mind to the satisfaction of the manufacturer or to the satisfaction of the FDA or to whom? DR. DICKINSON: I think criteria need to be established for the adequacy of the evidence, and I think that is something that the industry, FDA and all of the other stakeholders here need to work through as we proceed on this. I certainly do think there should be an external standard for what is adequate. DR. SCHWETZ: Dr. Greene. DR. GREENE: I have a question for all of the panelists from the herbal industries and that is, one of the concerns that we always have about any product on the market is issues of purity. What standards exist in the herbal industry to assure purity of the products as they are marketed? DR. BRINCKMANN: First of all, as I mentioned in my discussion, our products, our dietary supplement products in the United States are also traditional herbal medicines in Canada, so we are already familiar with operating under GMPs for the identity requirements. Health Canada requires that herbs used in a THM must conform to a currently valid pharmacopoeia quality test. For our internal standards, we have individual specification sheets for every herb that we use. Those specifications are pharmacopoeia grade depending on the origin of the herb. We primarily use the German pharmacopoeia, the currently valid European pharmacopoeia, the British. For Asian herbs, we used the Japanese pharmacopoeia, the Chinese and the Indian. We run the same tests known as pharmacopoeia standards for identity. We do HTPLC, macroscopic, microscopic, and grain aleptic(?) for every herb before it is approved for use in a product. MR. MC GUFFIN: I think the mechanisms that Josef are describing for his company are rather broadly used in our industry, especially in the most long-established companies. In terms of an industry overview, I was a member of the Food Advisory Committee's GMP working group. We continue to support and work closely with other trade associations to develop the industry draft GMPs and have continued to support FDA in keeping that at the top of their agenda. Our belief is that the GMPs as proposed are already largely in place in the manufacture of products, and of course, part of the good manufacturing practices is the proper identification of the ingredients. DR. SOLLER: Bill Soller, CHPA. In surveying our members, we know that they are manufacturing their products per the GMPs that the industry proposed to FDA or as subsequently refined and modified and reinserted by CHPA with some nuances that were appropriate for that particular product category. I think what Mr. Brinckmann specified in terms of the types of tests are what we are seeing in our membership as well. I would add in one additional thing which I think is important here. We, as an industry, collectively, I think all who are here on this panel have urged FDA to move forward expeditiously on the GMPs. Again, please do that. In doing that, we would also ask that there be a reasonably effective enforcement program that would insure there would be the compliance loop that would be applied. DR. GREENE: I specifically asked with respect to purity first and then the next sort of follow-up question is also with respect to dose. Do all of these studies that you perform guarantee uniform dosage across preparations from week to week, month to month, year to year? DR. BRINCKMANN: We believe that we are able to produce best batch uniformity, and we do adjust batches in some cases based on chemistry composition. For example, our stimulant laxative product, the amount of senna leaf per batch is batch specific depending on the amount of senna sites that we measure by HPLC. DR. DICKINSON: A company operating under appropriate GMPs would be able to assure batch to batch uniformity. We know from many tests that are published in various places that not all of these products are in fact meeting label claim. That makes it an illegal product. I think all of us in the industry believe that the industry is being undermined when companies are able to market products of that type. As Dr. Soller indicated, we need FDA enforcement to make those people believers. DR. WOODCOCK: We know that for natural drug products, there is a tremendous amount of complexity often. Do you have relief specifications or are you relying primarily on identification of the raw ingredients and then process controls? All of you, yes. PARTICIPANT: That would be just for product manufacturers? DR. WOODCOCK: Yes. To control the active ingredients, say, in the final dosage form, whatever it might be, there are several ways of doing that. The usual starting, basic way is to, as you said, control the starting ingredients, the raw materials. A more refined way is to do final product testing and look at level of ingredients. That is more difficult, of course, because of the complexity of the ingredients, often. I am curious, for most compounds, are you basically at the raw material control stage? MR. MC GUFFIN: Another element of that that is relevant is stability issues. DR. WOODCOCK: That is correct. MR. MC GUFFIN: Our position has been that it depends upon what your label states. If your label states that it was manufactured with 500 milligrams of Echinacea root and in fact it was measured at the beginning, and you did not lose it in the meantime, that that would constitute an appropriate measurement. If, on the other hand, as we see more of the products in the marketplace actually measure a constituent, we think that the only way you can assure that is by measuring the finished product and doing the stability testing that shows that the amount on the label is in the product at the time the consumer buys it, which gets all into dating principles and things like that. I will reiterate what Dr. Dickinson has said, that the way that we will start to find that consistency is that we will see enforcement of products delivering what they are labeled to deliver. DR. SOLLER: We would also, in terms of our membership, be in conformance with what you have heard. The identification of the source is often done with a certificate of analysis as the interaction between the manufacturer, the distributor and the supplier. In-process control and release specs are typical of our part of the industry. DR. WOODCOCK: The reason that this is germane, I think, is that any testing that might be done for safety or are other types of testing would have to rely on the fact that a standardized product was being tested and that it reflected products of that type in the market. DR. SOLLER: That is correct, and we have encouraged also the establishment of final monographs by the United States Pharmacopoeia as a means to create that loop. We think there are other pharmacopoeia or other compendia that also can be used by FDA in that regard but would concur with what you are saying. DR. DICKINSON: Even given that standardization, however, and even given pharmacopoeias, there will, of course, be variability in the strengths of various products that are offered which needs to be taken into account in the epi studies. DR. BRINCKMANN: I would like to add to that. Of course, the pharmacopoeias that have herbal monographs, as you may be aware, have limits and ranges to fit into. With a natural product such as ours, we are not selling the final dosage form. Our directions for preparation are key, so the information in our supplement facts box is only true if prepared according to the directions. We do assay. In our case, we have herbal teas. The water soluble constituents that are stable, that are perhaps relevant, and those in the supplement facts box, and we always round down, and we are doing real time stability studies on that so that we have relevant information to provide to the consumer. Again, it is only relevant if prepared. The other point that you make with regard to, of course, these are natural products, so one of the mechanisms goes back to GMPs. When we select a lot of raw material, we select a lot, a specific lot, that we use and contract on and draw from, from that point until the next harvest to minimize any chance of variability or minimize variability in general between harvests. They are natural products. We do know the complexity of it. We had one product that was the subject of a double blind placebo trial last winter, and the study will be published sometime this fall in a peer review journal. We are realizing that in the meantime, we have also been doing phytochemical and bioassay tests on every batch since the study was done because we realize this product cannot change from here on out. DR. DICKINSON: Right. DR. BRINCKMANN: You understand what I am saying. That is the challenge for us, is to demonstrate that we can make a uniform product within reasonable ranges of variability for a natural product. DR. SCHWEIZ: Louisa. DR. NICKERSON: I would like to hear from the other panelists, particularly those from industry, whether they support Dr. Dickinson's_- or I should say CRN's recommendations with regard to FDA issuing guidance documents, setting criteria for substantiation of pregnancy-related claims and also taking the position that a dietary supplement presents a significant or unreasonable risk if it is not recognized as safe for use during pregnancy or if there is not data to support such a finding? DR. SOLLER: Let me comment on that, if I could. That is the basis on which we would be going forward to suggest that you issue a regulation that would adopt our voluntary labeling program. I think what I heard from Dr._Dickinson is also that it might be a guidance or regulation. If in that regulation there is an amplification, as I answered Joe earlier in terms of the type of evidence, I think that would make it a workable document. MR. MC GUFFIN: AHPA would certainly be supportive of that approach. We would like to be involved in the development of such guidance because we think that we do have unique access to unique information about the products that we sell, but certainly the idea of establishing a level playing field so that we all understand exactly what the substantiation is, exactly where the line should be drawn, would be perceived as quite valuable. DR. BRINCKMANN: We would be open to that as well. We already have substantiation files produced according to the guidelines of the President's Commission, and we have them_- the files are written by clinical herbalists and reviewed by an outside pharmocognicist. At this point, we believe that we have adequate evidence to support our claim statements based on what the President's Commission's guidance was, but we would like to see further clarification. With regard to a panel that would specifically_- or a proposal that would specifically evaluate products that could be used during pregnancy and lactation, we would welcome that as well. We would just urge that the panel included experts in the field of traditional herbal medicine so that they are qualified to evaluate the material. DR. SOLLER: If I could add a postscript onto what I said, and that is in the context of recognizing this as a unique issue in the context of what has been FDA's longstanding policy vis-�-vis scientific documentation as a basis for changing and labeling. Here, we are dealing with a question as to whether there is a significant absence of information. I think that is somewhat different. I think that creates the uniqueness that is appropriate in this area so that we still maintain what we are working under vis-�-vis DSHEA. DR. SCHWETZ: Dr. Greene. DR. GREENE: I have one other follow-up question on the dose issue, and that is, that there is a natural tendency for people to think that if some is good, more is probably better. We know that is not true. When you take into account_- do you take into account that problem of controlling dose with natural products that people may be inclined to think that if some is good, more is better? Do you take those issues into consideration, for example, when you proscribe the use of these medications in your pharmacopoeia or when you discuss their use in pregnancy? MR. MC GUFFIN: I think that is addressed in two ways. One is, both in our work here and in other activities that we have undertaken to develop specific cautions for specific products, we have established dose recommendations and a statement that says the product should not be consumed in excess of that dose. We have not done that universally for all products, but we have initiated some of that work where we believe that it is necessary. MS. DOTZEL: Dr. Friedman recommended a labeling statement that is different from other labeling statements that we talked about today, and I would be interested in hearing others' reactions to that. DR. SOLLER: I would like to offer a reaction. If you had not brought it up, I was going to ask for a moment along those lines. I am recalling that that is on page seven, I think, of the statement, if I have it correctly here. That is Mattison's, I'm sorry. I did write it down, and I want to refer to it. I think safety is unknown. Reference to something like that_- MS. DOTZEL: Dr. Friedman wrote_- what I wrote down was a statement that safety in pregnancy is unknown. DR. SOLLER: Yes, thank you. I think, stand back and look at this from a broader perspective and understand that that could also be said for OTC medicines that have gone through the OTC review and trying to place that up against a standard that would look at the reproductive toxin, the genotox(?) battery that might be done if you were going for an NDA today. I think the way it was effectively handled, and it has been a success story, has been with the kind of label statement that we are suggesting. We would oppose a label statement that would create a higher standard here than for OTC medicines. We think that there is a parity level and a reasonable level to have the kind of statement that we have in our program that would be applied to dietary supplements, similar to what OTCs have. MR. MC GUFFIN: I would also have to ask the question again, do you want to put that on all of the foods. DR. FRIEDMAN: Well, we are not really talking about foods today, we are talking about chemicals or substances that people take for structure/function benefits including possibly benefits related to pregnancy. I think that most people assume that things that are available for them to purchase over the counter or in the health food store are safe. This is simply intended to inform the consumer that that assumption is incorrect. We just do not know. They may be safe; they may not be safe. We just do not know. DR. DICKINSON: I think that would be an excessive statement. For example, nutritional products and even many of the botanical products or other kinds of products that are included in this, but we would certainly be willing to work with various parties to work on some acceptable language. I think that kind of statement across the board would be excessive. MR. LEVITT: A question for Annette Dickinson, and others may want to comment also. I see, and tell me if I see it right. Your proposal, which is more directed to what I will call targeted claims of pregnancy, that there be criteria for substantiation and an enforceability, to be complementary not contradictory to CHPA's kind of general caution across most products. It sounded like he was supporting what you were proposing, and I will let him correct or not from that. My question is, do you also support the CHPA general precaution kind of across the board as part of a total package? DR. DICKINSON: We have mixed views, frankly, among our members on that point. I think that if we can resolve these safety issues that a uniform caution across the board may not, in all cases, be the right answer. We certainly think that it is a productive and excellent thing to have on the table to discuss. I think that perhaps we should also discuss some more targeted indications or contraindications that might actually provide more information to consumers. For example, AHPA's recommendation that certain products specifically not be used during pregnancy. There may also be, as I think Dr._Soller also mentioned in his presentation, a positive list of either supplements that actually could be either labeled for use in pregnancy or that were not required the contraindication. I think that we are all certainly working our way toward the same end point. MR. LEVITT: Did I get you right? DR. SOLLER: Yes, pretty close. You had asked earlier that evidence-based process that precedes claims in pregnancy. That was your summary. CHPA, AHPA and CRN all agreed with that. That is consistent with what Annette has on page four in terms of the guidance document. She mentioned also possibly regulation if that is incorporated into a regulation that adopts not an across the board labeling statement, that is not what we were asking for, but a labeling statement that would be applied with certain exemptions that would be cut out. With that proviso, then for us, it would be a compatible situation. DR. SCHWETZ: One more question before we break for lunch. Dr. Greene. DR. GREENE: I would just like to respond. Suggesting that this regulation would be equally appropriate for foods is really what I would think would be called a reductio absurdum(?). It is not really appropriate for several reasons. First of all, we are not talking about taking a large quantity of broccoli and grinding it up and extracting its active ingredient, first. Second of all, there are situations where foods have been eaten to the point where they do cause toxicity. The most obvious example that comes to mind right away is animal liver which can contain toxic amounts of Vitamin A if eaten in gross excess. I am not sure that those analogies are helpful or appropriate or accurate when we are talking about regulating these biologicals. DR. SCHWETZ: To preserve as much time as we can for the speakers in the afternoon, I recommend that we break for lunch and reconvene at 1:15. Thank you. [Whereupon at 12:15 p.m., a recess was taken until 1:15 that same day.] A F T E R N O O N S E S S I O N (1:15 p.m.) Agenda Item: Introduction of Afternoon Public Panel Members. DR. SCHWETZ: Welcome back, everybody, and a special welcome to the afternoon panel members. We look forward to comments one by one. Let's go ahead and get started. The first speaker this afternoon is Sidney Wolfe, Director of the Public Citizens' Health Research Group. Sidney. Agenda Item: Afternoon Public Panel Presentations. DR. WOLFE: I would like to thank FDA for at least what is the world record fastest response to anything we have ever brought to their attention_- it was a week or a week and a half_- and all of the other people who voiced similar kinds of concerns. The FDA is obviously taking it seriously, and that is what this hearing is about. The FDA regulation issued under the 1994 Dietary Supplement Act, Health and Education Act, and put forth in final form on January 6th categorized ordinary morning sickness and leg edema associated with pregnancy as common conditions that are not diseases. Under the dangerous provisions of DSHEA, that categorization allows dietary supplement manufacturers to promote products as treatments for those conditions without first proving that the products are safe and effective. We strongly disagree with that categorization. Both morning sickness and edema of pregnancy, when uncomfortable enough_- and the word comfort was used a lot this morning. I think it is an important word amongst others to think about. 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, as we did before, to immediately 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 claims for a pregnancy-related condition, be it structure/function or disease masquerading as non-disease such as nausea and vomiting or edema of pregnancy, that none of these 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, as was mentioned before by Dr._Mattison, one that could cause significant or permanent harm, to use legal language. For example, edema of pregnancy could well be an early symptom of preeclampsia or other types of toxicity of pregnancy which has protein in the urine, hypertension, which if undiagnosed and not properly treated can jeopardize the health of both the mother and infant. Again, as Dr. Mattison mentioned, morning sickness can progress to severe vomiting, hyperemesis gravidarum, and severe dehydration and therefore become life threatening to the mother and to the 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, all of them associated with pregnancy, would be diseases under FDA's own reasoning. Even if FDA decides, based on the concerns that we and others have raised about maternal and fetal harm to disallow all pregnancy-related claims, this is not enough. Even if someone is using one of these products who does not have the pregnancy-related claim, be it morning sickness or edema, they are pregnant and are thereby exposing themselves and the fetus to risk. Given that millions of Americans use herbals and dietary supplements, even in the absence of any claims for treating problems of pregnancy, pregnant women may continue to use the supplements they started to use before they became pregnant or start using new ones, as I will mention in a minute. 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. Using the logic that we heard from Louisa Nickerson this morning, I would argue that unless that kind of claim, that kind of statement, "Do not use if you are pregnant," is on the label, we are misleading people into thinking that something that may well not be safe is safe and damage, not for most of the chemicals but for some unknown proportion could occur. Given that three such chemicals, caffeine, ephedra and Vitamin A, used alone or in some of the worst conditions, caffeine plus ephedra, 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 and/or the clinical studies, epidemiologic studies, necessary to determine these risks. Since the generation of women who are now in the childbearing age range are much more likely than their counterparts five or ten years ago, or people such as I, 30 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 and food supplements. On one such website, I checked this originally, and it actually got worse between a couple of months ago and now. On one website, there is a list of herbals recommended for use by pregnant women. It includes such substances as black cohosh, which has estrogenic properties amongst other things, blue cohosh, both to be used only during the third trimester, something called cleavers and horse tail. The company sponsoring this website is Snowbound Herbals, and I have the URL in testimony. One level of confusion is that on another part of the same website, Snowbound Herbals, under a section entitled, Herbs to Avoid In Pregnancy, two of the herbs that are to be avoided, lavender and fennel, are listed on the other part of the same company's website as don't use, whereas the first part of the website listed them as useful for pregnancy. Within one website, the company does not seem to be able to get it together. One is a uterine stimulant, has essential oils, which can be toxic, and the other has essential oils and bitter principles. On another website, information compiled by a registered nurse and an OB/GYN discusses herbs to avoid during pregnancy and breastfeeding. Among the list of herbals which are said to be too dangerous to use by pregnant women are several herbals mentioned on the first website as recommended for use by pregnant women. They are black cohosh, and I will just quote what the second website says. "Black cohosh can cause abortion. Diuretic. Blue cohosh can cause abortion, induce contractions, diuretic. Cleavers, strong diuretic, not good for diabetics either. Horse tail, diuretic, astringent." The cause of most birth defects remains unknown, and although we do not have the evidence to identify which of these dietary supplements have been and continue to cause birth defects, it is reasonable to assume that humans are now consuming some of such agents. A government regulation that facilitates consumption by pregnant women of such agents with or without the claims being made 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 listed in FDA's pregnancy Category X defined as studies in animals or humans demonstrate fetal abnormalities or adverse action reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible benefit. As I mentioned earlier, included on this list are things like ephedra, caffeine and Vitamin A, 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 and 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. In addition to the lack of meticulous evaluation of safety and effectiveness of the ingredients which are supposed to be in these herbals or diet supplements, there is the additional problem with this dangerously underregulated industry of contamination. In a study recently published in the New England Journal of Medicine in 1998, scientists from the California Department of Health picked off the shelves of stores in California some Asian herbal supplements. Thirty-two percent of the 260 products that they picked up were contaminated with lead, arsenic or undeclared pharmaceuticals such as digitalis. Specially for the developing child, these toxic substances can be extremely dangerous. Lead for a developing child can do the IQ problem that was discussed by Dr._Mitchell before. 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. I would argue that this is an excellent example of that. Beyond this current battle concerning pregnancy-related conditions and labeling of all supplements against use in pregnancy is the larger issue of DSHEA itself. How many more people have to be injured or killed by essentially unregulated dietary supplements such as ephedra and many others before DSHEA is significantly amended if not repealed. This law is a dangerous step back into the 19th century just as we are entering the 21st century. Thank you. If I can take eight more seconds, I would just say that the comments that were made earlier by Dr._Soller and others that you should not hold these products, dietary supplements and herbals, to a higher standard than over the counter drugs does not make a lot of sense because unlike over the counter drugs, these do not have any requirement to be shown to be effective. Over the counter drugs have had to go through a series of reviews, particularly after 1972, to show that they actually work. When we know something works, we believe it falls into an entirely different category. Thank you. DR. SCHWETZ: Thank you, Dr. Wolfe. The second speaker in this earlier panel is Dr. Susan Panny for the American Academy of Pediatrics. DR. PANNY: Good afternoon. I would like to thank the FDA for the opportunity to address everyone at this hearing. I represent the American Academy of Pediatrics which is a professional organization of over 54,000 pediatricians. We are all committed to helping all children, adolescents and young adults attain optimal physical, mental and social health and well being. Because of the potential harm for the fetus, infant and child, the academy is deeply concerned about the marketing of dietary supplements during pregnancy for structure/function claims under the Dietary Supplement Health and Education Act. I would like to address specifically the points that were offered for comment by the Center for Drug Evaluation and Research. There are significant risks posed to both the pregnant woman and the fetus by the use of dietary supplements that do not undergo prior FDA review. It should be recognized that the fetus and newborn present a very special population with characteristics that differ from others. First, there are important developmental events occurring prenatally that are not mirrored postnatally. During the first eight weeks after conception, all of the organ systems are forming. Drug or dietary exposures occurring during this time may therefore be responsible for birth defects. This developmental period is during a time when many women experience nausea for which they might seek a dietary supplement for relief. Next, in the time period between eight weeks and the birth, the fetus undergoes maturation of the body including important aspects of brain development and growth as well as physical development. Exposures during this time can produce permanent growth abnormalities or brain dysfunction. This would be a time period in which a pregnant woman might seek dietary supplements or other products for relief of both nausea and leg edema. Nausea and leg edema are two conditions that the FDA has designated as being targeted for structure/function claims. In the absence of good human data to support the safety of these compounds, there exists the potential to place the four million children born in the U.S. annually at serious risk for birth defects, growth abnormalities and developmental disabilities. Most of the products that would be marketed under the DSHEA for structure/function claims have, at best, unknown safety. In some cases, these substances are known to be harmful. For example, some of these supplements contain ephedra or ephedra-like compounds which present a known risk to the fetus. There are other products such as veraxum californicum(?), the use of which has been advocated during pregnancy, and yet animal studies have shown serious birth defects in exposed offspring. For this substance and for many others, there is virtually nothing known about the effects on humans during pregnancy. Even if the supplement has been found to be safe in non-pregnant adults, this does not necessarily mean that it is safe during pregnancy, especially for the fetus. The way that substances are metabolized in the fetus and in the newborn is different in most circumstances. There may be variability in how a substance is handled by the placenta including the possibility that the substance will be concentrated above levels seen in the pregnant woman. This is true for many amino acids. Therefore, a claim or finding of safety in other populations is insufficient to insure safety or efficacy in this particularly vulnerable population. It is understandable that the FDA has chosen to distinguish structure/function claims from claims made in regard to the treatment of disease states. However, there are problems with this distinction in the case of pregnant women. As has been noted, the difference between a normal physiological variance such as leg edema or nausea and vomiting and a disease state for which the leg edema or nausea and vomiting is only one symptom cannot be made reliably by consumers without appropriate monitoring. There will undoubtedly be those women who will treat a serious disease such as toxemia of pregnancy with one of these substances leading to potentially disastrous consequences for both the mother, the fetus and the newborn. The AAP has a general concern about the use of dietary supplements throughout pregnancy and believes that structure/function claims should not be permitted in any circumstances without prior FDA review. We recommend that all supplements that are marketed for structure/function claims in the pregnant woman undergo procedures similar to those for drugs that are marketed to treat disease states in this time. This would mean, in most cases, animal testing and the design of human trials and the collection of data about adverse effects and the monitoring of adverse effects data. At the very least, the supplements marketed for use during pregnancy should bear specific warnings about their use in pregnancy. Labels should state that the supplements have not been tested in humans and that there is a potential to cause birth defects, birth abnormalities or developmental disabilities. The supplements should only be used with the consultation of the woman's physician or health care provider. Furthermore, we believe that this type of warning should be required for all dietary supplements that have not undergone prior FDA review. We certainly recognize that some of these products may have beneficial effects and that consumers should have ready access to those that are safe and efficacious. However, we also recognize the great potential for harm in the use of these supplements in pregnant women unless there are good data to document that they are not causing harm. It has been suggested that this new rule will provide consumers with better information and allow them to select appropriate products. On the contrary, it appears that this rule will allow products to be marketed without any demonstrated record of safety in the pregnant woman, fetus or newborn. It is difficult to see how this will provide better information to the consumer. In closing, the American Academy of Pediatrics urges the FDA to seek and heed the advice of all of the organizations whose focus is on the health and welfare of America's children before making this ruling effective. If dietary supplements are allowed to be marketed to pregnant women under these structure/function claims, the FDA needs to determine the necessary and appropriate safeguards to minimize the risk for future children. Thank you very much. DR. SCHWETZ: Thank you, Dr. Panny. The third speaker in this part of the panel is Dr. Juliette Kendrick, Medical Epidemiologist, Centers for Disease Control and Prevention. DR. KENDRICK: Thank you. I am representing the Pregnancy and Infant Health Branch at the Division of Reproductive Health at the Centers for Disease Control and Prevention in Atlanta. I am a family physician and medical epidemiologist. Since CDC collects statistics, I thought we might start with some background statistics on the topic. First of all, for the most recent data for the United States, in 1996, there were 6.2_million pregnancies, 62 percent of which ended in live births. I put this statistic in to point out to you that any exposure during pregnancy could be expected to affect a large number of women and infants. Medication use in the United States studies, across the board, has found that approximately somewhere between 44 to 92 percent of pregnant women have used at least one drug during pregnancy, somewhat contradicting the myth that pregnant women are excessively careful about their health care or their exposures. Those average around three to five and a half medications per woman among users. As best we have been able to determine, there is no U.S. data on dietary supplement use. I have the token comments on nausea and vomiting and on edema, and I think I am going to go through them rather quickly because you have heard the same story over and over again. However, one thing that I think has not been pointed out is how common these conditions are. Nausea and vomiting affects 60 to 80 percent of pregnant women. It is most severe in the first trimester, the period of maximal fetal exposure that we are concerned about, and goes through a wide range of severity, in some cases culminating in hospitalization of one to two percent of pregnant women, not a trivial number. There are a couple of things about nausea and vomiting that we do not really understand. There are some aspects of the physiology that have not been worked out which point out the fact that exposures that may be directed at preventing nausea and vomiting may have unanticipated effects. First of all, there is increased severity of nausea and vomiting predicts better pregnancy outcome. Also, there is increased severity when the fetus is female. Edema affects around 75 percent of pregnant women at some point during their pregnancy. As has been pointed out, it can progress through a wide range of severity from mild ankle swelling all the way up to eclampsia with seizures, which is a life-threatening condition. In the case of both edema and nausea and vomiting, delay in seeking care intentionally because of self-medication may result in more severe disease and maternal complications including death. I went to look to see what women could find out on their own. Looking through rather quickly a popular on-line bookstore, I found, right off the top of the bat, four books that seemed to have some relevant comments, some of which I am going to summarize for you. What do the books recommend to women. Well, one says, "Treat medicinal herbs as you would any drugs during pregnancy. Do not take them except under the advice of your doctor." Another says, "Herbs can play a part in this vision," the vision is of a healthy mother and a healthy baby, "by helping to ease the minor ills of pregnancy, to sooth the pains of childbirth, and to set baby on the road to a contented and well-balanced life." Another book says, "It is particularly rewarding," this is now in the third edition of this book, "to be able to recommend medical herbalism for treatment of recurrent miscarriages." It goes on in a slightly, about three pages further down, to say, "Taking the whole plant or plant part is a far safer method of using its healing properties than that employed by modern pharmaceuticals." Some might find that comment disturbing. Here is a list of some conditions chosen from these various books for which treatment during pregnancy is recommended by the authors. They range from abdominal pain to edema to backache to insomnia, quite a wide range. How are these dietary supplements or herbal medications to be used. Well, it is a bit confusing because as others have pointed out, the lists of contraindicated supplements vary according to which source you are looking at. Recipes are provided for making teas, infusions, decoctions and syrups to be used during pregnancy. Often the comment is made that these are things that you can make using herbs that you grow yourself, but do be very careful that you identify the correct substance. I feel obliged to point out that I made this slide with peppermint on it on Monday. Since peppermint became the subject of the morning, I thought that was kind of interesting. In one source, peppermint is recommended for problems with conception, headache during pregnancy, heartburn, nausea and vomiting. Another source says that it is a uterine stimulant, avoid the oil entirely, although low doses of the dried herb can be used. In another part of the same book, it says peppermint is an effective remedy for nausea and vomiting but is best avoided in regular doses during pregnancy. I personally find that information a little hard to interpret. The second author is a respected medical herbalist trained in Britain, and I think she would beg to differ with the comment that peppermint tea is perfectly safe or should be used as one of our categories. What is available in the medical literature. We did the Medline and various other searches and did not find very much that was terribly helpful. There was an excellent review, I felt, of alternative therapies for nausea and vomiting of pregnancy done at Columbia University. I wanted to read a couple of key quotes from this article. The first, "Herbal remedies are recommended commonly for nausea and vomiting in pregnancy, and the more common ones are available readily over the counter in health food stores and pharmacies. Many have pharmacologic effects in the body and a number are contraindicated in pregnancy. Of the many suggested herbal remedies encountered in various lay publications, only ginger has been studied, and only in one trial. In summary, women seeking alternative, non-pharmacologic therapies for nausea and vomiting of early pregnancy have few evidence-based guidelines to assist them." I think I might amend that to say women and their health care providers. So what do women assume. We have some data from a work in progress from a study that CDC has been working with an outside organization on which conducted focus groups on the use of feminine hygiene products. It was among non-pregnant women. Of the women who were users of these products, many appeared during the sessions to be reading the labels for the first time and were somewhat surprised by some of the things that they found on the labels of products that they were using regularly. They also expressed what our focus group facilitator commented on as a tacit seal of approval from the marketplace. Women believe that the government has approved these products as safe and effective because they are readily available. A common quote, "I feel like if it were really harmful, they would take it off the market." What are our conclusions. First, the lack of consistent, scientifically-documented information available to both women and their health care providers. Second, women might be misled if there were pregnancy claims on dietary supplements. They might assume safety based on the mere fact of marketing. Recommendations. First, with regard to safety, we believe that there should be safety testing before any supplements are marketed for use during pregnancy. We would like to see ongoing surveillance for adverse effects of any supplements used during pregnancy whether marketed directly or not. We would like to point out that in the absence of accurate safety information, the health care professional who we are all relying on to provide advice will not be able to give accurate advice. Second, with regard to warning labels. We recommend warning labels on dietary supplements for which safety has not been satisfactorily demonstrated. The warning label could focus on safety with a statement somewhere along the lines of, "Use during pregnancy and nursing: the safety and effectiveness of this drug have not been proven," or they could be similar to the traditional warning on over-the-counter drugs. In any case, we would urge that we need studies of the impact of labeling on the actual habits of pregnant women. Thank you. DR. SCHWETZ: Thank you, Dr. Kendrick. Dr._Erickson, I have a question for you even before you give your talk. We are running ahead about the amount of time that it would be for your talk. If it makes sense to have your talk after this one, we could do it and then open it up for all discussion, or you could be the first one in the next part of the panel. DR. ERICKSON: I would be happy to go now. DR. SCHWETZ: If yours is tied to this one, why don't we do yours, and then we can discuss all of these together and then do the last two after the break, after the next panel. If you are ready, David, go ahead. DR. ERICKSON: Thank you very much. I am Dave Erickson. I am Chief of the Birth Defects and Genetic Diseases Branch at CDC, and I am happy to have the opportunity to be here to talk with you about our concern that there may be harm which could result from the promotion of certain types of dietary supplements for use during pregnancy. Our group at CDC uses epidemiologic research to increase our knowledge of why birth defects occur. When modifiable factors are found, we promote prevention. Thus, we are keen promoters right now of increased consumption of folic acid before conception and during early pregnancy for the prevention of neural tube defects. It is not surprising that we promote the increased use of dietary supplements containing folic acid for preventing neural tube defects by women during early pregnancy. You heard many stories today_- you have heard over and over again today that substances that are innocuous in adults have the potential to cause substantial embryonic and fetal damage. I will not repeat those stories; you have all heard them this morning and this afternoon and long before you came into this room. I think they give us substantial concern that unexpected fetal damage may be done by promoting the use of seemingly innocuous dietary supplements among women who are pregnant. I want to say that I do not see any contradiction in our advocacy for increased folic acid intake through the consumption of supplements and our generic concern that unregulated promotion of dietary supplements for use by pregnant women might be dangerous. To me, the crucial difference is that folic acid use during pregnancy has been studied extensively in high-quality studies even including well done randomized, controlled trials. It has been found to be efficacious in preventing a large fraction of some types of very serious defects, and in the same studies, it has been found to be safe for fetuses, safe in the sense that babies whose mothers have used folic acid-containing supplements have a better chance of being born healthy than babies whose mothers do not use supplements. The first question that FDA asks participants in this hearing is related to the potential hazards of supplements by pregnant women and thus by their fetuses and whether the hazards should be considered different than potential hazards to other classes of users. To me, it is undeniable that pregnancy is a natural, essential, normal part of the human life cycle, and perhaps this was the rationale for FDA specifically mentioning two common complications of pregnancy, morning sickness and mild edema as potential candidates for supplement labeling under the so-called structure/function rule. However, to me, it is just as undeniable that pregnancy is a very special and potentially vulnerable stage of life. A pregnant woman is vulnerable, potentially of course, but there is an additional and unique concern for the developing child. This concern is most acute during early pregnancy when the critical processes of organogenesis are taking place and when women have to deal with problems like morning sickness. Because of this concern of potential special vulnerability, I believe that the standards that govern the labeling of supplements relative to use by pregnant women should be more stringent than the standards that govern the use of supplement labeling by non-pregnant adults. I think that permission for labeling a supplement as being helpful during pregnancy should be held to not less than the standard that is set for allowing health claims to be made for folic acid supplements for neural tube defect risk reduction. Even better in my opinion would be to hold supplement labeling for pregnancy use to the same standard as are drugs. Anyway, I feel not less than the standard that was set for the health claim on folic acid. I get the idea that FDA is asking how under the Dietary Health and Education Act it can acknowledge the special situation that is pregnancy, the special time of life and the special vulnerabilities. I am not a lawyer or a regulator, and I do not have any personal expertise that would allow me to give you legal or regulatory advice. I feel that all I can offer is common sense. To me, allowing labeling of a supplement as being good for alleviating common and unpleasant complications of pregnancy carries to the potential consumer an implicit message of safety for the fetus. My idea of common sense in this matter is that if a woman is pregnant and if she desires to continue her pregnancy, she wants a healthy baby. If she thinks that a supplement is presented as being helpful to her as a pregnant woman that it is also being presented as being okay for her baby. What I have heard is that the Dietary Supplement Health and Education Act requires truthfulness and requires some sort of substantiation of the message being conveyed by the label. If a recommendation for use of something during pregnancy carries with it an implicit message of safety for the fetus, which I believe that the proposal would do, and if there is no substantiation of that safety, then, in my non-lawyer mind, that label would be untruthful, the product might be mislabeled. From my point of view, a case ought to be able to make a case, that a label that conveys an implicit message of safety for the fetus should be backed up by an explicit substantiation of safety for the fetus. In my way of thinking, there is no condition connected with pregnancy for which a structure/function label claim should be allowed unless there is a substantiation of safety for the fetus. As I have said before, if a supplement is to be labeled for use by pregnant women, it should at a minimum meet the standard for a supplement health claim, or better yet a standard for a drug. By saying this, I do not feel I am necessarily advocating that pregnancy be labeled as a disease; it is a natural part of life. I am just merely saying that the standard of evidence for substantiation ought to be high. I think that in what I have already said, I have already answered the questions that FDA posed except for the one about whether supplement labels should contain a caution against supplement use by pregnant women. Like my colleague, Dr._Kendrick, before me, I think this might be judicious, might be a good idea, except in the case where the supplement in question has already met the standard for a health claim for a drug, as is the case with folic acid. That is all that I have to say. I thank you for your attention and the opportunity to be here to talk with you today. DR. SCHWETZ: Thank you, Dr. Erickson, for your comments. I apologize for not introducing you properly after changing the schedule. Fortunately, you did it yourself, so thank you. Let's open this up for questions of these four panel speakers. Agenda item: Questions from FDA Panel. MR. LEVITT: I would like to start with just comments, and we can go right down the row, of some of the proposals that were made this morning. Maybe we could just do_- I guess there were three specific ones, so in fairness, we ought to do all three. I do not necessarily think of them as mutually exclusive of each other necessarily. The first one made was from CHPA which involved the_- it was on one of the previous slides up here, similar to OTC drugs, if you are pregnant, see a health professional before using. There were some exemptions from that, but that was the general suggestion. You all heard this, so I will not try to repeat it more precisely. Reactions to that as useful? DR. WOLFE: I do not think that it is useful. I think that I would reiterate what I had said, which is that unless it has met clear, high standards of evidence for safety in pregnant women, it should say, "Do not use during pregnancy." Given that this category of products are ones which people not only are not likely to go to their physician for but are often too embarrassed to talk to their physicians about_- in fact, that scenario about talking to your physician for some things is obviously important and very useful and likely. Here, there is not a substitute for what I think is the message, which is, do not use this during pregnancy because we do not have enough reason to assure you that it is safe during pregnancy. DR. PANNY: I think the academy would say very much the same thing, but we would not feel that dietary supplements should be marketed for structure/function claims without prior FDA review. As Dr._Erickson says, we think that these supplements should indeed meet the same standards that folic acid did. However, we do believe that the labels should contain, if it is decided that these things will be marketed, the kind of warning that we were talking about, similar to the OTC drugs. We certainly think that we have been trying to teach expectant mothers for years that you really do not take anything without checking with your health care provider. I think that is still a very valid thing. If they see it on enough jars, maybe some of them will do it. MR. LEVITT: Thank you. DR. KENDRICK: I think substantially I agree except that the real issue is what does the health professional know. Given that the range of information that is available is conflicting and hard to interpret, I think we are putting a bit of an excess burden on the healthcare provider and that what is most likely to happen is that the healthcare provider will simply say, "These things are unsafe and you should not take them." DR. ERICKSON: I guess my point of view is in many ways similar to that expressed by Susan Panny. I think there has been a movement in this country to encourage women who are pregnant not to use any drugs or other substances that they do not need to use, and if they do feel the need to use them that the ought to consult with their healthcare provider before that use. That would seem to me to be a reasonable approach. Try to continue to build upon an attitude which has been generated over the past few decades which I think is a good one. MR. LEVITT: Thank you. Now, a second suggestion made by Council for Responsible Nutrition spoke to the suggestion, if there are going to be claims that FDA ought to set clear, high standards for evidence and take action against any company that makes a claim that does not meet that standard of evidence. DR. WOLFE: Well, just as is the case with drugs, prescription and over-the-counter drugs, the evidence of effectiveness has to be taken in the context of safety. In terms of the question, which is an efficacy-based question, there is no reason why the standard for evidence should be any different than for a prescription drug, but that would not be enough because unless there were also safety studies showing that it clearly met the hurdles for safe use during pregnancy, the efficacy alone would not do it. DR. PANNY: Exactly. I think the first thing that a physician does is do no harm. I think safety here is a much more important consideration than efficacy. DR. GREENE: Just to clarify, I think their proposal did include both safety and efficacy, is that right? PARTICIPANT: Yes. DR. PANNY: Yes, I think high standards should be set. They certainly were set to those of us who were trying to encourage women to use folic acid to prevent neural tube defects. We met those standards, and I think that many other supplements should meet the same standards. I think that folic acid is beneficial, and I think there may be other things that we do not know about that are beneficial, but we need to show that they are both beneficial and safe. DR. KENDRICK: I agree with Dr. Panny. DR. ERICKSON: Me, too. DR. PANNY: I would like to make one more plea for some research in this area because as my colleague, Dr._Kendrick, says, the issue is when they come back to you as a health care provider, what do you tell them. It is very hard. I am also board certified in medical genetics, and we get a lot of calls about the possibility of teratogenic effects of all sorts of substances. Even when you know the literature very well and have a good teratogen information system at your fingertips, it is often very difficult to give good advice. I think this is an area where if there is potential for good in these supplements, which I think there is, we really need to study them, and we need to be able to demonstrate that. MR. LEVITT: Thank you. If I am not overusing my time, a speaker has suggested the use of a compendium such as the one they put together. They both had a list of_- kind of a negative list and a positive list and probably some in the middle that were neither in the positive or the negative list. Do you see that as a useful model? DR. WOLFE: Well, I would just repeat that I said in the question to the gentleman whose organization helped put the book together. There are extraordinarily varying standards of evidence for safety in pregnant women or safety generally amongst these products. He agreed that the overwhelming majority of them for which they are saying that it is okay to use in pregnancy have not been put through either animal or human tests that are adequate to really establish that. So, to use something like that, I think, would be to mislead people about a huge proportion of the chemicals in the book. DR. PANNY: Given that we have the solid scientific evidence to make those distinctions, I think it would be extraordinarily helpful. However, if we do not have the scientific evidence to classify those drugs, then I do not see really what help the compendium is. DR. KENDRICK: I would just like to chime in on the solid scientific evidence part. DR. ERICKSON: I am not familiar with the compendium, so I do not know to what standard the evidence that is presented in there has been reviewed and vetted. I would repeat my position that a reasonable standard, at least for a start in all of this, would be the standard which was set when the FDA approved health claims and a fortification rule for folic acid. MR. LEVITT: Thank you all. DR. SCHWETZ: Other questions from the panel members? DR. GREENE: I was interested, Dr. Kendrick, in your finding in your focus groups in something that I think most people assume is that if it were dangerous, the "government" would not allow it to be sold. Would it be sufficient to require labeling stating that the government is not allowed to regulate the sale of these compounds? DR. KENDRICK: Well, first of all, you know we are concerned about whether women read the labels at all. I do think that a statement that were as direct as that would be helpful, but I think it was quite clear from listening to folks that the mere fact that these products are there on the shelves implies to them that there is no significant harm that can come to them and that someone is watching out for them. Their belief is that it is the government that is looking out for them. DR. SCHWETZ: Other questions from the panel members? Are there any questions from the panel members of this morning for the panels of this afternoon? Dr._Friedman. DR. FRIEDMAN: The point has been mentioned by some of the panel members this afternoon that encouraging women to consult their healthcare providers might result in the healthcare provider saying, "I don't know; therefore, do not use it." I wonder if you would care to comment on the possibility that the healthcare provider of the woman is likely to identify if she is taking an herbal product will not be a physician but an herbalist or a health store clerk or a naturopath or an acupuncturist or someone else who may have a different view of the world than that very cautious "First, do no harm," that every physician is taught on the first day of medical school, I think. DR. WOLFE: About two years ago, when our office was on P Street near Dupont Circle, I walked into the local health food store which made good sandwiches if not other products, and I overheard a conversation between a pregnant woman and the expert in that store, which you are talking about. She said, "I am pregnant in my first trimester, and I hear that Vitamin A is really good for pregnancy. How much would you recommend?" This man with expertise said, "Well, there is a doctor in Northern Virginia who recommendations 150,000 units a day." I interrupted the conversation at that point, but I think that your point is well taken. I think that is why I had suggested just saying clearly, "Do not use for pregnancy," because I think the variety of people to whom they can go and the largely absent amount of information in the form of even if they wind up going to a physician is such that we need something stronger. Otherwise, you have to worry about offsetting the implicit, "It is safe because it is allowed to be marketed." The only what that you are going to offset that is to say, "Do not use it if you are pregnant." DR. MATTISON: Don Mattison from the March of Dimes. I wonder if I could ask the panelists to comment on the recommendation beginning with the knowledge of the couple that pregnancy has occurred. Does it bother you to wait that long for that kind of a recommendation? In that context, the recommendation for folic acid focuses on its use prior to conception because many of us know that many pregnancies are unanticipated or unintended. As a result, use prior to conception is beneficial. What about the reverse, that is the potential for harm prior to the recognition of pregnancy? DR. PANNY: I think that is a very significant issue. As you say, about 50 percent of pregnancies are unintended. Certainly the first couple of weeks are really a crucial time. We certainly have advocated for a pre-conception health visit, but many people do not get that kind of a visit. That is a very ideal time for this kind of information to be reinforced. Yes, I am very concerned about somebody taking a supplement which is potentially toxic to the fetus without knowing they are pregnant and then finding, oh, yes, I am actually really quite far along, and I didn't really quite expect this. That is a very, very significant issue. I think that when women are planning, many of them try to get in the absolutely best possible health before conception, before even trying, and that includes making sure that you are not taking any toxic substances and making sure that you are taking those things that you need to do like folic acid. DR. WOLFE: So maybe it can be modified to say, "Do not use if you are pregnant or considering getting pregnant," or the farther extreme would be, "Do not use if you are of childbearing age." I think that the intermediate position which would be, "If you are pregnant or if you are considering being pregnant, do not use this product." DR. ERICKSON: I think the spirit of Don's question was promoted or the substance of it anyway was prompted by the fact that such a large fraction of pregnancies in this country are not planned. If half of pregnancies occur without planning, then the notion that you might take care of this by suggesting, "Do not use if you are pregnant or thinking about being pregnant," I do not think that is going to take care of the concern. I feel that it is a real concern, but in my thinking about coming to this panel, I have been focused on the promotion of substances for women who are already pregnant. I had not thought much about the issue of inadvertent exposures to women who were not already pregnant. I think it is an issue, and it ought to be discussed, but my major concern here today is relative to the promotion of substances for women who are already pregnant or perhaps the marketing would not do much good. DR. PANNY: We did in fact see problems like this with retinoic(?) acid exposure. There were people who were using retinoic acid preparations and became pregnant without knowing that. Some of them had even stopped the retinoic acid preparations, but there were some cases in which, when they got pregnant very rapidly, there were still some problems for the fetus. Consistent certainly with retinoic embryopathy. It is a concern. I guess the feminist in me would like to say women are smart and they know what they are doing, and I would go with the middle ground which is to say, "Please do not take this if you are pregnant or if you are considering pregnancy." I would also like to see something saying that we do not know that it is safe in pregnancy. I would like to see that in big print. DR. KENDRICK: I would like to suggest just maybe the wording, "Do not use if you are pregnant or if you might become pregnant," which takes a little bit of the intentionality out of it. One of the studies that we have been involved in has shown basically that the women who can benefit most by preconception changes in behaviors are the ones who are least likely to seek any sort of preconception counseling. I think it we make it a little more open, that might be a possibility. DR. SCHWETZ: Other questions among the panel members? Otherwise, I would open it up for a few minutes if there are questions from the audience beyond the panel members. Bob. Agenda Item: Discussion from Floor. MR. TEMPLE: Bob Temple, FDA. I think the last discussion has clarified this, but when Joe first asked which of the various warning statements people liked, it was not clear whether they liked his proposal which is basically, "Do not use," or Bill Soller's which is, "See your healthcare professional." I conclude from the last that most of you think something more than Bill's suggestion is needed, something more directive. I had another question about the evidence. That question relates to products that are not specifically directed at pregnancy but that might be used by somebody who is or could become pregnant. I want to ask a question now about the specific situation where someone is going to propose use in pregnancy. There seems to be a general view that there should be evidence of effectiveness for the use and some kind of reproductive testing and so on. It is not clear from the discussion whether people think that kind of information ought to be reviewed by somebody like FDA or some other body. Dr._Erickson's suggestion was cold mall(?) drugs which would mean they would be reviewed. I wonder if other people have views on where the review should be or if this is something that people should evaluate on their own. DR. WOLFE: I think the reviews have to be_- just as the standards have to be set external to the industry, the reviews have to be external of the industry. Despite attempts to privatize the review of medical devices, I think that this should not be privatized. I think the FDA should be reviewing. I think in essence we should stop pretending that anything recommended for use in anyone who is pregnant should be any different than a drug just because it happens to be called a dietary supplement. I think that is the drift of the conversation, at least that I have heard. For this group of substances, this group of chemicals, just treat them as though they were drugs with the same standards of evidence for safety and effectiveness and the same source of the review. That is, at least, my view. DR. ERICKSON: I would agree. I think that they are in as great a need for review. I sort of had two levels of my recommendation. The first one was not less than a standard that at least I think was set when health claims for folic acid were approved. In my understanding, they were not much different than for drugs, but it was for a food. It was for a supplement and treated like a food. The standard was very high, in my opinion. Good. Good that it was high. DR. KENDRICK: I think that yes, there should be FDA review, and I think that that is implicit in what women think is happening. DR. PANNY: The academy would vote for FDA review. DR. OAKLEY: I would ask the FDA lawyers, can the FDA do that under DSHEA? MS. NICKERSON: Let us get back to you on that. [Laughter.] DR. OAKLEY: You can take an aspirin and call me in the morning, okay? DR. OAKLEY: Just to maybe go further with the question, and again, I am not a lawyer. Although I am married to one, she has not given me any advice on this, so I am on my own. The stuff about substantiation. Is it possible that the FDA could sort of publish some regs that said, This is what we expect the substantiation to be, what the quality of that evidence would be, and set the bar very high, and then leave it up to industry to make sure that they have done it. If they did not do it, then people get fried. I think that is a question that is_- I mean, that is what would happen. The courts would fry them and so on. MS. NICKERSON: I do not think that we are here to give answers today about what the agency is going to do. DR. ERICKSON: May I make one comment, please, just to be explicit about my ideas of the level of the bar. My recollection is that FDA declined to issue permission for health claims on folic acid until there appeared on the scene high quality, randomized control trials in humans. DR. OAKLEY: I guess you and I were together at the same time. I have a bit of a different recollection of that. In June of 1992, after there were two randomized control trials, the FDA wrote a reg that said folic acid does not prevent spina bifida. When the CDC reg and the FDA reg got to HHS's desk, somebody said, "You guys need to talk to each other." Between June, at the end of June when these two pieces of_- drafts were on the table, in September, yes, we got a public health recommendation out of that. I think that part of my presentation is that I think part of the reason that happened is we did not have a process for standardized information about what evidence is. Often in this world, people say there is no evidence unless there are randomized, controlled trial proof. There clearly are other levels of good evidence that we make public policy on all of the time, and I think a discussion about what is the quality of the evidence and how do we measure it is a really key part of the discussion that goes on after this meeting. DR. SCHWETZ: [Initially commenting off microphone.] I am sorry. Dr._Marietta Anthony, Director of Women's Health, Department of Pharmacology, Georgetown University. Marietta. Agenda Item: Afternoon Public Panel Presentations (Continued). DR. ANTHONY: Good afternoon. I appreciate having the opportunity to comment on this very important health issue and that is the use of dietary supplements in pregnant women. The Dietary Supplements Health and Education Act or DSHEA allows manufacturers to make claims related to the effect of their products and structure and function of the body but no claims about diseased states. Interestingly, since pregnancy and menopause are considered normal conditions, claims for dietary supplements are allowed. Today, I am going to direct my remarks to pregnant and nursing women. There are many difficult questions on this issue. One is, why are drugs for treating disease held to a more stringent standard than botanicals or dietary supplements used by healthy people? I am not advocating that we should have lower standards for drugs but that products used by healthy people, particularly pregnant and nursing women, need to have standards which are based on sound, scientific research and FDA review. DSHEA was crafted to allow truths and non-misleading claims. However, how can claims be truthful and non-misleading without a solid basis of information derived from well-designed scientific research. If dietary supplements can have claims to improve health or, in the case of pregnant women, to alleviate nausea, certainly the public needs to know the basis for those claims. Accurate information and labeling about the basis of a product's claim is needed both for what the claim is based on but also what the claim is not based on. Consumers need to know if there have or have not been well-designed animal studies or randomized clinical trials in human subjects. Consumer education is important particularly on this issue. My remarks will try to address a few of the questions, and I have abbreviated my remarks because several of the points have already been made today. A few words about dietary supplements. We know that these are not compounds consisting of one ingredient that has been tested in animals and humans to demonstrate safety and effectiveness. In dietary supplements, there may be potential hazards since the active ingredient may not be known. The other ingredients may not be known. The products may be contaminated with heavy metals or arsenic as Dr._Wolfe has pointed out, with microbes, with pesticides, with radioactive compounds. We know that calcium tablets were contaminated with high lead concentrations for a while. The concentrations and doses in dietary supplements may not be known. Additionally, the concentration and even the ingredients can vary from batch to batch. Good manufacturing practices are strictly optional. Shifting to pregnancy, there are several concerns. One, as Dr._Mattison clearly articulated, the changes that occur in pregnancy. When a product is used by pregnant women, two individuals are affected, the mother and the unborn fetus. One person willingly is taking the compound, and the fetus is unwillingly exposed. Pregnant women may discontinue prescription medications for which scientific information exists and go onto a dietary supplement for which no scientific information exists. There is false sense of security that because dietary supplements may be natural, they are safe. However, we know that there are poisonous plants. There has been experience with dietary supplements in serious medical problems. I am sure several of you remember e-a-sin-e-a-filia(?) myalgia syndrome with tryptophan. There could be a possibility of interactions between dietary supplements and drugs. For example, both could be metabolized by the same enzymes, and one or both of the drug or dietary supplement could build up to toxic concentrations and affect the mother, the fetus or both the mother and the fetus. We do not know how dietary supplements interact with foods. Lastly but certainly not least, there is always concern about exposing the fetus to an unknown, untested and potentially dangerous compound. There are many possibilities for harm to the fetus beyond major structural abnormalities and carcinogenic potential such as affects on the nervous system, the immune system, and many other organ systems. In thinking about what may affect the developing fetus, timing of exposure is critical. For example, dietary supplements for nausea of pregnancy are used in the first trimester of pregnancy which coincides with a critical period of organ development for many systems in the fetus. I am going to end with two suggestions. First, labeling. Dietary supplements should not be recommended or marketed to pregnant or nursing women until safety and efficacy for both the mother and the fetus have been demonstrated by standard, rigorous, scientific methods. I spoke to Norman Farnsworth, who is head of the Botanical Centers at the University of Illinois. He told me that WHO has issued a series of monographs on dietary supplements. There is one statement that follows each of these dietary supplements, and that statement is, "It should not be used in pregnant and nursing women and in children under 15." This is because there is so much that is unknown about these products. There is a need for labeling to warn pregnant and nursing women against taking dietary supplements." I feel that the warning is necessary because women will not discuss taking dietary supplements even with their healthcare provider. We had a meeting with the head of the Center for Complementary and Alternative Medicine at Columbia a few weeks ago. They conducted a survey in their patients who came to the emergency room and found out that patients routinely did not check off if they were taking any dietary supplements. When sitting down with an interviewer, an interviewer who was skilled in probing and asking specific questions about whether they might be taking certain dietary supplements, it came out that most of these women or people were taking them. Just asked routinely, they would not disclose it. My second suggestion is that there needs to be much, much more scientific research to answer the questions on effectiveness but particularly for questions on safety. NIH can play a role in promoting research in this area and has already established the Office of Dietary Supplements. The NIH Office of Research on Women's Health has, as one of its priorities, building an evidence base for dietary supplements. Both of these offices have very limited resources. Government and the taxpayer cannot do it alone, and I think industry would not be happy with the results. One of the problems is, for example, what products would be tested. What manufacturer would be chosen. If only one manufactured product were chosen for study, what are the implications this has for all of the other products on the market? That means that only that one manufactured product could have claims in its label, and therefore, that has tremendous implications for the rest of the marketplace and for the consumer. So, I think industry needs to join with the government in supporting research on dietary supplements. Yes, I think there should be requirements for animal studies and human safety information. This data or the lack of it should be in the labels. A lack of evidence does not mean that these products are safe and effective. Anecdotal evidence, even accumulated over years of use, is not the same as solid, scientific data. We know that FDA's history has been shaped by public health crises and human tragedies that occurred in vulnerable populations, mainly women and children. The Congressional response to these events has given stronger regulatory laws to the FDA to protect the public health. However, we are all here today to try to avoid this from happening again. Thank you. DR. SCHWETZ: Thank you, Dr. Anthony. The last speaker this afternoon is Dr._Godfrey_Oakley, Visiting Professor of Epidemiology. Rollins School of Public Health of Emory University. Godfrey. DR. OAKLEY: Thank you. I am a pediatrician, epidemiologist and geneticist who has worked in birth defects prevention, research and policy for most of my professional career. Thank you very much for the opportunity to present to you. I am going to make my main points, and they are on this slide for people to look at the whole time that I am talking. The United States Prevention Services Task Force has produced two clinical guides to preventive services and scored each possible preventive service based on the quality of the evidence for that service. I have placed this scoring system on the overhead, and it is on page six of my written comments. I believe the evaluation of herbs and supplements would be vastly improved were this quality of evidence approach taken. I suggest that FDA and the industry make this quality of evidence approach the basis for substantiating health and structure/function claims under DSHEA. We are here today to address safety issues associated with dietary supplement use during pregnancy. In my opinion, the current regulatory policies and practices regarding dietary supplements are not in the best interest of the public health. There is great distrust among the academic, medical and nutrition communities, the regulatory agencies and industry. This distrust goes beyond safety of dietary supplement use during pregnancy and has undermined the public health. This distrust is in contrast to the trust among those in the same communities in the vaccine industrial complex. There is a public health need for a better way to manage herbs and dietary supplements. I call to your attention two recent rulings that suggest to me that the current system is broken and needs fixing. In one instance, the FDA's position harms the public health by denying a health claim and in the other by permitting if not encouraging the unnecessary use of supplements in pregnancy actually potentially hurting fetuses. There are near hundreds of controlled studies performed at the leading universities in the world showing that homocystine is a powerful risk factors for heart attacks and strokes. The most recent NHANES study showed that essentially all Americans who do not consume a multivitamin have blood folate concentrations associated with an elevated homocystine. Randomized control trials have shown that among those not taking folic acid supplements, those consuming the amount of folic acid in a multivitamin will substantially reduce homocystine concentrations. The evidence that the homocystine cardiovascular risk is causal is very strong. The evidence that increased consumption could prevent an estimated 50,000 deaths from heart attacks in this country alone is strong. In spite of these data, the FDA recently turned down the following proposed health claim for a product with 400 micrograms of folic acid, and I quote, "As part of a well-balanced diet rich in fresh fruits and vegetables, daily intake of at least 400 micrograms of folic acid, 3 milligrams of Vitamin B-6 and 5 micrograms of Vitamin B-12 may reduce the risk of vascular disease." The rationale for denial was that there was "not significant scientific agreement." After reading the long document, I inferred that the FDA denied the claim simply because it had not met the drug standard for multiple randomized control trials showing efficacy. The second example of how the process is broken is why we are here today. The FDA issued a regulation on January 6 that opened the door for pregnant women to be exposed to increased consumption of herbs and supplements for which there are few, if any data about safety for the embryo or efficacy for the pregnant woman. We know from tragic experience of rubella, thalidomide and alcohol during pregnancy can cause permanent disability to infants exposed in utero. Plus, any regulation that promotes the use of untested substances in pregnancy sets the stage for the tragic induction of birth defects. I believe that the chance for the two types of errors that I have been discussing could have been substantially reduced if we had had a grading protocol based on the quality of the data had been used. A useful prototype is available from the United States Preventive Services Task Force. This department of HHS task force has now published two editions of the guide for clinical preventive services. The recommendations in each chapter reflect a standardized review of current scientific evidence and include a survey of published clinical data research regarding the clinical effectiveness of each prevention service. They had to deal with hundreds of potential tests and with varying amounts of data and quality of the data. In the end, they decided to rate each test on the quality of the evidence supporting its use in clinical medicine. They created a scale of the quality of the evidence that decreased from randomized control trials to anecdotal evidence. As you can see on the overhead, the best evidence is from at least one properly-controlled, randomized control trials, for two evidenced from well-designed control trials without randomization, to two evidenced from well-designed cohorted case control studies, evidenced three from time series. Then the least powerful and some might even argue not data is the opinions of respected authorities based on clinical experience, descriptive studies and case reports or reports of expert committees. I believe this system that has been used by DHHS for many years could be very helpful in improving the way that we deal with supplements and herbs. If there is proof of effectiveness from randomized controlled trials, a standard high enough for drug approval, it should be reported in the way that the consumers can understand. An herb in a consistently-formulated form, or a supplement with such high quality data should receive the highest grade, Grade_A, for example. Placing the grade on the package would be a quick way to inform consumers about the strength of the evidence for this product. Folic acid-containing multivitamins for the prevention of spina bifida would receive a Grade_A. Multivitamins containing folic acid or folic acid, B-12 and B-6 for the prevention of cardiovascular disease would receive at least a B. There is actually one randomized control trial that everybody forgets about, and it probably should be an A, but just to make it conservative, it should be a B. It certainly would become A if additional randomized control trials demonstrated benefits. Herbs and supplements for which there were no control data on efficacy or safety would receive a Grade_F. Considerable judgment, obviously, would be required the intermediate grades and intermediate qualities of data. A scoring system such as I suggest here, I think, could go a long way to reduce the risk to the public health that the current situation brings. DSHEA requires substantiation, and evidence-based scoring systems such as I have mentioned could be the foundation for policy and practices for substantiation. Such a system could provide industry, the FDA and consumers the best interpretation of the existing data. Assuming that Grade_A products sold better than Grade_F products, there would be market-driven reason for industry to support studies that would improve the quality of the data available for setting the grading. Who should conduct such a scoring system I think is open to question. The key is that the body should be independent, and it should provide an objective, science-based review of the effectiveness and safety or herbs and supplements. It could be entirely supported by industry, jointly supported by industry and government or supported by government alone. There may be many other possibilities. Again, wherever and however it is supported, it must be independent and perceived as independent as a source for independent, reliable, trustworthy interpretations of the existing data. I hope these comments are of help to the FDA, industry, the academic community and the new Commission on Alternative and Complementary Medicine recently announced by President Clinton. Thank you. DR. SCHWETZ: Thank you, Dr. Oakley. Panel members, are there any questions either for Dr._Anthony or Dr._Oakley? Agenda Item: Questions from FDA Panel. MS. LEE: Marietta, I wanted to ask one question of you. You were describing women_- I am assuming it was women who you indicated that they did not disclose their dietary supplement use unless the interviewer was very well-trained in eliciting that type of information. I am wondering whether that lack of disclosure was because the question asked of them what was, "Are you using drugs?" and they did not associate dietary supplement use with the drug question, or was it truly a dietary supplement_- how the questions were worded? DR. ANTHONY: The question was, "Are you using any dietary supplements?" MS. LEE: So it was very explicit that way? DR. ANTHONY: [No audible response.] MS. LEE: Did they make any evaluation as to why people were so unwilling to disclose it? DR. ANTHONY: No, they did not go into that. They just were trying to find out what people were taking. MS. LEE: Thank you. DR. SCHWETZ: David. DR. ERICKSON: I have a question for Dr._Oakley. Godfrey, let's suppose that this system were put into place. I think it is a very interesting idea. Where would you see on that scale the bar should be set to permit labeling for the use of a supplement in pregnancy? DR. OAKLEY: Can I call you in the morning? [Laughter.] A stone wall like the FDA lawyer. To me, I think the first point is to use this process to have a description of the quality of the data that exists and have people understand that and to know what it means. That would be a step forward that does not exist. For women and pregnancy, clearly I am someplace between 1 and 2-1. I think the bar needs to be very high. I guess I would like to think a little bit more about exactly how high it should be, but I think one might discover in reviewing the literature, which I have not done, that there might be something there that deserves a slightly less stringent standard, but I think it is unlikely. DR. GREENE: Just a comment. DR. SCHWETZ: Go ahead, Dr. Greene. DR. GREENE: I am sorry that Allan Mitchell who was here earlier has left because he did a study very similar to the one that you described for standard drugs. He found when he did this epidemiological study that he got very different responses depending on how he asked the questions. If he asked, "Are you taking any drugs?" a certain percentage of people responded that they were taking a drug. Then he asked, "Are you taking a drug for headache, nausea or such," and then he got a few more people who responded positively. Finally, he asked the very specific question, "Are you taking aspirin?" or are you taking X-Y-Z drug, and finally, he got even more responses. It is hardly a surprise that many people do not respond to sort of a general question of, "Are you taking...?" whatever. DR. SCHWEIZ: Ms. Dotzel. MS. DOTZEL: I have a question for Dr._Oakley. This quality of evidence, the varying levels that you set out here, I guess I may not be familiar with how this is used, but I am assuming that this is used in a clinical setting where clinicians have used this as a basis for making medical decisions. I am wondering how that would translate into consumer use. Even if you were to translate it into very, very simple terms like an A through D or A through F, would consumers really be able to draw those distinctions? For example, would consumers really know what the difference would be in B and C, and would they really be willing to take or really be willing to understand the gradations, or would it just be a system where it was really up or down? Maybe all consumers would say if it is not A, we are not interested? DR. OAKLEY: Obviously, I do not have any randomized control trials upon which to base an answer to a question like that. It seems to me that_- again, for me, I took a broad view and not just the pregnancy question. I think the pregnancy or during pregnancy is different. The broad view is, I suppose, I would think that we could teach people to understand something about the differences between an A and an F. They know what that is in the school room situation. How successful we would be, I do not know. It seems to me that it is better than what we have now. When we say significance_- even the health claim, significant scientific agreement" is not driven by a process that makes the person reviewing it go through this and categorize whether it is 1 or 2-1 or 2-2. I had an experience at my lunch table on Sunday when I asked a friend I had not seen for 30 years, who is in the School of Medicine, if he had ever heard of this scale. He had this great big grin on this face. He said, "Yes, we use it all of the time. We buy for every student admitted to Rochester University to use." What it does, it does give the doctor at least something to look at and to know there is another_- you will see in the handout there is another scale on which they actually make recommendations. They have gone over this. I believe it essentially says, there is good evidence that it works; there is some evidence that it works; we do not have much evidence; there is evidence that it probably does not work; or we have strong evidence that it does not work. I think people could understand that if we could figure out how to say it. Obviously, this needs a lot more discussion and thought than we were able to do here today. I just wanted to get that idea on the table because I think it would help both on the safety and something like the homocystine thing where I think, as you know, that I would have made a different judgment than some of the people have made at the FDA. DR. GREENE: To follow up on that, this schema that Dr._Oakley has on the screen is a schema that is used by professional societies as they make recommendations for the best practices for the members of their societies in terms of_- the AAP uses it, the American College of Obstetricians and Gynecologists uses it. All of their documents now are very specifically labeled when they make recommendations on best practice where this comes from and what the best recommendation is based upon. DR. OAKLEY: I think I saw a document as I was leaving from the recommendations on exercise after a heart attack that ACPER(?) did. ACPER used exactly the same scale, so I think there is some experience. I have not used it myself personally very much, but I think it might be something_worth it. DR. PANNY: For this reason, I think that it would be very helpful to health professionals. I do not know whether we can really make it so that consumers would really use a scale like this or understand it, and I am not sure that we could say that the A drugs would sell better than the F drugs. Certainly, I think it would help health professionals looking at a drug to give advice to their patients, which I think is an issue, too. DR. WOLFE: I think most of the_- I think the manual is excellent and the methodology whereby they make the recommendations are good. I have talked with some of the people involved in redoing it. I think it is important to distinguish between products such as diagnostic products or drugs or supplements, which are the domain of the FDA to regulate, and the use of the products. For example, the kinds of things that are discussed in the manual are how often should a colonoscopy be done on someone over the age of 50 or 60. The FDA regulates the testing for prostate-specific antigen, PSA, but the preventive task force is asking should this be done routinely or how often and on what groups of people. So, I think that there is a distinction between the decision making on whether a product is safe enough to be used, and I think that particularly for prevention or anything else, treatment having to do with pregnant women, the standard has to be at the top. So, a difference between the standard for FDA approval for mass marketing as opposed to decision making, diagnostic or therapeutic decision making. It is mainly diagnostic decision making that makes up the preventive task force recommendations. It is two different spheres. DR. FRIEDMAN: Dan Friedman, University of British Columbia and Teratology Society. Godfrey, this is a system, as I understand it, that largely is geared toward efficacy. It seems to me that there are real difficulties in applying it to safety especially in the context of pregnancy where the safety for the fetus may be in a completely different dimension than the safety for the mother. How would you deal with an issue where an herb, say, was say, an "A" for efficacy in the mother and "Z" for safety in the fetus? DR. OAKLEY: I need to make my point that this is a system that one could begin to use and grapple with some of the things. Obviously, the people dealing with putting thalidomide back on the market have wrestled with those things and sort of have maybe not the best solution to that. There is a solution that is in place and so on. I think that is_- for me, the fact that we are likely to find from this is that there is not much data at all. To be able to say that clearly, I think, would actually move this and get this on the table a bit better than it had been. Then maybe we could get people moving in the direction of doing more data. Certainly I am not in the_- and please do not misunderstand anything that I say here to think that I think we should expose fetuses to products that have not been tested. I do not believe that. Clearly, the whole idea of this is to_- admittedly, this is efficacy, not safety. Safety needs to be a part of this. DR. FRIEDMAN: Let me just make one other comment, and it has to do with the simple A, B, C, D things that the FDA has been grappling with getting rid of A, B, C, D, X for safety in pregnancy for the last few years. I would be loathe to reintroduce it. DR. PANNY: I just wanted to, at the risk of belaboring the point, point out that there really is a difference between safety and efficacy. I think that some of us really feel that the issue of safety is more important than the issue of efficacy. The bar needs to be very, very, very high for safety for both mother and fetus. Perhaps the efficacy bar may not need to be so high, but safety has to be our first concern. DR. SCHWETZ: Any other comments or questions? Any questions from the rest of the audience? [There were no audible responses.] I think in view of none, we can bring this public meeting to a close. Let me just make a couple of comments, and then I would ask the two center directors at my right and left to make comments as this meeting relates specifically to their centers. I, first of all, want to thank all of the panel members who spoke this morning and this afternoon. Your willingness to take the time and to put the amount of thought that you have into this is very positive in terms of helping the agency to hear the opinions that we need to hear, to raise the questions that need to be asked, to help move this in a direction that is best for public health, and for the wise use of these kinds of compounds. We really appreciate the work that you have put into being here today and spending this whole day with us to help work this discussion through. We really, sincerely thank you for that. I do think that some good comments, some very good comments, have come out of this. It has been a constructive process to hear from the industry and from health professional and from other organizations that have firm opinions about how this can be done, how it can be done right, how it can be done less than right. It is helpful to hear all of that, and I think that we heard it in a very constructive atmosphere today. I thank all of you for helping to create that atmosphere and to provide the information and the opinions and the data that you have provided today. I have asked Dr._Woodcock to comment specifically from the standpoint of the Center for Drugs, and then I have asked Mr._Levitt to talk about and bring this to a closure from the standpoint of the Center for Food Safety and Applied Nutrition. Janet. DR. WOODCOCK: Thank you. I would like to join Bern in thanking everyone who contributed today. I think this was a very useful and constructive meeting. In addition, I believe that we have identified some common ground. There is a mutual concern by everyone involved around the safety of the pregnant woman and the fetus and a recognition of that vulnerability and the need to put safety first. I think that is very important, and it will help guide us in our deliberations. That is a very positive outcome. I think there are other issues. The discussion today has really clarified some of the issues around the quality of evidence and other matters, how do you define safety. I think that also has been very helpful to us to hear the different points of view on this, and we can take them into account in our deliberations. I thank everyone very much. MR. LEVITT: I, too, would join in both reflecting that I think that we have a number of these meetings, and they are all useful in their own way. This one, I think, is probably most remarkable by the confluence of opinions, at least within a smaller margin of difference than we often have in other settings. That itself, I think, is a reflection that everybody involved sees the uniquely important task we have of special protections that need to be taken for_- in the case of pregnancy and for protection of the fetus. It is refreshing to see that from all quarters. I think the discussions have helped draw out that we have two related but somewhat different tasks before us. One relates specifically to claims directed to women who are pregnant, whether it is for morning sickness or leg edema and so forth, whether they ought to be permitted at all under this setting. Whether or not they are, there seems to be a large call for a high standard of evidence. Though it is not necessarily clear everybody has the same view of what that standard is, nevertheless, everybody feels it ought to be a rigorous standard. Probably less agreement overall on exactly who ought to make that decision, some strong advocate for the government making that, some feeling that it ought to be an industry responsibility. Nevertheless, at least there seems to be strong movement toward a rigorous standard in that setting. Related but different is whether_-what we ought to be doing regarding labeling for supplements generally that may be used by women who do not yet know they are pregnant, whether or not they are trying to become pregnant. That really becomes a wide range of dietary supplement products. We have had suggestions for cautionary statements, some for stronger warning statements, but again, I think a call from a number of quarters that we need to address that in some way that is visible on the label in a way that is useful to consumers. Within that, I have maintained_- recognize there is a degree of flexibility within ranges that we have to go back and consider, but I think this meeting has been very helpful in framing the issues and in narrowing in the range for us to try to choose from and really do the right thing for the American public. Thank you all. DR. SCHWETZ: With that, I think that we will call this meeting to a close. Thank you. [Whereupon, at 3:05 p.m., the meeting was concluded.]
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