Ephedra Is Back? Yes, No, Maybe So...

Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule - 1997

SUMMARY: The Food and Drug Administration (FDA) is proposing to make a finding, which will have the force and effect of law, that a dietary supplement is adulterated if it contains 8 milligrams (mg) or more of ephedrine alkaloids per serving, or if its labeling suggests or recommends conditions of use that would result in intake of 8 mg or more in a 6-hour period or a total daily intake of 24 mg or more of ephedrine alkaloids; require that the label of dietary supplements that contain ephedrine alkaloids state ``Do not use this product for more than 7 days''; prohibit the use of ephedrine alkaloids with ingredients, or with ingredients that contain substances, that have a known stimulant effect (e.g., sources of caffeine or yohimbine), which may interact with ephedrine alkaloids; prohibit labeling claims that require long-term intake to achieve the purported effect (e.g., weight loss and body building); require a statement in conjunction with claims that encourage short-term excessive intake to enhance the purported effect (e.g., energy) that ``Taking more than the recommended serving may result in heart attack, stroke, seizure or death''; and require specific warning statements to appear on product labels. FDA is proposing these actions in response to serious illnesses and injuries, including multiple deaths, associated with the use of dietary supplement products that contain ephedrine alkaloids and the agency's investigations and analyses of these illnesses and injuries. FDA is also incorporating by reference its Laboratory Information Bulletin (LIB) No. 4053, that FDA will use in determining the level of ephedrine alkaloids in a dietary supplement.

Subpart D--Restricted Dietary Ingredients

Sec. 111.100 Dietary supplements that contain ephedrine alkaloids.

The ephedrine alkaloids include ephedrine, pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine, methylpseudoephedrine, and related alkaloids. These substances are chemical stimulants contained in particular botanical products, including those from the botanical species Ephedra sinica Stapf., Ephedra equistestina Bunge, Ephedra intermedia var., tibetica Stapf., Ephedra distachya L., and Sida cordifolia or their extracts.

1. 1. Dietary supplements that contain 8 milligrams (mg) or more of ephedrine alkaloids (the total of ephedrine, pseudoephedrine, norpseudoephedrine, norephedrine, methylephedrine, methylpseudoephedrine, and related alkaloids) per single serving shall be deemed to be adulterated under sections 402(a)(1) and 402(f)(1)(A) of the Federal Food, Drug, and Cosmetic Act.

   2. The Food and Drug Administration will use high performance liquid chromatography (HPLC) to determine the level of ephedrine alkaloids in a dietary supplement as specified in its Laboratory Information Bulletin (LIB) No. 4053, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be obtained from the Director, Office of Constituent Operations, Industry Activities Staff (HFS-565), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C St. SW., rm. 5827, Washington, DC 20204, or may be examined at the Center for Food Safety and Applied Nutrition's Library, Food and Drug Administration, 200 C St. SW., rm. 3321, Washington, DC, or at the Office of the Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.

2. The labeling of dietary supplements that contain ephedrine alkaloids shall not suggest or recommend conditions of use that would result in an intake of 8 mg or more ephedrine alkaloids within a 6-hour period or a total daily intake of 24 mg or more of ephedrine alkaloids.
3. The label of dietary supplements that contain ephedrine alkaloids shall state ``Do not use this product for more than 7 days."
4. No ingredient, or ingredient that contains a substance, that has a known stimulant effect (e.g., sources of caffeine, yohimbine) may be included in a dietary supplement that contains ephedrine alkaloids.
5. No dietary supplement that contains ephedrine alkaloids may purport to be, or be represented as, either expressly or implicitly, for use for long-term effects, such as weight loss or body building.
6. 1. The label or labeling for dietary supplements that contain ephedrine alkaloids that purport to be or are represented, either expressly or implicitly, to be used for short-term effects, such as increased energy, increased mental concentration or enhanced well-being, shall state ``Taking more than the recommended serving may cause heart attack, stroke, seizure, or death."
   2. This information shall appear on the same label panel or same page of labeling as the claim and shall be connected to the claim by use of an asterisk. This information shall appear in easily legible print or type, in distinct contrast to other printed or graphic matter, and in a type size no less than is required by Sec. 101.105(i) of this chapter for the net quantity of contents statement, except where the size of the claim is less than two times the required size of the net quantity of contents statement, in which case the information shall be no less than one-half the size of the claim, but no smaller than one- sixteenth of an inch. Where the label or labeling contains multiple claims, the information shall appear once on each label panel or on each page of labeling.
7. 1. The labeling of any dietary supplement that contains ephedrine alkaloids shall bear the following warning: WARNING: If you are pregnant or nursing, or if you have heart disease, thyroid disease, diabetes, high blood pressure, depression or other psychiatric condition, glaucoma, difficulty in urinating, prostate enlargement, or seizure disorder consult a health care provider before using this product. Do not use if you are using monoamine oxidase inhibitors (MAOI) or for 2 weeks after stopping a MAOI drug; certain drugs for depression, psychiatric or emotional conditions; drugs for Parkinson's disease; methyldopa; or any product containing ephedrine, pseudoephedrine or phenylpropanolamine (ingredients found in allergy, asthma, cough/cold and weight control products). Stop use and call a health care professional immediately if dizziness, severe headache, rapid and/or irregular heart beat, chest pain, shortness of breath, nausea, noticeable changes in behavior, or loss of consciousness occur. Do not exceed recommended serving.
   2. The phrase ``Do not exceed recommended serving'' is not required to appear in the warning statement when the disclaimer required in paragraph (f)(1) of this section appears on the same label panel as the warning statement.
   3. The warning statement required by paragraph (g)(1) of this section shall appear prominently and conspicuously on the product label and shall be set off in a box by use of hairlines.

Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part - 2000

SUMMARY: The Food and Drug Administration (FDA) is announcing that it is withdrawing certain provisions of a proposed rule that published in the Federal Register of June 4, 1997 (62 FR 30678), relating to dietary supplements containing ephedrine alkaloids. FDA is taking this action because of concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products. Elsewhere in this issue of the Federal Register, FDA is announcing the availability of new adverse event reports and related information associated with these products and its plans to participate in a public forum to discuss this new information at some future date. In addition, FDA is announcing elsewhere in this issue of the Federal Register the availability of additional documentation associated with certain adverse events referenced in the 1997 proposed rule.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of June 4, 1997 (62 FR 30678), FDA published a proposed rule (hereinafter referred to as the ``ephedrine alkaloids proposal'') to establish that a dietary supplement is adulterated if it contains 8 milligrams (mg) or more of ephedrine alkaloids per serving, or if its labeling suggests or recommends conditions of use that would result in an intake of 8 mg or more within a 6-hour period or a total daily intake of 24 mg or more of ephedrine alkaloids (hereinafter referred to as ``dosing level'' or ``dietary ingredient level''), and to require that the label of such supplement state that the product is not to be used for more than 7 days (hereinafter referred to as ``duration of use limit''). The agency also proposed to prohibit the use of ephedrine alkaloids in dietary supplements with ingredients, or with ingredients that contain substances, that have a known stimulant effect, such as caffeine, which may interact with ephedrine alkaloids; and to prohibit labeling claims, such as weight loss or body building, that require long-term intake to achieve the purported effect. In addition, the agency proposed to require a statement to accompany claims that encourage short-term excessive intake to enhance a purported effect, such as an increase in energy, that taking more than the recommended serving may result in serious adverse health effects; and to require specific warning statements to appear on product labels.

The agency proposed these actions in response to reports of serious illnesses and injuries, including a number of deaths, associated with the use of dietary supplement products containing ephedrine alkaloids and the agency's investigations and assessment of these illnesses and injuries. This action was also supported by many of the recommendations made during the October 1995 meeting of an ad hoc Working Group of the FDA Advisory Committee (Working Group) and the August 1996 meeting of the Food Advisory Committee (FAC) and the Working Group concerning the potential public health problems associated with the use of dietary supplements containing ephedrine alkaloids and the recommended steps FDA should take to address the serious health concerns associated with their use (see Refs. 25 and 27 of the ephedrine alkaloids proposal (Docket No. 95N-0304)).

The comment period for the June 4, 1997 (62 FR 30678), proposed rule closed on August 18, 1997. In a notice in the Federal Register of August 20, 1997 (62 FR 44247), FDA announced its intent to reopen the comment period after the agency corrected a number of inadvertent omissions in the administrative record. Subsequently on September 18, 1997 (62 FR 48968), the agency reopened the comment period for an additional 75 days until December 2, 1997.

The agency received approximately 350 letters regarding the use of ephedrine alkaloid-containing dietary supplements prior to publication of the ephedrine alkaloids proposal. These comments have been considered by the agency along with those commenting in response to the proposal. The agency received approximately 14,775 comments on the ephedrine alkaloids proposal. Individual consumers who use ephedrine alkaloid-containing dietary supplements and independent distributors of these products submitted most of the comments. Other comments were received from persons who had, or who knew persons who had, suffered adverse events or who were reporting adverse events associated with the use of an ephedrine alkaloid-containing dietary supplement. The remaining comments included those submitted by medical professionals, scientists, a scientific association, State and local health departments, medical associations, government agencies, dietary supplement manufacturers, Chinese medicine practitioners and associations, dietary supplement industry trade associations, public health associations, and consumer groups.

The House Committee on Science requested that the Government Accounting Office (GAO) examine the scientific bases for the ephedrine alkaloids proposal and the agency's adherence to the regulatory flexibility analysis requirements for Federal rulemaking. On August 4, 1999, GAO released its report entitled ``Dietary Supplements: Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids.'' A copy of this report is available in Docket No. 95N-0304.

Generally, GAO concluded that FDA was justified in determining that the number of adverse event reports relating to dietary supplements containing ephedrine alkaloids warranted the agency's attention and consideration of steps to address safety issues. However, GAO expressed concerns about the use of the reported adverse events in supporting the proposed dosing level and duration of use limit, and concluded that the agency needed additional evidence to support these restrictions.

GAO also concluded that FDA's economic analysis contained the basic elements expected in a Federal agency's cost-benefit analysis, and the ephedrine alkaloids proposal complied with regulatory flexibility analysis requirements under the Regulatory Flexibility Act. GAO noted, however, that FDA's cost-benefit analysis was not always transparent regarding why certain key assumptions were made, the degree of uncertainty involved in those assumptions, or the effect that alternative assumptions would have had on the agency's estimates of the costs and benefits of the proposed action.

GAO recommended that FDA ``provide stronger evidence on the relationship between the intake of dietary supplements containing ephedrine alkaloids and the occurrence of adverse reactions that support the proposed dosing level and duration of use limits." In addition, GAO recommended that FDA improve the transparency of its cost-benefit analysis in its final rulemaking.

In light of GAO's conclusions, comments from others on the ephedrine alkaloids proposal, and having further considered issues related to the proposed dietary ingredient level and the duration of use limit, FDA believes that these aspects of its proposed approach to regulating these products should be reassessed. Whether there are appropriate alternative approaches to these aspects of the proposal for regulating dietary supplements containing ephedrine alkaloids will require evaluation of additional information not available to the agency when it issued the proposal. Accordingly, FDA is withdrawing the provisions of the ephedrine alkaloids proposal relating to the dietary ingredient level and duration of use limit for these products. This action will allow FDA to reconsider, with public input, whether any dietary ingredient level or duration of use limit for these products is appropriate or whether alternative measures should be considered. The withdrawn provisions are described briefly below.

II. Withdrawn Provisions of the Ephedrine Alkaloids Proposal

A. Dietary Ingredient Limit for Ephedrine Alkaloids: Per Serving Basis Sec. 111.100(a)(1)) and Frequency and Per Total Daily Intake Basis (Sec. 111.100(b))

As stated above, the agency tentatively concluded in the ephedrine alkaloids proposal that a dietary supplement is adulterated if it contains 8 mg) or more of ephedrine alkaloids per serving (Sec. 111.100(a)(1)), or if the labeling suggests or recommends conditions of use that would result in an intake of 8 mg or more within a 6-hour period or a total daily intake of 24 mg or more of ephedrine alkaloids (Sec. 111.100(b)). Having reconsidered the basis for these limits, including comments on that basis by GAO and others to the proposal, FDA believes that it should consider additional information not available to the agency when it issued the ephedrine alkaloids proposal to determine whether a dietary ingredient limit, or some alternative approach, would be appropriate to regulate these dietary ingredients. Therefore, FDA is withdrawing these provisions of the ephedrine alkaloids proposal.

FDA continues to be concerned about the potential risk for individuals who are particularly sensitive to the effects of ephedrine alkaloids, or whose sensitivity or likelihood for adverse effects may be increased through chronic use of these products or other means (e.g., physical exercise). FDA expressed this concern in the proposal, and noted that many members of the FAC agreed.

B. Proposed Compliance Procedures (Sec. 111.100(a)(2))

In the ephedrine alkaloids proposal, FDA stated that it would use a high performance liquid chromatography method as specified in Laboratory Information Bulletin No. 4053 to determine the level of ephedrine alkaloids in a dietary supplement. Without a requirement that would establish an unacceptable dietary ingredient level for dietary supplements containing ephedrine alkaloids, this provision, alone, is no longer necessary. Accordingly, the agency has determined that this provision should also be withdrawn.

C. Proposed Limitations on Duration of Use (Sec. 111.100(c))

FDA proposed in Sec. 111.100(c) to require that the label of dietary supplements that contain ephedrine alkaloids state ``Do not use this product for more than 7 days.'' FDA intended to require this provision in conjunction with the 8 mg per serving dietary ingredient limit proposed in Sec. 111.100(a)(1). FDA noted in the ephedrine alkaloids proposal that concern about serious adverse events with the long-term use of ephedrine alkaloids led several members of the Working Group (see Ref. 27 of the ephedrine alkaloids proposal) and of the FAC (see Ref. 25 of the ephedrine alkaloids proposal (Docket No. 95N-0304)) to recommend that, in conjunction with a per serving dietary ingredient limit, FDA require a statement on the label of ephedrine alkaloid-containing dietary supplements to warn consumers not to use the product for a period longer than 7 days. FDA also cited evidence from the scientific literature about the adverse effects of long-term use of ephedrine alkaloids (62 FR 30678 at 30695).

FDA remains concerned with the long-term use of such products and the potential adverse effects such use has in combination with the use of other ingredients that have a stimulant effect. However, having reconsidered the basis for the proposed duration of use limit, including the comments on that basis by GAO and others to the proposal, FDA believes that it should consider additional information not available to the agency when it issued the ephedrine alkaloids proposal to determine whether any duration of use limit, or some alternative approach, is appropriate to regulate these products. In addition, the agency is also withdrawing the proposed 8-mg dietary ingredient limit. Therefore, the agency has determined that the proposed labeling requirement concerning duration of use should also be withdrawn.

D. Prohibition on Claims (Sec. 111.100(e) and (f))

FDA stated in the proposal that restrictions on claims are necessary to maintain the integrity of the limit on the level of ephedrine alkaloids in dietary supplements that it proposed and of the other proposed restrictions on the conditions of use of these dietary supplements. For example, because safe and significant weight loss and body building cannot be achieved in a 7-day period, FDA tentatively concluded that claims that promote these uses promote long-term use of ephedrine alkaloid-containing dietary supplements, which have been associated with serious adverse events. For this reason, FDA tentatively concluded that any claims that promote long-term use of ephedrine alkaloid dietary supplements, such as those for weight loss and body building, promote conditions of use that present a significant and unreasonable risk of illness and injury. Consequently, FDA proposed in Sec. 111.100(e) to require that no dietary supplement that contains ephedrine alkaloids may purport to be, or be represented as, either expressly or implicitly, for use for long-term effects, such as weight loss or body building.

Similarly, many claims found on the labels of, or in the labeling for, ephedrine alkaloid-containing dietary supplements, including increased energy, increased mental concentration, and enhanced well-being, encourage the consumer to take more of the product than is indicated on the label to achieve more of the purported effect. Consequently, FDA tentatively concluded that claims that promote excessive consumption are inconsistent with the dietary ingredient limit for these products. Accordingly, FDA proposed in Sec. 111.100(f)(1) that the label or labeling for dietary supplements that contain ephedrine alkaloids that purport to be or are represented, either expressly or implicitly, to be used for short-term effects, such as increased energy, increased mental concentration, or enhanced well-being, must state ``Taking more than the recommended serving may cause heart attack, stroke, seizure or death.'' FDA proposed in Sec. 111.100(f)(2) certain requirements on the size, type, and placement of this statement on the label. Because FDA is withdrawing the proposed dietary ingredient limit and duration of use limit, FDA has determined that the proposed provisions in Sec. 11.100(e) and (f) should also be withdrawn. FDA believes that it should consider additional information not available to the agency when it issued the ephedrine alkaloids proposal before finally determining whether such provisions with respect to claims, or some alternative approach, is appropriate to regulate these products. Nonetheless, FDA remains concerned that adverse effects are associated with long-term consumption of such products and with consumption of such products in excess of labeled serving sizes.

III. Current Provisions of the Ephedrine Alkaloids Proposal

Despite this action to withdraw the proposed dietary ingredient level and duration of use limit, and related provisions of the ephedrine alkaloids proposal, there remain provisions that the agency is not withdrawing in this notice. These provisions concern FDA's proposed prohibition on the use of ingredients with stimulant effects with dietary supplements containing ephedrine alkaloids (Sec. 111.100(d)) and the proposed warning statement (Sec. 111.100(g)).

FDA proposed in Sec. 111.100(d) to require that no ingredient, or ingredient that contains a substance, that has a known stimulant effect (e.g., sources of caffeine, yohimbine) may be included in a dietary supplement that contains ephedrine alkaloids. FDA proposed this provision in response to the many adverse events that had been reported to the agency. These adverse events involved the use of dietary supplements that contain ephedrine alkaloids in combination with other ingredients, some with known physiological or pharmacological effects, including kola nut, yohimbe, willow bark, senna, and Uva ursi (see Ref. 164 of the proposed rule (Docket No. 95N-0304)). These adverse events suggested that the other ingredients may act in combination with the ephedrine alkaloids to produce more frequent, more severe, or potentially different patterns of adverse effects than those noted with the use of ephedrine alkaloids alone.

In the ephedrine alkaloids proposal, FDA also tentatively concluded that a warning statement on the labels of dietary supplements containing ephedrine alkaloids is necessary, in conjunction with dietary ingredient limitations and other requirements proposed in that document, to protect the public health. The warning statements proposed in Sec. 111.100(g) contained several elements, including cautions that consumers not use the product if they have certain diseases or health conditions or are using certain drugs, and to stop the use of the product if they develop certain signs or symptoms. As noted in the preamble to the ephedrine alkaloids proposal, persons having certain diseases or taking specific medications known to interact with ephedrine alkaloids are at risk of suffering adverse events with the use of dietary supplements containing ephedrine alkaloids. Generally, use of ephedrine alkaloids at any intake level by these persons is contraindicated. For these persons a warning label statement can be a useful means of alerting them to potential consequences that can result from the use of the product. In addition, many consumers who are unaware that they are sensitive to the effect of ephedrine alkaloids may not recognize the significance of early warning signs and symptoms as potential indicators of more serious side effects (e.g., dizziness or severe headache may be early symptoms of hypertension or stroke). Under these circumstances, a warning statement could provide information on what actions the consumer should take if certain symptoms occur (62 FR 30678 at 30700).

The agency has not at this time concluded that it will finalize the provisions in Sec. 111.100(d) and (g). Rather, the agency intends to consider whether to finalize these provisions, or take additional or alternative regulatory action, after it receives public input on the significance of new information collected by the agency about the safety of dietary supplements containing ephedrine alkaloids.

IV. Continued Monitoring and Follow-up

Although FDA is withdrawing certain provisions of the ephedrine alkaloids proposal, FDA continues to have a public health concern with respect to the use of dietary supplements containing ephedrine alkaloids. The agency will continue to monitor and provide appropriate follow-up on adverse events associated with the use of these products. n a notice of availability published elsewhere in this issue of the Federal Register, FDA is seeking public input about the significance of new information collected by the agency about the safety of dietary supplements containing ephedrine alkaloids. The agency is also requesting the submission of any other information that the submitters believe is relevant to such a safety assessment. Should additional information suggest that additional action is necessary, FDA will consider what action is appropriate, and take appropriate steps to protect consumers and the public health.

V. Enforcement

Withdrawal of certain provisions of the ephedrine alkaloids proposal does not limit the agency's discretion to initiate enforcement actions with respect to ephedrine alkaloids containing dietary supplements. For example, circumstances may warrant enforcement action against a dietary supplement containing ephedrine alkaloids if an evaluation of the relevant facts show a health hazard or that the product is otherwise adulterated or misbranded.

FDA maintains its street drug alternative policy, as articulated in the preamble to the ephedrine alkaloids proposal, which states that because alternatives to illicit street drugs are not intended to supplement the diet, products that purport to be or that are represented, either expressly or implicitly, for use as alternatives to street drugs are not dietary supplements within the meaning of section 201(ff) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(ff)). (See 62 FR 30678 at 30699 and 30700). FDA is publishing elsewhere in this issue of the Federal Register a notice announcing the availability of a guidance entitled ``Street Drug Alternatives.'' The guidance is intended to inform industry and the public that FDA considers any product that is promoted as a street drug alternative to be an unapproved new drug and a misbranded drug in violation of the act. To date, the agency has taken action against several products marketed as alternatives to illicit street drugs, and it may do so in the future, as well.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs, the proposed rule published on June 4, 1997 (62 FR 30678), is withdrawn in part for Sec. 111.100(a), (b), (c), (e), and (f).

United States General Accounting Office (GAO) Report to the Chairman and Ranking Minority Member, Committee on Science, House of Representatives , July 1999 , DIETARY SUPPLEMENTS Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids GAO/HEHS/GGD-99-90 [Note: this is an edited version of the GAO report, with the appendix removed, but will provide the reader with insights of the primary report contents.]

The Honorable James Sensenbrenner, Jr. Chairman The Honorable George E. Brown, Jr. Ranking Minority Member Committee on Science House of Representatives The dietary supplement industry estimates that as many as 2 billion doses of dietary supplements containing botanical ephedrine alkaloids are consumed each year in the United States. The principal source of botanical ephedrine alkaloids is the Chinese herb ma huang. Traditionally, this substance was used by Chinese physicians to treat conditions such as hay fever and asthma. In Western medicine, synthetic ephedrine alkaloids have been used in products such as over-the-counter asthma and cold medicines, while botanical ephedrine alkaloids have been used in dietary supplements that are promoted to provide health benefits, including helping individuals lose weight and increase energy levels.

In June 1997, the Food and Drug Administration (FDA) published a proposed rule that would establish a dosing regimen, require warning statements, and affect other aspects of product labeling for dietary supplements containing ephedrine alkaloids. FDA developed its proposed rule in response to what it termed "serious illnesses and injuries, including multiple deaths, associated with the use of dietary supplement products that contain ephedrine alkaloids." FDA based its rule, in part, on a number of adverse events reports (AER) it received that indicated that some health problems could have been associated with use of dietary supplements containing ephedrine alkaloids.

FDA determined that its proposed rule on dietary supplements containing ephedrine alkaloids was an economically significant rule and, therefore, was required to conduct a cost-benefit analysis pursuant to the requirements in Executive Order 12866.¹ Other regulatory analysis requirements for federal rulemaking are those under the Regulatory Flexibility Act (RFA), which directs agencies to consider the potential impact of regulation on small businesses and other small entities,² and the Unfunded Mandates Reform Act (UMRA), which generally requires agencies to prepare cost-benefit analyses for any proposed regulation that would impose mandates likely to result in expenditures of $100 million or more in any 1 year.³

Industry groups and the Small Business Administration's (SBA) Office of Advocacy have challenged FDA's proposed rule, claiming that the scientific information and AERs supporting the rule were poor and unreliable. Further, industry groups and the Office of Advocacy claimed that the cost-benefit analysis performed by FDA understated the costs of the regulation and overestimated the benefits. They also had concerns about compliance with RFA's and UMRA's procedural requirements. In light of the concerns expressed by SBA and industry groups, you asked us to examine:

1. the scientific basis for FDA's proposed rule and
2. the agency's adherence to the regulatory analysis requirements for federal rulemaking.

In examining the basis for the rule, you asked that we examine scientific evidence, FDA's past use of and internal guidance on AERs in rulemaking, and information contained in the AERs for determining dosing regimens and benefits that would arise from the proposed rule. Regarding the rulemaking requirements, you asked that we determine the extent to which FDA's analysis contained elements expected in a federal agency's cost-benefit analysis and to analyze FDA's compliance with the requirements in RFA and UMRA.

To meet these objectives, we interviewed representatives of and obtained documents from FDA, SBA's Office of Advocacy, the Office of Information and Regulatory Affairs (OIRA) in the Office of Management and Budget (OMB), and the dietary supplement industry. We also examined the public docket of the proposed rule, performed a content analysis of a random sample of AERs, and reviewed scientific literature and case reports of adverse events from products containing ephedrine alkaloids. We conducted our review from September 1998 to May 1999 in accordance with generally accepted government auditing standards. (See app. I for further information on our scope and methodology.)

Results in Brief

FDA based its proposed rule on numerous reports of adverse events associated with products thought to contain ephedrine alkaloids; it also used evidence from scientific literature indicating that ingestion of ephedrine alkaloids adversely affects some individuals. The number and type of AERs warranted FDA's consideration of steps to address safety issues. However, we have concerns about the strength of some of the information FDA used to support two aspects of the proposed rule: the dosing level and duration of use limits. While there was scientific evidence showing adverse events at levels above 20 mg per serving, FDA's dosing level proposal of 8 mg per serving was based on information associated with only 13 AERs-the quality of which is questionable. For the duration of use limits, FDA relied on scientific studies that showed problems associated with extended use, well beyond the 7-day limit proposed. Moreover, FDA did not establish a causal link between the ingestion of ephedrine alkaloids and the occurrence of adverse events for either its proposed dosing level or duration of use. FDA also based its estimate of the benefits of the proposed rule on the annual number of adverse events reported to FDA. However, because FDA did not document which AERs it identified as containing "serious" events, we could not determine the accuracy of FDA's estimated benefits. In addition, FDA has no internal guidance on the use of AERs for rulemaking related to foods and dietary supplements, and the AERs were used differently in this proposed rule than in prior rulemaking.

The agency generally complied with the statutory and executive order requirements for rulemaking, but the cost-benefit analysis that accompanied the rule does not reflect the full range of uncertainty associated with the proposed rule. FDA's cost-benefit analysis and other analyses included the primary elements required under E.O. 12866 and related "best practices" guidance and RFA. UMRA's requirements did not appear to apply to the rule. Although FDA disclosed the basic methodology, data, and assumptions used in its cost-benefit analysis, the agency did not always disclose why certain key assumptions were made or the degree of uncertainty involved in those assumptions. It also did not disclose that alternative assumptions would have had a dramatic effect on the agency's estimate of the benefits of the proposed actions.

While FDA's conclusions regarding the desirability of the proposed action may be valid, we believe these conclusions are open to question because of limitations and uncertainties associated with the agency's scientific and economic analyses. Given these uncertainties, we recommend that FDA obtain additional information to support the proposed dosing levels and duration of use limits and improve the transparency of its cost-benefit analysis before proceeding to final rulemaking.

Background

FDA is responsible for overseeing the federal government's regulation of drugs, medical devices, food safety, veterinary medicine, and biological products. Unlike many of these products, dietary supplements do not have to undergo preapproval by FDA to determine their safety or efficacy. The Dietary Supplement Health and Education Act of 1994 created a new framework for FDA's regulation of dietary supplements as part of its oversight of food safety.⁴ The act allows dietary supplement products to bear a statement describing how consumption of the supplement can affect humans,⁵ but manufacturers of dietary supplements cannot make a drug claim for the product-that is, a statement claiming to diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases.⁶ Dietary supplements containing botanical sources of ephedrine alkaloids are currently marketed for weight loss and increased energy. These products are marketed in a variety of forms, including pills, powders, liquid drops, and teas. Currently, FDA has no requirements that the packages for these products include dosing regimens and warning labels.

Over-the-counter products containing synthetic ephedrine alkaloids are considered safe and effective for people ages 12 and older to temporarily relieve shortness of breath, tightness of chest, and wheezing due to bronchial asthma, if recommended dosages are followed. The recommended dosages-which range from 12.5 mg to 25 mg every 4 hours, not to exceed 150 mg per day-are provided on the label. Labels for over-the-counter drug products containing ephedrine alkaloids list side effects, such as nervousness, sleeplessness, nausea, and loss of appetite. The labels also warn against using the product if, for example, the potential user has high blood pressure, heart disease, thyroid disease, or diabetes, or has been hospitalized for asthma or is taking a prescription drug for asthma, unless directed by a doctor. Labels also note that if symptoms persist or become worse, users should discontinue taking the drug and consult a doctor. After reports of stroke in asthmatics who had taken ephedrine along with prescription monoamine oxidase inhibitors,⁷ precautions against using both drugs concurrently were added to the label.

FDA's Proposed Rule on Ephedrine Alkaloids

FDA has no authority to require submission of reports of adverse events. FDA must generally rely on consumers or their friends and family members, physicians or other health care professionals, product manufacturers, and state health agencies to voluntarily report adverse events. FDA uses these AERs as a passive monitoring tool to identify potentially serious public health issues that may be associated with the use of a particular product or type of products. Like all passive surveillance systems, AERs have certain limitations such as underreporting and poor report quality (see app. II for a further discussion of the adverse event monitoring system). FDA's analysis of AERs and information from the scientific literature relating to ephedrine alkaloids indicated to the agency that there was cause for concern regarding a potential public health problem associated with dietary supplements containing ephedrine alkaloids. At the time of the proposed rule, FDA had received over 800 AERs for products thought to contain ephedrine alkaloids-more AERs than the agency had received for any other dietary supplements.

According to agency officials, FDA found that, unlike most AERs related to foods, the AERs relating to ephedrine alkaloids commonly involved visits to a physician or emergency room. Some of these reports were very serious, including effects such as strokes, and the events were occurring in a population of young adults in which such serious events are not expected. FDA officials also stated that the adverse physiological and pharmacological effects from dietary supplements believed to contain botanical sources of ephedrine alkaloids were similar to those reported for drugs containing synthetic sources of ephedrine alkaloids, but these effects were being seen at lower doses and potencies for botanicals than in the drug products.

From 1994 through 1997, FDA took a series of steps to respond to what it perceived was a public health concern related to these products. In 1994, FDA's Center for Food Safety and Applied Nutrition (CFSAN), which oversees dietary supplements, issued a medical bulletin outlining potential adverse reactions from dietary supplements containing ephedrine alkaloids. The agency issued a press release warning consumers not to purchase a particular brand of dietary supplement containing ephedrine alkaloids that the agency determined could cause severe injury or death in some people.

In October 1995, FDA convened a special work group composed of pharmacologists, physicians, and industry representatives to address concerns related to the use of dietary supplements containing ephedrine alkaloids, but no consensus developed on how to address the public health concerns outlined by FDA. In August 1996, FDA's Food Advisory Committee was asked to provide opinions on and rationale for specific ways to address problems associated with dietary supplements containing ephedrine alkaloids. Over half the committee members concluded that no safe level for ephedrine alkaloids could be identified and recommended that these products be removed from the market. Most of the other members felt that a fairly low level of ephedrine alkaloids would be "reasonably safe." The Food Advisory Committee was unable to identify a benefit for ephedrine alkaloids in terms of supplementing the diet.

In June 1997, FDA published a proposed rule regarding dietary supplements containing ephedrine alkaloids.⁸ In two subsequent notices the agency reopened and extended the comment period on the proposed rule until December 1997.⁹

The Proposed Rule:

• defines levels of the amount of ephedrine alkaloids in a serving of dietary supplements at and above which the product would be deemed adulterated (8 mg),
• places restrictions on the frequency of use and daily dosages (24 mg or more),
• requires that labels on these supplements contain a statement warning that the product should not be used for more than 7 days,
• prohibits the use of ephedrine alkaloids with ingredients that have a known stimulant effect (for example, caffeine),
• prohibits certain labeling claims that require long-term intake of the supplements to achieve the purported purpose,
• requires a warning statement in conjunction with claims that encourage short-term excessive intake, and
• requires a specific warning statement to appear on product labels.

Federal Regulatory Analysis Requirements

Executive Order 12866 establishes certain rulemaking responsibilities for covered agencies. Among other things, the order states that, in deciding whether and how to regulate, agencies should assess all costs and benefits of available regulatory alternatives, including both quantifiable and qualitative effects. The order also states that, in choosing among alternatives, an agency should select those approaches that maximize net benefits and "base its decisions on the best reasonably obtainable scientific, technical, economic, and other information concerning the need for, and consequences of, the intended regulation." The order requires agencies to conduct cost-benefit analyses for all regulatory actions that are likely to result in a $100 million annual effect on the economy or are otherwise economically significant. In January 1996, the Administrator of OIRA issued "best practices" guidance on preparing cost-benefit analyses under the order. The guidance indicates that an analysis should contain certain basic elements and should be "transparent"-disclosing how the analysis was conducted, what assumptions were used, and the implications of plausible alternative assumptions.

During the past 20 years, the Congress has attempted to improve the federal rulemaking process by enacting a number of statutes that impose certain analytical requirements on agencies issuing proposed regulations. For example, RFA of 1980 was enacted in response to concerns about the effect that federal regulations could have on small entities. RFA directs all agencies to give particular attention to the potential impact of regulation on small businesses and other small entities and requires consideration of regulatory alternatives that are less burdensome to small entities. Under RFA, an agency must prepare an initial regulatory flexibility analysis at the time proposed rules are issued unless the head of the agency determines that the proposed rule would not have a "significant economic impact upon a substantial number of small entities." The act also requires agencies to ensure that small entities have an opportunity to participate in the rulemaking process. Other statutory rulemaking requirements are set forth in UMRA. UMRA generally requires agencies (other than independent regulatory agencies) to prepare cost-benefit and other analyses for any regulations imposing mandates that are likely to result in expenditures of $100 million or more in any 1 year either by state, local, and tribal governments, in the aggregate, or by the private sector. Although UMRA's scope and requirements differ from E.O. 12866, the provisions on economic analysis are very similar. Accordingly, the guidance for implementing the executive order states that the economic analysis that the agency prepares should also satisfy the requirements of UMRA.

FDA Analyses Relied on Poorly Documented Reports of Adverse Events

To develop its proposed rule, FDA used a combination of scientific evidence on the effects of ephedrine alkaloids and a set of reports it received on adverse events associated with dietary supplements containing ephedrine alkaloids. While the signs and symptoms described in the AERs were consistent with available scientific evidence and known physiologic and pharmacologic effects of ephedrine alkaloids, the AERs were poorly documented. FDA also used the AERs differently than in its past rulemaking. Specifically, the agency used AERs as the sole source of support for specific dosing levels, relied on weak information to set limits on duration of use, and did not perform a causal analysis to determine whether ingestion of a dietary supplement containing ephedrine alkaloids caused or contributed to the adverse events. FDA also used these AERs to determine the number of serious events that could be attributed to the dietary supplements and the expected benefits that would arise if the proposed rule were implemented. However, FDA did not document which AERs it determined to be serious. Moreover, it did not establish criteria to determine which events were serious and did not perform any reliability assessments of its analyses.

Scientific Information Indicates Ephedrine Alkaloids Can Affect the Cardiovascular and Nervous Systems

Our review of the scientific literature found case reports that suggested that ephedrine alkaloids could increase blood pressure in persons with normal and high blood pressure;¹⁰ predispose certain individuals to tachycardia (rapid heart rate);¹¹ and cause cardiomyopathy (disease of the heart muscle),¹² stroke,¹³ or myocardial necrosis (death of cells in the heart).¹⁴ We also found descriptions of adverse events associated with ephedrine alkaloids that affected the central nervous system, such as mania,¹⁵ paranoid psychoses,¹⁶ and seizures.¹⁷

Our review found only one clinical study examining the effects of a botanical source of ephedrine alkaloids, ma huang, on heart rate and blood pressure. The study of adults with normal blood pressure found a statistically-but not clinically-significant increase in heart rate but variable effects on blood pressure.¹⁸ However, "in combination with other stimulants and at higher doses, effects of magnification of the heart rate and blood pressure response could be expected." One report also highlighted a case of mania as a result of ingestion of a dietary supplement ¹⁹ containing ma huang.

We also reviewed a number of studies using clinical trials that evaluated the efficacy of ephedrine (a synthetic ephedrine alkaloid)-alone or in combination with caffeine-for weight loss. Although these trials were not designed to determine whether ephedrine is safe to use during weight loss programs, FDA concluded that this body of literature showed "clinically significant adverse effects in populations with no known risk factors with the use of ephedrine and that synergistic adverse effects can result when ephedrine and caffeine are combined." FDA further concluded that "The patterns and types of the adverse effects reported in these trials are consistent with the known effects of sympathomimetic agents²⁰-that is, they mainly involved nervous and cardiovascular system effects."

AERs Were Used Differently For Developing The Proposed Rule Than For Prior Rulemaking.

To develop FDA's proposed rule on dietary supplements containing ephedrine alkaloids, CFSAN used AERs differently than in prior FDA rulemaking. FDA officials acknowledge that the agency does not have any formal internal guidelines on the use of AERs for rulemaking and provided five examples of past rulemaking in which CFSAN used several sources of information in addition to AERs to support the agency's proposals. For the proposed rule on dietary supplements containing ephedrine alkaloids, CFSAN used AERs alone to determine specific dosing levels.²¹

In a prior rulemaking, FDA used prevalence estimates among people with asthma to determine sensitive populations who might be affected by sulfiting agents²² and convened a scientific panel to examine exposure estimates and evidence from clinical experiments.²³ For its rulemaking on protein supplements, FDA used data collected through a telephone survey, conducted jointly with the Centers for Disease Control and Prevention (CDC), and information on death rates from the National Center for Health Statistics. FDA also initiated its own experimental protocols to examine the basic metabolic mechanisms of protein diets.²⁴ FDA's proposed rule on supplements and drugs containing iron relied on data from the American Association of Poison Control Centers and the U.S. Consumer Product Safety Commission to determine fatalities from accidental iron poisonings. Data from the National Electronic Injury Surveillance System were also incorporated to estimate the number of cases of hospital emergency room treatment for iron ingestion.²⁵ FDA did not establish dosing levels in any of these rulemakings.

Although AERs were used as early warning signals in many of these cases, the proposed rule on ephedrine alkaloids relied more heavily on AERs than did prior rulemaking efforts. (See app. III for additional information on the use of AERs in prior rulemaking.)

Shortcomings Of AERs And FDA's Reliance On Them Add Uncertainty To FDA's Proposed Rule.

The inherent weaknesses of AERs-along with FDA's heavy reliance on them-lead to uncertainty regarding the dosing regimen outlined in the proposed rule. The AERs used in the rule lacked or had inconsistent information relevant to FDA's analysis, such as the amount of product used, how often it was used, or for how long it was used. The limitations of a passive surveillance system such as AERs call into question FDA's ability to determine a specific dosing level based solely on these reports.²⁶ FDA did not perform a causal analysis to determine if, in fact, the 13 AERs it used to set dosing levels were caused by supplements containing ephedrine alkaloids. FDA indicated in the proposed rule that 10 to 73 percent of reported adverse events might not be related to consumption of dietary supplements containing ephedrine alkaloids. FDA's support for its recommended limit on duration of use was also weak.

FDA's lack of documentation on which adverse events it classified as serious makes it difficult to determine the validity of FDA's estimates of the benefits that would arise from the proposed rule. In addition, FDA did not have specific criteria to determine which events should be considered serious and did not perform a reliability assessment to ascertain the validity of its estimates of serious events.

Adverse Event Reports Were Incomplete And Inconsistent.

Prior to the proposed rulemaking, FDA received 864 AERs on dietary supplements containing ephedrine alkaloids-more AERs than for any other single dietary supplement. However, the AERs that we examined often lacked important information, and the information that they did contain was sometimes inconsistent. These problems suggest that AERs should be used with caution, and their use can contribute to uncertainty in FDA's conclusions.

In examining a random sample of the AERs (92 out of 864 reports), we found that 39 percent lacked information on the amount of product consumed, 41 percent lacked information on the frequency with which the product was consumed, and 28 percent lacked information on the duration for which the product was consumed. A total of 45 percent of the AERs lacked information on either dose, frequency, or duration, and 24 percent lacked information on all three dimensions. Finally, 62 percent of the AERs in our sample did not contain medical records, which are important in determining potential underlying conditions that might have caused the adverse event (rather than assuming ingestion of dietary supplements containing ephedrine alkaloids caused the event).

We also found cases where the amount of product consumed or the duration for which it was consumed was listed differently in multiple locations within an AER. In addition, the name of the product consumed sometimes varied within an AER. As a result, it is difficult to identify the FDA Relied Solely on AERs for Setting Specific Dosing Regimens and Did Not Determine If These Events Were Caused by Ephedrine Alkaloids correct information that corresponds to the event being reported and to make inferences from such reports.²⁷

FDA Relied Solely On AERs For Setting Specific Dosing Regimens And Did Not Determine If These Events Were Caused By Ephedrine Alkaloids.

In its proposed rule, FDA concluded that one possible strategy for addressing these adverse events was to restrict the level of ephedrine alkaloids in dietary supplements. To determine a possible dosing level, FDA reviewed clinical trials on therapeutic uses for ephedrine alkaloids used alone and in combination with other pharmaceutical substances to treat obesity. These trials indicated that 20 mg ephedrine alkaloids per dose could cause adverse events to occur in the subjects taking part in the clinical trial.28 Thus, FDA concluded that 20 mg per serving of ephedrine alkaloids presented potential risks for some individuals.

However, the studies did not provide information on risk at levels below 20 mg per serving for use in the general population, and lean or moderately overweight persons have been shown to be more sensitive to substances like ephedrine alkaloids than are obese individuals. To determine if serious adverse events were occurring at levels below 20 mg per serving, FDA obtained and tested the dietary supplement products associated with AERs that were serious, where available.²⁹ FDA then identified the levels of ephedrine alkaloids in those AERs by performing laboratory analyses of ephedrine alkaloid levels for dietary supplements turned over to the agency by the consumers who suffered adverse events (consumer samples). FDA also performed tests on samples obtained from the marketplace for situations in which the consumer experiencing the adverse event no longer possessed the product (consumer-related samples). In all, from more than 800 AERs submitted to the agency between 1993 and the time of the proposed rule, FDA collected and tested 34 samples of consumer or consumer-related products.

From the 34 samples tested, 13 product samples met two criteria: the results of the analytical tests were valid and supportable and the products contained less than 20 mg of ephedrine alkaloids. FDA then set a specific dosing level of 8 mg per serving. In other words, FDA relied on these 13 AERs where the products tested yielded ephedrine alkaloid levels below 20 mg per serving as the sole source of support for the specific dosing level found in the proposed rule.³⁰ Table 1 provides information on these 13 cases. [Note: table not included in this overview]

While FDA used these 13 AERs to set a dosing level, the agency did not perform a causal analysis to determine whether the reported events were, in fact, caused by the ingestion of dietary supplements containing ephedrine alkaloids. Our review of these 13 AERs found numerous problems that raise questions about the causal relationship between ingestion of the implicated product and the adverse events observed. For example,

• three AERs included physician reports that stated the cause of the event was not related to a dietary supplement;
• one consumer-related sample was obtained and tested 2 years after the initial event, and possible reformulations of the product might have resulted in different levels of ephedrine than the product implicated in the reported adverse event;
• three individuals reporting adverse events had experienced similar problems prior to or well after using the dietary supplement; o one individual who experienced the event was eating only one meal a day; and
• one AER contained no medical records.

Some of the 13 AERs had more than one of these problems. As a result, there are uncertainties in FDA's conclusions in setting a specific dosing limit since this limit was based on a small number of adverse events-events which may or may not have been a result of ingestion of dietary supplements containing ephedrine alkaloids.

Weak Support For FDA's Proposed Limitation On Duration Of Use.

In its proposed rule, FDA also recommended a 7-day limit on the use of Proposed Limitation on dietary supplements containing ephedrine alkaloids. FDA used the Duration of Use recommendations of some members from its special work group and Food Advisory Committee, scientific literature, and data from the AERs to support this limit. However, we found several weaknesses in FDA's evidence.

First, FDA did not present scientific evidence specifically pointing to an increase in adverse events beginning at 7 days and under normal use conditions. Rather, the scientific information FDA used to support a 7-day limit outlined problems associated with extended use (months and years) of ephedrine alkaloids. The agency also cited support for its 7-day limit from studies involving other sympathomimetic agents, such as cocaine and methamphetamines, but these studies also involved long-term use of the drug. Second, FDA did not demonstrate a causal relationship between ingestion of dietary supplements containing ephedrine alkaloids and adverse events reported to the agency. Since FDA indicated in the proposed rule that 10 to 73 percent of the reported adverse events might not be related to consumption of dietary supplements containing ephedrine alkaloids, the use of the AERs to describe a pattern of response across time is questionable.³¹ Finally, the agency did not demonstrate the relationship between both dose levels and frequency of ingestion and duration of use. As a result, there are uncertainties in the agency's analysis of the relationship between duration of use of dietary supplements containing ephedrine alkaloids and the occurrence of adverse events.

FDA Based Its Risk Reduction Value On Poorly Documented Estimates Of Serious Adverse Events.

FDA noted in the proposed rule that there were an average of 174 adverse events reported each year between January 1993 and June 1996 and that 81 were serious events. FDA divided the serious adverse events into five categories and outlined examples for each type:

1. cardiovascular (dysrhythmia or abnormal heart rhythms, severe hypertension, cardiac arrest, heart attack, angina, myocardial infarction, stroke, and cardiomyopathy or muscle damage to heart);
2. central nervous system (psychosis, suicide or attempted suicide, altered or loss of consciousness or disorientation or confusion, seizure, mania, and severe depression);
3. liver damage or hepatitis; (4) death; and (5) other events (vestibular orinner ear disturbances, altered serum enzymes, myopathies or muscle disease, genitourinary system disturbances or urinary tract problems, prostate problems, and dermatological syndromes or rashes).

However, FDA did not record which AERs it considered to be serious. FDA officials stated that a count had been performed by medical doctors of the agency on the number of serious events, but there was no record of the specific cases that they had identified as serious events. In addition, rather than providing AER reviewers a standard definition, FDA told them to use their clinical judgment in determining what they considered a serious event.³² Also, FDA did not perform any assessments of interrater reliability among reviewers to ensure that their judgments were consistent.

Based on the yearly average of serious adverse events reported to FDA from January 1993 to June 1996, FDA estimated an annual value of risk reduction that would occur as a result of the proposed actions outlined in the rule. However, because FDA did not record which AERs were deemed serious, we could not determine the accuracy of FDA's conclusions regarding the actual benefits that would arise from the proposed rule.

FDA's analysis of imports generally adhered to rulemaking requirements but was not fully transparent.

FDA generally complied with executive order and statutory requirements for rulemaking. It prepared a cost-benefit analysis containing the basic elements expected for an economically significant rule under E.O. 12866. It also prepared an initial regulatory flexibility analysis and provided opportunities for small businesses to participate in the rulemaking process, as required by RFA. FDA's analysis of impacts would also likely satisfy most, if not all, of the analytical requirements of UMRA, although its proposed rule does not appear to trigger these requirements.

However, OIRA's guidance on preparing cost-benefit analyses under E.O. 12866 states that an agency's analysis must be "transparent"-that is, disclose how the analyses were conducted and what assumptions were used. FDA's analysis was only partially transparent. Although FDA described its key assumptions and identified substantial uncertainties regarding the data supporting its proposed rule, it did not fully disclose why certain key assumptions were made, the degree of uncertainty involved in those assumptions, or that alternative assumptions would have had a dramatic effect on the agency's estimates of the costs and benefits of the proposed regulatory actions. Because of these uncertainties and limitations, the results of FDA's analysis are still open to question.

FDA's Analysis Addressed the Basic Cost-Benefit Elements but Was Only Partially Transparent

Under E.O. 12866, agencies are required to conduct cost-benefit analyses for all regulatory actions that are likely to result in a $100 million annual effect on the economy or are otherwise economically significant. OIRA's "best practices" guidance states that a federal agency's cost-benefit analysis should contain three basic elements: (1) a statement of the need for the proposed action, (2) an examination of alternative approaches, and (3) an analysis of benefits and costs. Although the guidance provides forflexibility and professional judgment in conducting the analysis, it establishes a clear expectation that the analysis of the risks, benefits, and costs associated with the regulation "must be guided by the principles of full disclosure and transparency." For example, the guidance says the analysis should identify and explain the data or studies on which the estimates of benefits and costs are based "with enough detail to permit independent assessment and verification of the results." The guidance also states "where benefit or cost estimates are heavily dependent on certain assumptions, it is essential to make those assumptions explicit and, where alternative assumptions are plausible, to carry out sensitivity analyses based on the alternative assumptions."³³ (See app. IV for a more detailed discussion of the analytical requirements under E.O. 12866 and related guidance, as well as our assessment of FDA's cost-benefit analysis in terms of that guidance.)

FDA's cost-benefit analysis contained the three basic elements stipulated in the guidance, but certain other specific elements in the guidance appear to be lacking:

• With regard to the first element, FDA stated that the proposed rule was needed because of a significant market failure-specifically, inadequate consumer information on the health risks associated with dietary supplements containing ephedrine alkaloids. However, the OIRA guidance indicates that even where a market failure exists, agencies should also discuss the appropriateness of alternatives to federal regulation, such as state or local regulation. FDA's analysis did not recognize efforts in several states to regulate these products or say why federal regulation was a better approach.

• For the second element, FDA discussed seven regulatory options, including 1) a baseline alternative of taking no action, (2) taking no action but generating additional information, (3) taking the proposed action, 4) taking the proposed action but allowing a higher potency limit for the supplements, (5) banning dietary supplements that contain ephedrine alkaloids, (6) taking the proposed action but not requiring the warning statement, and (7) requiring only the warning statement. FDA also generally discussed the agency's reasoning for selecting the proposed regulation over other alternatives. However, FDA's options primarily focused on alternative levels of stringency and informational measures-not on other basic types of regulatory alternatives suggested in the guidance. Also, while FDA included some contextual information in the proposed rule, it did not provide a complete picture of the baseline risks that may be associated with supplements containing ephedrine alkaloids.

• For the actual analysis of potential benefits and costs-the third element-FDA generally adhered to the principles and specific recommendations in OIRA's guidance. For example, FDA discussed the distributional effects of the proposed rule and alternatives in terms of lost sales to the dietary supplement industry. FDA also identified nonmonetized costs associated with the proposed rule. However, FDA did not provide monetized or quantified benefit or cost estimates for all of its regulatory alternatives, and the agency's discussion of those alternatives' benefits and costs were compared to the proposed rule-not the baseline condition of no regulation as recommended by the guidance.

The OIRA guidance also stresses the importance of full disclosure and transparency in agencies' cost-benefit analyses. We assessed the transparency of FDA's cost-benefit analysis of the proposed rule using three criteria suggested by the guidance:

• first, whether it identified the data, models, inferences, and assumptions used to calculate the estimates of benefits and costs;
• second, whether it disclosed the reasons why those data, models, inferences, and assumptions were selected; and
• third, whether it assessed the effects of plausible alternative assumptions and choices on the results of the analysis-what is often referred to as a "sensitivity analysis."

Overall, we concluded that FDA's analysis was only partially transparent. Using the first criterion, FDA's analysis was very transparent. The agency provided a clear and lengthy description of the data, assumptions, and methodology that it used to calculate the benefits and costs of the proposed rule. Against the second criterion, FDA's analysis was only partially transparent. For most elements of the analysis, FDA identified the underlying data sources used and the rationale for the assumptions and conclusions reached by FDA's analysts and experts. However, FDA did not fully disclose the underpinnings of all of its assumptions and choices. For example, FDA said that between 27 percent and 90 percent of adverse event reports were "probably" related to the consumption of dietary supplements suspected of containing ephedrine alkaloids and that it assumed the value was 80 percent, but it did not indicate why it made this point-estimate assumption. In response to our questions, FDA officials acknowledged that their analysis of impacts was not as transparent as it should have been in explaining how the agency arrived at some of the assumptions regarding its treatment of uncertainty in the underlying data.

Against the third criterion, FDA's cost-benefit analysis was also only somewhat transparent. For example, FDA estimated that the benefits of the proposed rule would be between $240 million and $670 million per year. That estimate was driven by three factors: (1) FDA's estimate of the actual number of adverse events each year (1,110), (2) FDA's estimate of the degree to which the proposed rule would reduce these events (35 percent to 100 percent across all types of proposed actions), and (3) the values FDA assigned to the estimated risk reduction per case (for example, $5 million per death avoided).³⁴ Changes in any of these values could have dramatically changed FDA's estimates of the proposed rule's benefits.

For example, FDA's estimate of 1,110 adverse events each year was based on an average of 174 adverse events reported per year and three assumptions: (1) that 80 percent of the adverse event reports involved consumption of dietary supplements suspected of containing ephedrine alkaloids, (2) that 80 percent of the supplements actually contained ephedrine alkaloids, and (3) that only 10 percent of all adverse events related to supplements containing ephedrine alkaloids were reported. Using these point estimates (instead of ranges) does not reflect the uncertainty FDA indicated was possible regarding these values and, therefore, the uncertainty associated with the agency's final benefit estimates.

Had FDA used its own initial estimates of the possible ranges (instead of the 80-percent point estimates) for the first two assumptions (27 to 90 percent for the first assumption and 25 to 90 percent for the second assumption), its estimate of the number of adverse events each year would have been 117 to 1,409 instead of a single estimate of 1,110. (See table 2.) If FDA's projected effects for the proposed actions were applied to this range, the expected reduction in annual adverse events would be between 41 and 1,409 cases per year (not the 390 to 1,110 in the published analysis).

This ultimately results in a range of potential benefits of roughly $25 million to $850 million per year-a much wider range of possible benefits than the $240 million to $670 million per year estimates that FDA included in the proposed rule. [Note: Table 2 was not included in this overview.] Table 2 also shows that changes in the third assumption yield similarly dramatic changes in the estimated benefits. FDA indicated in its proposed rule that reporting rates might be higher than 10 percent if, for example, the potential health risks were widely publicized, or lower than 10 percent if consumers and physicians assumed that dietary supplements are incapable of producing adverse events. If, keeping all other factors constant, FDA had assumed that 20 percent of serious adverse events were reported, FDA's benefits estimate would have been reduced by about half. Conversely, if FDA had assumed that only 5 percent of events were being reported, the benefits estimate would have doubled.

FDA Met RFA Requirements Although Questions Remain Concerning Imports Or Indeglary.

RFA requires agencies to consider the effects of their rules on small entities and to take certain actions during the rulemaking process. For example, before publishing a proposed rule for which a notice of proposed rulemaking is required, sections 603 and 605(b) of RFA require a federal agency to prepare and make available for public comment an initial regulatory flexibility analysis that describes the anticipated effects of the proposed rules on small entities, unless the head of the agency certifies that the rule will not have a "significant economic impact on a substantial number of small entities." (See app. V for a more detailed discussion of RFA requirements and our analysis of the actions FDA took to comply with RFA.)

FDA determined that its proposed rule on ephedrine alkaloids would have a significant economic impact on a substantial number of small entities and prepared an initial regulatory flexibility analysis to identify those impacts. FDA's proposed rule addressed the basic elements that RFA requires agencies to include in an initial regulatory flexibility analysis. For example, the rule describes the reasons the agency was considering the action, states the purpose and legal basis of the rule, describes and provides an estimate of the number of small entities to which FDA believed the rule would apply, and describes the compliance requirements. In addition to describing direct compliance costs of between $3 million and $80 million, FDA said that the proposed rule could have significant distributive effects in the form of reduced sales of as much as $230 million a year. FDA explicitly stated that costs and sales reductions of this magnitude might threaten the viability of many firms. FDA also discussed significant regulatory alternatives in the rule's regulatory flexibility analysis section, noting that most of the regulatory alternatives discussed in the cost-benefit analysis section would reduce the impact of the rule on small businesses.

When a rule is promulgated that will have a significant economic impact on a substantial number of small entities, section 609(a) of RFA further requires agencies to ensure that small entities have been given an opportunity to participate in the rulemaking process through the "reasonable use" of outreach efforts. Our review of the regulatory docket for this rulemaking, as well as information obtained during interviews with dietary supplement industry representatives, indicated that FDA provided opportunities for small business participation during this rulemaking process. For example, in addition to the proposed rule itself, FDA published public notices; held public meetings, during which industry representatives participated and provided testimony; and collected written comments on the issue. Representatives of industry trade associations also told us that FDA had placed notices about the proposed rule in trade literature.

However, SBA's Office of Advocacy criticized the quality of FDA's regulatory flexibility analysis. Along with generally criticizing FDA's scientific analysis for the proposed rule, the office contended that FDA did not consider the large numbers of independent distributors of dietary supplements in its analysis and, as a result, underestimated the number of affected small businesses and the impacts of the proposed actions. In response to SBA's criticism, FDA officials told us that the agency did not need to consider the impact of its proposed rule on distributors of ephedrine alkaloids. FDA officials cited several court decisions that support the proposition that, under RFA, an agency is under no obligation to conduct a small entity impact analysis of effects on entities that the agency does not regulate-that is, distributors.³⁵

None of the major parties-FDA, SBA's Office of Advocacy, or industry associations-have information on the actual number of entities involved in the market for dietary supplements containing ephedrine alkaloids. All three parties acknowledge this as a limitation in attempts to analyze the effects of the proposed rule. According to FDA, it has no authority to require companies in the dietary supplement industry either to register with or contact the agency unless they are seeking approval to make a claim in product labeling. However, the industry representatives we met with confirmed that manufacturing and labeling of these products are generally limited to a relatively small number of manufacturing firms. Such firms would bear almost all of the direct expenditures required for compliance with the proposed rule. SBA's Office of Advocacy recommended that FDA develop an outreach strategy to obtain more reliable industry data, and FDA officials said that they have contracted for a marketing study of the dietary supplement industry that should provide better information for future FDA analyses.

Proposed Rule Does Not Appear To Trigger UMRA Requirements.

UMRA generally requires covered agencies to prepare specific types of analyses for certain rules that include a federal mandate and that may result in the expenditure in any 1 year of $100 million or more by the private sector.36 FDA did not explicitly address UMRA in its proposed rule on ephedrine alkaloids because its economic analysis indicated that direct expenditures imposed on the private sector would not rise to the level requiring additional analysis under UMRA. FDA estimated that the total compliance costs for the proposed action would be between $3 million and $80 million, with, at most, $70 million of those costs in the first year of implementation. Although FDA also estimated that the rule might result in lost sales for the dietary supplement industry of as much as $230 million per year, lost sales cannot be considered direct expenditures by the private sector and, therefore, cannot be used to trigger UMRA's analytical requirements. (See app. VI for a more detailed discussion of UMRA requirements and our analysis of FDA's compliance.)

However, SBA's Office of Advocacy contended that FDA overlooked the UMRA requirements and commented that if the agency had properly estimated the number of affected businesses and the costs that would be imposed on those entities, "it would have been apparent that the economic impact of the instant rule would impose in excess of $100 million in costs to the industry," triggering UMRA requirements. However, the Office of Advocacy does not have data on the number of entities involved in the market for dietary supplements containing ephedrine alkaloids that it believes should have been included in FDA's analysis. Therefore, the Office of Advocacy could not demonstrate that FDA had underestimated the number of manufacturers that would be affected by the relabeling and reformulation requirements in the rule or that FDA's cost estimates for those manufacturers were in error. Furthermore, even if the expenditures associated with the proposed rule had triggered UMRA's analytical requirements, FDA appears to have satisfied most, if not all, of those requirements. For example, FDA quantitatively and qualitatively assessed the anticipated costs and benefits of the rule. FDA also identified and considered a number of regulatory alternatives, indicating that the other alternatives would not be as effective as the proposed rule.

Conclusions

FDA was justified in determining that the number of AERs relating to dietary supplements containing ephedrine alkaloids warranted their attention and consideration of steps to address safety concerns. The available scientific information suggests that the use of products containing synthetic ephedrine alkaloids can result in adverse experiences for some individuals, and over-the-counter products containing ephedrine alkaloids have dosing recommendations. Furthermore, dietary supplement trade associations have suggested specific dosing limits for dietary supplements containing ephedrine alkaloids.

However, while FDA's conclusions regarding the desirability of the proposed actions may be valid, we believe these conclusions are open to question because of limitations and uncertainties associated with the agency's underlying scientific and economic analyses. We have concerns about the strength of the information upon which FDA based specific elements of its proposed rule. There is no scientific information on the specific dosing levels and duration limits proposed. FDA, therefore, relied heavily on its AERs to determine a dosing regimen and to outline benefits that would accrue from the proposed rule. However, the AERs suffer from several problems that weaken the conclusions drawn by FDA for their specific dosing regimen; the number of AERs used to support the dosing regimen is small, their quality is questionable, and FDA did not establish a causal link between the ingestion of ephedrine alkaloids and the occurrence of particular adverse events. Finally, because FDA did not document which AERs it identified as involving serious adverse events, it is impossible to verify FDA's calculation of the number of these events and the accuracy of the benefits that FDA estimated would occur as a result of the proposed rule.

FDA's analysis contained the basic elements expected in a federal agency's cost-benefit analysis, and the proposed rule complied with rulemaking requirements under RFA. The proposed rule does not appear to trigger the UMRA analytical requirements. However, FDA's cost-benefit analysis was not always transparent regarding why certain key assumptions were made, the degree of uncertainty involved in those assumptions, or the effect that alternative assumptions would have had on the agency's estimates of the costs and benefits of the proposed action.

Recommendations

Given the uncertainties in the information upon which FDA based its proposed rule, we recommend that the Secretary of Health and Human Services direct the Commissioner of FDA to obtain additional information to support conclusions regarding the specific requirements in the proposed rule for dietary supplements containing ephedrine alkaloids before proceeding to final rulemaking. Specifically, FDA needs to provide stronger evidence on the relationship between the intake of dietary supplements containing ephedrine alkaloids and the occurrence of adverse reactions that support the proposed dosing levels and duration of use limits. We also recommend that the Secretary direct the Commissioner to improve the transparency of FDA's cost-benefit analysis in its final rulemaking. Specifically, FDA should more fully explain the bases of its cost-benefit assumptions, the degree of uncertainty associated with those assumptions, and the implications of plausible alternative assumptions to the proposed action and other regulatory alternatives.

We sent a draft of this report to the Commissioner of FDA, the Administrator of SBA, and the Director of OMB. FDA and SBA's Office of Advocacy provided written comments, which are reprinted in appendixes VII and VIII; OMB did not have comments on the report.

In its comments, FDA concurred with our recommendation that it obtain additional information to support its conclusions on specific requirements relating to dietary supplements containing ephedrine alkaloids before proceeding to final rulemaking. FDA also concurred with our recommendation to improve the transparency of the agency's cost-benefit analysis, noting that it intends to take appropriate steps to correct the deficiencies of the analysis prior to publication of a final rule. However, FDA was concerned that our report (1) did not sufficiently highlight the agency's justification in examining safety concerns related to dietary supplements containing ephedrine alkaloids, (2) implied that FDA relied principally on AERs to develop the proposed rule, (3) overemphasized the agency's failure to conduct a causal analysis linking dietary supplements containing ephedrine alkaloids to the AERs, and (4) was not clear on whether it was appropriate to use AERs in rulemaking. Throughout our report, we express the clear view that given the number and type of AERs, it was reasonable for FDA to investigate the safety of the supplements. We also acknowledge that FDA's actions were based on information from scientific literature as well as AERs. However, although clinical trials suggest that adverse events could occur in some individuals using ephedrine alkaloids at levels approaching 20 mg per serving, they did not provide information relating to adverse events below the 20 mg level. Therefore, to conclude that an 8 mg per serving level would be appropriate, FDA turned to results of tests it performed on a small number of products implicated in 13 AERs. In other words, information from these AERs was the sole source of support for the specific dosing level of 8 mg per serving that FDA proposed. Finally, we continue to hold the view that without a causal link between the AERs and the ingestion of products containing ephedrine alkaloids, the exclusive use of AERs to support a specific dosing regimen is questionable. FDA also asked that we clarify that using AERs to develop a proposed rule of this type is neither inappropriate nor unscientific. For this report, we examined whether the use of AERs in the proposed rule on dietary supplements containing ephedrine alkaloids was consistent with the use of AERs in prior rulemaking; however, we did not take a position on the appropriateness of the general use of AERs in rulemaking.

SBA's Office of Advocacy stated that our recommendations are reasonable and would result in a more rational-and possibly less burdensome- regulation. However, the officials questioned how we could conclude that FDA had complied with RFA while at the same time suggesting that the agency had prepared an "inadequate analysis" by using unreliable data and not clearly demonstrating that the benefits of the proposed rule exceed the cost. Although our report raises concerns about several aspects of FDA's analysis, we did not conclude that FDA prepared an inadequate analysis. Rather, we concluded that FDA's proposed rule contained the primary elements required under E.O. 12866 for a cost-benefit analysis and under RFA for an initial regulatory flexibility analysis. Furthermore, RFA contains no standards or criteria that define an "adequate" regulatory flexibility analysis. As noted in SBA's comments, section 607 of RFA notes that agencies may provide "general descriptive statements" to comply with the act's analytical requirements if quantification is not practicable or reliable. Determining whether a regulatory flexibility analysis was in compliance with RFA would require analysis and judgments concerning the totality of the circumstances relating to the specific regulation in question. We have no basis and are not in a position to make such a determination regarding the quality of FDA's analysis, nor does our report do so.

SBA's Office of Advocacy also expressed its concern that FDA's analysis did not identify the indirect effects of the rule on distributors. Office of Advocacy officials said that, although certain court decisions stemming from Mid-Tex Electric Cooperative, Inc. v. FERC37 indicated that agencies need not prepare regulatory flexibility analyses if the effects of a rule on an industry are indirect, they disagreed with those interpretations and contended that agencies should be required to conduct analyses of indirect effects. They also stated that the Office of Advocacy was unaware of any comparable case law with respect to direct and indirect effects as they apply to E.O. 12866, so they said FDA should have prepared an analysis of the rule's effects on distributors. We disagree with these comments for three reasons. First, as the Office of Advocacy officials acknowledged, prior case law indicates that agencies need not take the indirect effects of their rules into account when conducting a regulatory flexibility analysis. That interpretation was recently reaffirmed in a May 14, 1999, decision by the U.S. Court of Appeals for the District of Columbia Circuit.38 Second, the absence of case law comparable to Mid-Tex with respect to direct and indirect effects as they apply to E.O. 12866 says nothing about FDA's analytical obligations under the order. Third, our review shows that FDA did address the potential indirect effects of the rule through its estimates of total lost sales for the dietary supplement industry. FDA also explicitly acknowledged in the proposed rule that such lost sales are "obviously very significant to the affected parties" and might threaten the viability of many firms in this industry.

We also obtained comments on a draft of this report from a professor of pharmacology with expertise on dietary supplements. He agreed that while there is adequate reason for FDA to be concerned about the safety of products containing ephedrine alkaloids, he believed that there are too few AERs of substantive quality to allow for the setting of a maximum safe dose. He also concurred with our conclusions and recommendations. FDA provided technical comments, which we incorporated as appropriate.

As agreed with your office, unless you publicly announce its contents earlier, we plan no further distribution of this report until 30 days from the date of this letter. At that time, we will send copies to the Honorable Donna E. Shalala, Secretary of Health and Human Services; the Honorable Jane E. Henney, Commissioner of FDA; the Honorable Aida Alvarez, Administrator of SBA; the Honorable Jacob J. Lew, Director of OMB; and others who are interested. We will also provide copies to others upon request. GAO contacts and major contributors to this report are listed in appendix IX.