Office of Advocacy

February 3, 1998

Dockets Management Branch
HFA-305
Food and Drug Administration
12410 Parklawn Drive
Room 1-23
Rockville, MD 20857

Re: Initial Regulatory Flexibility Analysis of the Proposed Rule for Dietary Supplements Containing Ephedrine Alkaloids, 62 Fed. Reg. 30,678 (June 4, 1997); Docket No. 95N-0304 [PDF File]

Dear Dockets Management Clerk:

On June 4, 1997, the Food and Drug Administration (FDA) published a notice of proposed rulemaking concerning the regulation of dietary supplements containing ephedrine alkaloids (from botanical sources rather than pharmaceutical sources). Because of the holiday season and the Office of Advocacy's unexpected participation in pending litigation of agencies' compliance with the Regulatory Flexibility Act (RFA),(1) the Office of Advocacy was not able to file these important comments in a timely fashion.

Under the proposed regulation, a dietary supplement would be considered adulterated if it contains 8 milligrams or more of ephedrine alkaloids per serving, or 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. In addition, the new regulation would require that the label of dietary supplements that contain ephedrine alkaloids state the following: 1) "Do not use this product for more than 7 days" ; 2) "Taking more than the recommended serving may result in heart attack, stroke, seizure or death"; and 3) other specific warning statements. Finally, the proposed regulation would prohibit: 1) the use of ephedrine alkaloids with ingredients that contain substances like caffeine known to have a stimulant effect; and 2) labeling claims that require long-term intake to achieve the purported effect. This massive regulation is designed to address certain incidents of illness, injury and death purportedly associated with the use of dietary supplement products containing ephedrine alkaloids.

The Office of the Chief Counsel for Advocacy of the U.S. Small Business Administration was created in 1976 to represent the views and interests of small business in federal policy making activities.(2) The Chief Counsel participates in rulemakings when he deems it necessary to ensure proper representation of small business interests. In addition to these responsibilities, the Chief Counsel monitors compliance with the Regulatory Flexibility Act (RFA), and works with federal agencies to ensure that their rulemakings demonstrate an analysis of the impact that their decisions will have on small businesses.

In order to get to the argument of whether the FDA has complied with the RFA expeditiously, the Office of Advocacy will assume arguendo that FDA has the statutory authority to promulgate this rule.(3) Upon publishing in the Federal Register a proposed rule, §§ 603 and 605(b) of the RFA require that an agency head must either certify that a proposed rule will not have a significant economic impact on a substantial number of small entities, or prepare an initial regulatory flexibility analysis (IRFA). Having determined that the rule would have a significant economic impact, FDA correctly chose the option to perform an IRFA. However, as explained below, FDA has done an inadequate job of analyzing the impact of the regulation on small entities and in identifying and analyzing less burdensome alternatives. In addition, FDA committed several other procedural errors including failing to observe the notice and comment requirements of the Administrative Procedure Act (APA). 5 U.S.C. § 553.

I. Number of Entities Affected

• In order to determine the impact of any regulation, an agency must make a reasonable effort to identify the type and number of entities likely to be affected by the regulation. This process of learning about the regulated industry not only helps the agency determine whether to certify a rule for regulatory flexibility purposes, it also helps the agency develop an analysis of impacts and choose appropriate regulatory alternatives that minimize economic burden.
• In the instant case, those industries likely to be impacted include distributors (wholesalers and retailers) and manufacturers of ephedrine alkaloids. FDA estimates that there are between 200 and 5,000 products on the market containing ephedrine alkaloids,(4) and, at the end of the proposed rule, FDA estimates that only 80 small businesses will be impacted.(5) This is a curious number because the Office of Advocacy received 159 letters from small distributors likely to be impacted directly by the proposed regulation-double the number estimated by FDA. Surely, the letters received by the Office of Advocacy represent a mere fraction of the number actually impacted. The Office of Advocacy is also aware that many ephedra products are sold by tens of thousands of home-based distributorships that are part of multi-level marketing companies. Many of these businesses, although part of a larger parent company, may nevertheless be independently owned and operated and considered to be "small business concerns" under the Small Business Act.(6)
• FDA should develop an outreach strategy to obtain more reliable industry data. Industry trade associations are typically a good starting place. In fact, FDA is obligated under § 609(a) of the RFA to engage in outreach efforts to ensure small business participation in the rulemaking process. In other words, § 609 requires agencies to do more than publish a notice of proposed rulemaking in the Federal Register, and may include such strategies as direct notification of interested small entities.

II. Cost-Benefit Analysis

• The discussion below paints a clear picture of FDA's failure to comply with the RFA. The heart of the RFA is the requirement for an economic impact analysis to determine the impact on small businesses and the requirement for proposing and analyzing less burdensome regulatory alternatives and explicitly stating the reasons for accepting or rejecting the alternatives presented. When an agency relies on faulty data in its analysis-as in the instant case-the result is a flawed analysis with inflated benefits claims and underestimated industry costs.
• Based on the information gleaned directly from the docket and the proposed rule, and from the accounts of industry experts, the Office of Advocacy opines that the benefits of the instant proposed rule are much lower than FDA's estimates-by FDA's own admission, possibly even zero. Simply, FDA's data do not demonstrate the need for the regulation. Having acknowledged that the rule will have a significant economic impact on a substantial number of small entities, FDA had a duty to analyze accurately the impact of its proposal and design appropriate regulatory alternatives.

A. Scientific Evidence?

FDA cites as the reason for its proposed rule, "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." 62 Fed. Reg. at 30,678. FDA, however, relies on adverse event reports (AERs) to suffice as evidence of the need for the regulation.

First, by its own admission, FDA states that AERs are not a reliable source of data upon which to draw conclusions regarding the health effects of a particular substance. In the proposed rule, FDA acknowledges that:

"a possible source of serious error in evaluating observational data, such as that found in FDA's postmarketing surveillance system, is the potential for inappropriately assuming that a cause and effect relationship exists between a particular exposure and a particular adverse event without evaluating the true relationship of the adverse event to the exposure," and that "many of the AERs did not provide enough information to adequately evaluate . . . [causality]." 62 Fed. Reg. at 30,689-90.

In numerous other instances within the docket the agency cites the unreliability of AERs. For instance, Docket Vols. 190 and 263 which catalogue the AER reports contain certain disclaimers:

The evaluation of data in [a] passive surveillance reporting system . . . is limited by several recognized factors:

• Because reporting is voluntary, adverse events may occur which are not reported, and are therefore not in SN/AEMS [Office of Special Nutritionals Adverse Event Monitoring System]
• A single case may be reported more than once, inflating the number of reports in the system . . .
• There is no certainty that an adverse event can be attributed to a particular product, or ingredient in a product
• An event may be related to or modified by an underlying disease or condition, to other products which are taken concurrently, or the event may have occurred by chance at the same time the suspected product was taken
• Accumulated case reports cannot be used to calculate incidents or estimates of product risk. They must be carefully interpreted as reporting rates, and not as occurrence or incidence rates. The length of time that a product has been marketed, the market share, experience and sophistication of the population using the product or evaluation of the adverse event, publicity about an adverse reaction, and regulatory actions are all factors that influence the probability that an adverse event will be reported. Comparisons of product safety cannot be directly obtained from these data.

With regard to the last disclaimer on accumulated case reports cited above, FDA ignores its own warning. That is, FDA states that between 1993 and 1996 it received "a rapidly escalating number of AERs associated with the use of dietary supplements, some that contained ephedrine alkaloids, some that did not." 62 Fed. Reg. at 30,680. Based on this "analysis," the agency concludes that increased AERs translate to increased risk to the general population. FDA, however, does not attempt to offer any other explanation for increased reports. Increased exposure is not the same as increased risk. For instance, increases in the number of people using such products could be a factor in increased reports. FDA's flawed "analysis" is misleading for reasons already acknowledged by FDA, and for other common sense reasons outlined below.

FDA never establishes a baseline for its analysis. In other words, FDA does not provide any information on the percentage of individuals in whom the purported side effects would occur naturally or randomly. General symptoms like increased heart rate, elevated blood pressure, nervousness or insomnia may occur after drinking two cups of coffee, taking an over-the-counter (OTC) product like Dexatrim(7)or Actifed(8), listening to a screaming toddler on an airplane, or a bad day at work. It would be easier to establish a causal relationship, for instance, if a higher than normal percentage of the population developed less common symptoms or diseases like Creutzfeldt-Jakob disease (a human variant of "mad cow disease") after consuming contaminated beef.

Also, the AERs contained in volumes 190 and 263 of the docket are inherently inconclusive and lacking in vital data, and no reasonable person could draw any conclusion regarding causality from the information provided-especially the conclusion that ephedrine alkaloids were the cause of the reported illness. There is no way to truly determine, for instance whether a particular reaction, if in fact caused by a dietary supplement, was due to a deliberate overdose or preexisting medical condition. Based on information assembled by the industry (at great expense and effort), out of 920 reports(9), 662 (approximately 72%) of the AERs lack medical records, and over 123 (approximately 13%) AERs list products for which there is no indication that the product contains any ephedrine alkaloids. In total, the industry experts cited 784 (approximately 85%) AERs that were lacking vital data.(10)

In addition to the lack of data in the AER reports, industry experts who carefully reviewed each AER in the docket discovered some astonishingly peculiar and irrelevant information. The experts found cases where adverse events occurred absent the use of an ephedra product, cases where no adverse effect was listed, events medically unrelated to ephedrine ingestion, and other bizarre reports like a case where a patient became pregnant though using an implanted birth control device.(11) These reports have no rational relationship to the safety or efficacy of ephedrine alkaloid products. If the industry accounts of the AERs are accurate, then the Office of Advocacy can only conclude that FDA never checked or approved the individual reports prior to their inclusion in the docket. In any event, the industry experts concluded that there were "no deaths or serious injuries from consumption of ma huang at levels approaching 25 mg per serving taken four times per day, even for prolonged periods."(12)

Finally, the data and/or studies primarily relied upon by the agency deal with the pharmaceutical equivalent of ma huang (botanical ephedra). FDA states:

the agency was not able to find definitive evidence to evaluate whether ephedrine alkaloids from botanical sources are metabolized differently than those from pharmaceutical sources, and in the absence of more directly relevant data for dietary supplement products, the agency considered it appropriate to rely on evidence from pharmaceutical sources of single ephedrine alkaloids in assessing the effects of botanical sources. 62 Fed. Reg. at 30,682.

There is an inappropriate leap of logic involved in assuming that botanical sources (ma huang) containing mixtures of ephedrine alkaloids are the same as a single ephedrine alkaloid found in pharmaceutical derivations. There is no evidence, for instance, that botanical and pharmaceutical derivations have the same potency or that they are metabolized in the body the same way.

B. Methodology of FDA's Analysis

Assuming FDA's data were accurate, the agency again departs from requirements of the RFA by failing to explain fully the process of its analysis of benefits. Specifically, the agency's claims regarding lives saved and the elimination of serious injuries are unsubstantiated. Table 6 is used to summarize estimated benefits in terms of risk reduction.(13)

In Table 6, titled, Estimated Value of Annual Risk Reduction From Proposed Actions, FDA lists six columns: 1) Type of adverse event 2) Annual reported cases, 3) Estimated annual cases, 4) Reduction in estimated annual cases, 5) Value of estimated risk reduction per case ($ thousands), and 6) Value of estimated risk reduction ($ millions). The totals for each column are based on the combined number of deaths, serious cardiovascular system events, etc. as they relate to each column.

• The source of the data for annual reported cases in column two is not apparent. FDA states that the annual reported cases are based on the average number of adverse event reports per year between January 1993 and June 1996. The total for this column is 174. If FDA is relying on the misleading and incomplete AERs appearing in the docket, the total for this column should be much lower-maybe even zero. If FDA is relying on some other data source, then that source should be revealed.
• The estimated annual cases in column three-1,110-are based on a number of peculiar assumptions. The agency assumes that 80% of the AERs involving the consumption of dietary supplements suspected of containing ephedrine alkaloids are actually related to the consumption of dietary supplements, that 80% of the supplements involved in the AERs that are related to the consumption of supplements actually contain ephedrine alkaloids,(14) and 10% of adverse events to the dietary supplements are reported. The agency, however, admits that "considerable uncertainty exists with respect to the validity of the assumptions on which this estimate is based." 62 Fed. Reg. at 30,708. FDA provides no information regarding the basis of their assumptions.
• The values of estimated risk reduction per case in column five are based on 1988 data that estimates the value consumers place on reducing risk of: 1) acute CNS and liver or kidney changes, 2) chronic CNS system impairment, and 3) heart disease and stroke. The dollar values were then converted from 1988 to 1996 consumer indices. The values consumers place on reduced risk per case is irrelevant if the risk does not exist. In other words, if there is no proven risk, then there is no risk to reduce and there is no benefit. The same is true for the figures in column six-value of estimated risk reduction-since they rely on the data in columns four and five. Moreover, if column two (which relies on false, misleading and confusing AERs) totals zero, then so does column six.

In the instant case, the faulty data, inappropriate data assumptions, and other serious errors all contributed to the faulty analysis-an analysis that overestimates the benefits and undermines the entire rulemaking.

C. Intake Restrictions

FDA proposes dosage limits by restricting the per serving amount and frequency, and also proposes limits on the duration of use. The agency proposes that 8 mg be the maximum serving/dose for dietary supplements.(15) Products with higher dosage amounts will be considered adulterated under the proposal. However, there is no research or data to support any of the proposed restrictions.

FDA relies on a study of ephedrine in 20 mg per serving dosages to support its 8 mg restriction, but there is a fourfold problem inherent in relying on this data. First, the study does not involve botanical sources of ephedrine alkaloids. Second, the agency does not adequately address how it concluded that 8 mg was an appropriate amount when the study relied on 20 mg dosages. Third, the 20 mg study did not apply to the general population, but to the morbidly obese-who are generally at higher risk for health problems. Fourth, the 20 mg study dealt with testing the effectiveness of the dosage and not its safety.

FDA then tries to buttress its 8 mg dosage requirement by referencing postmarketing surveillance data. The agency "[analyzed] the ephedrine alkaloid levels in the small number of available dietary supplement products that consumers who suffered adverse events turned over to the agency."(16) The levels were found to range from 1 to 50 mg per serving. This information does not necessarily support the agency's proposition that doses exceeding 8 mg are harmful because there is no way to know whether there were deliberate overdoses, whether consumers were taking products marketed as substitutes for illegal drugs, whether the reported reactions were related to some other cause, etc.

In addition, the agency admits that, "[g]iven the available evidence, it is difficult to ascertain whether there is a threshold level of ephedrine alkaloids below which the general population and susceptible individuals will not experience serious adverse events." (17)The agency goes on to say that, "[t]he evidence does not exist to establish a safe level."(18) It seems that the converse could also true based on the proposed rule as written. That is, a maximum safe level cannot be determined either. The data presented by the agency does not prove the need for any per serving restriction. In fact, FDA states that "all that can be said concerning the proposed potency limits is that they may reduce the expected number of adverse events by between zero to 80 percent."(19) If the FDA cannot demonstrate the lack of safety of a product, then, given the statutory burden of proof for dietary supplements, there is no basis to regulate the product.

Similar arguments can be made against FDA's proposed frequency and duration restrictions. The agency proposes a label statement prohibiting claims related to weight loss and concomitantly placing a 7-day limit on the use of ephedrine alkaloids with a maximum daily intake of 24 mg (three 8 mg doses per day). Many of the affected products are for weight loss and would exceed the proposed requirements-particularly the duration requirement. In fact, if a distributor stocks mainly weight loss supplements, then that distributor surely would go out of business because weight loss products must generally be taken for a longer period in order to be effective. To avoid unnecessary burden on the industry, thoughtful attention must be given regarding the basis for the duration requirement.

The agency states that its data shows that "long-term use of . . . ephedrine alkaloids, even at relatively low levels, is related to serious adverse events, including cardiomyopathy and myocardial necrosis."(20),(21) However, the presence of ephedrine alkaloids in the body is not dispositive of the fact that cardiomyopathy was the result. Reliance on AERs to prove cardiomyopathy is inappropriate because of he prevalence of the disease in the general population. According to the Montgomery Heart Foundation for Cardiomyophathy,(22) approximately one in 500 people carry an altered gene that can cause certain forms of the disease. Therefore, many who suffer or die from this disease, contracted it genetically. Others contract it through infection, endocrine disorders, metabolic disorders or other unknown causes. The agency has not identified any test or assay to prove dispositively that any reported incidents of cardiomyopathy truly are due to long-term use of ephedrine alkaloids. In fact, literature on the subject suggests that no such test exists.

D. Labeling Language

The proposed rule also contains provisions regarding new label requirements. The statement, "Do not use this product for more than 7 days,"(23) clearly would eliminate the product for use as a weight loss supplement as discussed earlier. However, as discussed above, no scientific evidence supports the statement. FDA's rationale for this statement is that weight loss claims, for instance, promote excessive consumption. However, it is not at all clear how weight loss claims can be differentiated from any other beneficial effect, or why beneficial effects automatically entice consumers to exceed the recommended dosage.

Similarly, the proposed "death" warning is unsubstantiated. The statement, "Taking more than the recommended serving may cause heart attack, stroke, seizure, or death," is at best, an over statement-at least based on the scientific evidence presented by FDA. In addition to the lack of scientific evidence, FDA's actions in the case of the death warning seem arbitrary and capricious because no such warning appears on over-the-counter (OTC) ephedrine products (pharmaceutical derivations). There is the appearance that FDA is arbitrarily singling out one industry for regulation.

If any label statement were to be required, the Office of Advocacy recommends label statements similar to those currently found on OTC ephedrine products.

III. Unfunded Mandates Act

• The agency apparently has also overlooked the requirements of the Unfunded Mandates Reform Act (UMRA)(24), which, as of 1995, applies not only to states, but also to private industry (including all sizes of businesses). UMRA, therefore, applies in the case of a federal private sector mandate where the aggregate estimated amounts that the private sector will be required to spend in one year in order to comply with the mandate exceeds $100 million. If the agency had performed an adequate analysis, 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.
• When UMRA applies, an agency must issue a written statement containing specific information and the agency shall also "identify and consider a reasonable number of regulatory alternatives and from those alternatives select the least costly, most cost-effective or least burdensome alternative that achieves the objectives of the rule."(25)
• Among other things, an agency's written statement must contain the following:
  a qualitative and quantitative assessment of the anticipated costs and benefits of the federal mandate, including the costs and benefits to the private sector, as well as the effect of the federal mandate on health, safety, and the natural environment;
  estimates by the agency, if and to the extent that the agency determines that accurate estimates are reasonably feasible, of the future compliance costs; and any disproportionate budgetary effects of the federal mandate upon any particular regions of the nation or particular segments of the private sector; and
  estimates by the agency of the effect on the national economy, such as the effect on productivity, economic growth, full employment, creation of productive jobs, and international competitiveness of U.S. goods and services.
• There was no such written statement in the instant rulemaking because the agency did not even identify Unfunded Mandates as an issue.
• The burden of achieving reduced economic impact for businesses subject to a regulation is higher in the case of UMRA than for the RFA. That is, the RFA requires only that agencies endeavor to reduce economic burden where possible by carefully analyzing and selecting less burdensome alternatives in the scheme of the agency's regulatory objectives. However, modifiers like "most" and "least" are used in describing the requirements of UMRA-the "least burdensome alternative", for example.
• It is the opinion of the Office of Advocacy that the instant rule is not the least costly, most cost-effective or least burdensome alternative for reasons previously expressed. In addition, the agency has not provided any explanation (as required by UMRA) as to why it has not complied with the requirements.

IV. Administrative Procedure Act

• The APA requires an agency to publish a notice of proposed rulemaking in the Federal Register and to provide the public with an opportunity to comment. 5 U.S.C. § 553. The notice and comment requirements of the APA serve three distinct purposes:
  [f]irst, notice improves the quality of agency rulemaking by ensuring that agency regulations will be "tested by exposure to diverse public comments: Second, notice and the opportunity to be heard are an essential component of "fairness to affected parties." Third, by giving affected parties an opportunity to develop evidence in the record to support their objections to a rule, notice enhances the quality of judicial review."
• Small Refiner Lead Phase-Down Task Force v. EPA, 705 F.2d 506, 547 (D.C. Cir. 1983) (citations omitted). Most importantly, the notice must "provide sufficient detail and rationale for the rule to permit interested parties to participate meaningfully." Horsehead Resource Dev. Co. v. Browner, 16 F.3d 1246, 1268 (D.C. Cir. 1994), cert. denied, 115 S. Ct. 72 (1994). Furthermore, an agency:
  must describe the range of alternatives being considered with reasonable specificity. Otherwise, interested parties will not know what to comment on, and notice will not lead to better-informed agency decision-making. Id. at 1268.
• In this case, FDA failed to establish a record upon which the public and affected entities could comment. There simply is not enough relevant information or data in the instant rulemaking for there to be adequate notice to the public regarding the likely impact of the regulation.
• Moreover, the method in which the record was updated and corrected placed a great burden on those entities attempting to decipher the administrative record on file at the agency.(26) Although the comment period was extended while adjustments were made to the record, the new materials apparently were lumped together with the original documents making it impossible to determine which materials were new. It was necessary, therefore, to undergo the expensive and time consuming task of reviewing the entire record to find the new information.

V. Other Alternatives

• FDA proposes implementation of the rule 180 days after publication of the final rule.(27) This seems unreasonable. The agency did not consider any alternative length of time for implementation. FDA does reference the fact that businesses were given 18 months to comply with the regulation for nutrition labeling of dietary supplements,(28) but did not explain why 6 months was an adequate period of time in the instant case.
• FDA should extend the length of time for compliance. The time required for reformulation of many products and printing new labels may be considerable and should be a major consideration. The Office of Advocacy suggests a period of not less than one year, but we defer the to the judgment and expertise of the industry if they determine that a period longer than one year is needed to comply.

VI. Conclusion

• Under no circumstances would the Office of Advocacy support any business, small or otherwise, that produces or sells misbranded or adulterated products to consumers. However, it is not clear why this rule will accomplish more than adequately enforced laws already in existence. Currently, unsafe or adulterated products that harm consumers may be seized or removed from the stores under FDA's existing authority. Moreover, false claims in advertising can be addressed on a case-by-case basis by the Federal Trade Commission. These alternatives warrant greater analysis.
• The Office of Advocacy realizes that industry data and conclusions regarding this or any other proposed rule many be somewhat skewed or self serving, but the information provided by the industry in this instance is so compelling and so different from the information provided by FDA, that the agency needs to address these serious concerns before publishing a final rule. FDA can accomplish this only through better data and more science-based analysis.
• The agency's claims regarding market failure and adverse event reports have no basis in science. Similarly, the dosage restrictions in the instant case have no scientific basis and practically prohibit small entity participation in free market competition. Without more specific scientific evidence and analysis, to require anything more than label warnings about possible reactions or drug interactions would likely be in violation of the Regulatory Flexibility Act, the Administrative Procedure Act, the Unfunded Mandates Act and Executive Order 12,866.

Sincerely,

Jere W. Glover
Chief Counsel for Advocacy

Shawne Carter McGibbon
Asst. Chief Counsel for Advocacy

Appendix B

Type of event	Annual reported cases	Estimated annual cases	Reduction in estimated an- nual cases	Value of estimated risk reduction per case ($ thou- sands)	Value of estimated risk reduction ($ millions)
Death	6	40	10-40	5,000	70-190
Serious CVS	27	170	60-170	837	50-140
Serious NS	29	190	70-190	1,483	100-280
Ab. Liver function	7	50	20-50	3	0
Other serious	12	80	30-80	775	20-60
Less serious	93	600	210-600	0.4	0
Total	174	1,110	390-1,110	n/a	240-670

ENDNOTES

1. Regulatory Flexibility Act, 5 U.S.C. § 601, as amended by the Small Business Regulatory Enforcement Fairness Act, Pub. L. No. 104-121, 110 Stat. 866 (1996).

2. Pub. L. No. 94-305, 90 Stat. 668 (codified as amended in 15 U.S.C. §§ 634a-g, 637)).

3. The Dietary Supplement Health and Education Act (DSHEA), Pub. L. No. 103-417, § 2(13), 108 Stat. 4325, 4326 (1994), places specific limits on how FDA can regulate or enforce against dietary supplements FDA believes are unsafe or adulterated. Specifically, DHEA requires the FDA to prove adulteration on a product-by-product basis rather than designate by regulation when a class of dietary supplements containing ephedrine alkaloids are adulterated under the Food, Drug and Cosmetic Act, 21 U.S.C. § 342(f)(1). The Office of Advocacy believes that there is considerable merit to the argument that FDA does not have the authority in the instant rulemaking to designate by regulation that all dietary supplements containing ephedrine alkaloids are adulterated.

4. 62 Fed. Reg. at 30,710.

5. 62 Fed. Reg. at 30,712. In reaching its determination on the number of small entities impacted, the agency relied on the estimates appearing in the final rule on nutritional labeling and on survey data. The estimated number of dietary supplement manufacturers in the nutritional labeling rule was between 500 and 850 firms, with 95 percent of those firms classified as small businesses. The proportion of manufacturers producing products containing ephedrine alkaloids was not revealed in the nutritional supplement rule, but two market surveys identified 85 manufacturers and distributors of dietary supplements suspected of containing ephedrine alkaloids. Using the 95 percent proportion from the nutritional labeling rule, the agency arrived at the figure of 80 small firms (95% of 85 firms equals 80 firms). The source and date of the market data is not clear. Moreover, FDA assumes that the estimates in the nutritional labeling final rule regarding the number of manufacturers corresponds to the information collected in the market data with regard to manufacturers and distributors.

6. See 15 U.S.C. § 632(a)(1).

7. The active ingredient in Dexatrim is phenylpropanolamine (PPA) with a daily recommended dosage of 75-mg. It is an amphetamine-like substance that disrupts hunger signals to the brain. Certain individuals who ingest PPA through weight loss or OTC cold products may experience nervousness, nausea, insomnia, headaches and elevated blood pressure. These warnings are on the product labels, yet FDA is not trying to remove these products from the market because they are unsafe at the recommended doses.

8. One of the active ingredients in Actifed is pseudoehpedrine hydrochloride with a daily recommended dosage not to exceed 240 mg. According to the product label, some people may experience "nervousness, dizziness, or sleeplessness."

9. The 920 reports should be placed in the context of billions of doses of dietary supplements taken by consumers over the past couple of years. FDA states that they have collected over 125 dietary supplement products labeled as containing a known source of ephedrine alkaloids during the past two years. See 62 Fed. Reg. at 30,679. Even if only one billion doses had been taken, it would amount to only .0000009% of doses consumed that resulted in a report. Statistically, speaking, it is very possible that an even higher percentage of the general population would have died or experienced general symptoms resembling those associated with the reported events contained in the AERs.

10. Starlight's and Nutraceutical's Comments to FDA's Proposed Rule on Dietary Supplements Containing Ephedrine Alkaloids (Vol. I) at 46 (December 2, 1997).

11. Id. at 47-49.

12. Id. at 50.

13. Table 6 is reproduced in Appendix B of this document.

14. The 80% figure was determined by FDA as follows: "the proportion of reported adverse events associated with dietary supplements that involve supplements containing ephedrine alkaloids is probably between 25 and 90 percent. Within this range, FDA believes the most likely value is around 80 percent

. . ." (Emphasis added). 62 Fed. Reg. at 30,707.

15. 62 Fed. Reg. at 30,692-93.

16. Id. at 30,693.

17. Id.

18. Id. at 30,694.

19. Id. at 30,707 (emphasis added).

20. Id. at 30,695.

21. Cardiomyopahty is a structural or functional abnormality of the heart muscle, causing weakening of the heart muscle and subsequent inability of the heart to pump blood efficiently.

22. The Montgomery Heart Foundation for Cardiomyopathy is the only organization in the country whose primary focus is cardiomyopathy, and is the sole advocate for research in the treatment of the disease as well as a clearinghouse for current information on the subject.

23. 62 Fed. Reg. at 30,718.

24. Pub. L. No. 104-4, 109 Stat. 48, (1995), (codified as amended in 2 U.S. C. §§ 1501-71 (Supp. 1996)).

25. 2 U.S.C. at § 1535(a).

26. Under § 609(a)(5) of the RFA,

"when any rule is promulgated which will have a significant economic impact on a substantial number of small entities, the head of the agency . . . with statutory responsibility for the promulgation of the rule shall assure that small entities have been given an opportunity to participate in the rulemaking for the rule through the reasonable use of techniques such as-- . . . the adoption or modification of agency procedural rules to reduce the cost or complexity of participation in the rulemaking by small entities."

27. 62 Fed. Reg. at 30,709.

28. See 60 Fed. Reg. 67,184 (December 28, 1995).