by Rakesh Amin, Esq, RPh, and Mark Blumenthal
On April 13, 2005, a federal district court in Utah overturned the Food and Drug Administration’s Final Rule on ephedrine-containing dietary supplements.1 The Final Rule, which was issued on April 12, 2004, prohibited the sale of dietary supplements containing ephedrine alkaloids. In its Final Rule, the Food and Drug Administration (FDA) declared dietary supplements containing ephedrine alkaloids adulterated under the Federal Food, Drug and Cosmetic Act (“FDCA”). Plaintiffs, Nutraceutical Corporation and its subsidiary Solaray, Inc., filed suit in a Utah federal court challenging the FDA’s determination of adulteration of ephedrine-containing dietary supplements and its subsequent ban on these products. The court held that the Final Rule was invalid and remanded to the FDA for further rulemaking consistent with its decision.
Ephedrine alkaloids, which include ephedrine, pseudoephedrine, and norephedrine, are naturally occurring chemical stimulants which include raw botanicals and extracts from botanical sources, the most common plant source being ephedra (Ephedra sinica Stapf., Ephedraceae), also called Chinese ephedra or its Chinese name ma huang.
Brief Regulatory History of Ephedra
The debate on dietary supplements containing ephedrine alkaloids and thus the herb ephedra came to an initial high point in June 1997 when the FDA published a proposed rule stating that a dietary supplement would be considered adulterated if it contained 8 milligrams (mg) or more of ephedrine alkaloids per serving, or if its labeling or suggested use resulted in 8 mg or more of ephedrine alkaloids in a 6-hour period, or a total daily intake was 24 mg or more of ephedrine alkaloids.2 The FDA proposed adding a statement on these products, stating that the products are hazardous and should not be used for more than seven days. The proposal also included prohibiting the use of ephedrine alkaloids with other substances that have a known stimulant effect.
Certain provisions of the proposed rule were modified in April 2000 due to concerns regarding FDA’s basis for its suggested level of use and duration of use limit for ephedra-containing dietary supplements.3 After the proposed rule was published, the House Committee on Science requested that the Government Accounting Office (GAO) examine the scientific basis for the proposed rule. The GAO concluded that the FDA was warranted in its investigation of dietary supplements containing ephedrine alkaloids but expressed concerns about the proposed suggested level of use and limited duration of use. Specifically, the GAO recommended the 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.”4 Based on this recommendation and comments received from other groups, the FDA removed the provisions relating to the amount of ephedra in the dietary supplement and the level of its use.
After mounting public pressure from members of Congress, medical groups, consumer organizations, the media, and others to curb the sale of ephedra-containing dietary supplements after the highly publicized death of Baltimore Orioles pitcher Steven Bechler in February 2003, the FDA issued a consumer alert in December 2003, stating the agency’s intent to publish a final rule, prohibiting the sale of dietary supplements containing ephedra and warning consumers to stop using any ephedra-containing dietary supplements.5 The FDA notified firms manufacturing and marketing these products of the upcoming publication, indicating that they would have 60 days from publication of the final rule to stop sales of these dietary supplements. The final rule was published on February 11, 2004, which banned the sales of all dietary supplements containing ephedra or any levels of ephedrine alkaloids.6 The FDA concluded that dietary supplements containing ephedrine alkaloids presented an “unreasonable risk of illness or injury” and were therefore adulterated. This decision was based on the pharmacology of ephedrine alkaloids, peer-reviewed scientific literature of the effects of these substances, and reported adverse events. However, the rule did not pertain to traditional Chinese herbal remedies that were dispensed by a licensed healthcare practitioner for the purposes for which ephedra has been used in Traditional Chinese Medicine, i.e., for treatment of bronchial and pulmonary complaints, nasal congestion, etc. Also the rule did not apply to herbal teas regulated as conventional foods and FDA-approved drugs that contain chemically synthesized ephedrine or pseudoephedrine, like nonprescription medications sold for coughs and colds, decongestants, hay fever and allergies, etc.
The Utah Court Case
Nutraceutical Corporation and subsidiary Solaray, Inc., a manufacturer of an ephedrine-containing dietary supplement, brought action in May of 2004 against the FDA in federal court to challenge the validity of the Final Rule, alleging that the Final Rule violates the FDCA as amended by the Dietary Supplement Health and Education Act of 1994 (DSHEA) through an improper determination of adulteration. Under Section 402(f)(1)(A) of the FDCA, the FDA may label a dietary supplement as adulterated if it determines that the product presents “an unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling”; if, however, no conditions of use are suggested or recommended in the labeling, the product may be deemed adulterated if it presents an unreasonable risk of illness or injury under the ordinary conditions of use.7 In its suit, Plaintiffs asked the court to: (1) declare the Final Rule invalid; (2) remand the matter to the FDA for further rulemaking consistent with the court’s opinion; and (3) enjoin the Defendants (FDA) from taking enforcement against the Plaintiffs (Nutraceutical Corp. and Solaray) for sale of their dietary supplement containing 10 mg or less of ephedrine alkaloids as a daily dose.8
Plaintiffs presented the following issues before the court: (1) whether the FDA’s use of a risk-benefit analysis in its determination of adulteration was appropriate under DSHEA; and (2) whether the FDA provided sufficient evidence to support its conclusion that dietary supplements containing 10 mg or less of ephedrine alkaloids per day poses a significant or unreasonable risk of illness or injury.9
When the FDA issued its Final Rule, the Agency relied upon a risk-benefit analysis test in its determination that ephedrine-containing dietary supplements were adulterated.10 Section 402(f)(1)(A) of the FDCA requires evidence of “significant or unreasonable risk” of illness or injury. As stated in the Final Rule, there is no requirement that evidence be provided that proves the product has caused actual harm to the public, only that scientific evidence supports the existence of a risk.11 The Final Rule explains the risk-benefit analysis by stating that the Government’s burden of proof for “unreasonable risk” is met when a product’s risk outweighs its benefits, considering the use of the product by its claims and directions for use in the product’s labeling, or, if no such labeling exists, under the ordinary conditions of the product’s use.
Public comments filed with the FDA prior to the publication of the Final Rule questioned if the FDA was premature in its determination of whether dietary supplements containing ephedrine alkaloids presented a significant or unreasonable risk before defining that standard. In its response, the FDA stated that the Agency did not need to define the term “unreasonable risk” before taking regulatory action as “[a]n agency may interpret a statutory provision through rulemaking or case-by-case adjudication.”12 Thus, the FDA reasoned that the Agency was not required to issue a separate rule or guidance defining this provision of 402(f)(1)(A) before issuing the regulation.
Plaintiffs argued that the risk-benefit analysis was improper as the plain language of DSHEA does not require this test and application of this test was improper because it impermissibly adds language into DSHEA that was not intended by Congress. Defendants (the FDA) asserted that the term “unreasonable risk” is consistent with the definition intended by Congress in other parts of the FDCA and other portions of similar statutes. The Defendants specifically referred to statutes governing medical devices (also found in the FDCA) and the Toxic Control Substance Act. The court stated that Defendants’ use of the medical device provisions was misplaced in that, although the provisions governing medical devices do call for a risk/benefit analysis, DSHEA does not contain any such provision and therefore, dietary supplements are not classified on the basis of a risk/benefit analysis. The court additionally responded that, under DSHEA, a dietary supplement is regulated as a food for the purposes of the FDCA and as with any food, is presumed to be safe.13 Food producers are not required to establish a benefit before sale. This supports Plaintiff’s argument; Plaintiffs argued that if food producers were required to show a benefit before the sale of a food product, the sale of foods such as potato chips might be prohibited.14
The court determined that the FDA’s use of a risk-benefit analysis improperly placed a burden on the manufacturers of ephedrine-containing dietary supplements to prove a benefit before sale, which was in direct contradiction with Congress’ intent. In 21 U.S.C. 342(f), Congress specifically stated that “[i]n any proceeding under this subparagraph, the United States shall bear the burden of proof on each element to show that a dietary supplement is adulterated.”15 The court reasoned that the FDA’s requirement for the manufacturers of ephedrine-containing dietary supplements to show a benefit was against Congressional intent and the use of FDA’s definition of “unreasonable risk,” thereby prompting a risk-benefit analysis, was improper.
In response to the second issue, the court determined that the government must establish that dietary supplements containing ephedrine alkaloids pose a “significant or unreasonable risk by a preponderance of the evidence.”16 Additionally, per the statute, the government must prove by this evidentiary standard the harmful effects of the dietary supplement under its recommended and suggested use in the labeling. The court interpreted this to mean that this analysis is dose-specific. The evaluation made by the court focused on dietary supplements containing low-doses of ephedrine alkaloids as the plaintiffs contended that the suggested dosage of no more than 10 mg per day did not present a significant or unreasonable risk of illness or injury. Defendants countered by providing certain evidence comparing the potency rates of epinephrine and ephedrine alkaloids. Epinephrine is similar to ephedrine in that both are amphetamine-like compounds, having stimulant effects on the cardiovascular and nervous systems, but vary in the relative intensity of these effects. The evidence cited a study which used a hypothetical mathematical model in its analysis of the effects of ephedrine alkaloids. The evidence produced was based on the potential physiological effects of orally ingested ephedrine from data obtained from those effects from intravenous injections of epinephrine. Extrapolating this data and using the potency rates, the evidence concluded that 9 mg per day of ephedrine alkaloids produced adverse health events based on chronic intake. The court stated that the suggested use on the Plaintiffs’ product labeling was not that of chronic use and concluded that the Defendants (FDA) failed to meet the burden of proof in establishing that 10 mg per day of Plaintiffs’ product presented a significant or unreasonable risk. The court further concluded that the Defendants, by failing to meet this burden of proof, failed to give effect to the dose-specific language of 21 U.S.C. A4342(f)(1)(A).
The court granted Plaintiffs’ motion for summary judgment and remanded to the FDA for further rulemaking on this issue, enjoining the FDA from taking enforcement action against Plaintiffs for sale of their ephedrine-containing dietary supplement having less than 10 mg per day of ephedrine alkaloids.
At this time, and until the situation is further clarified by the FDA as to what its enforcement priorities will be under the new ruling, dietary supplement manufacturers should use caution in the sale and marketing of any products containing ephedrine alkaloids. First, as expected, on June 13 the FDA appealed this decision.17 Prior to filing the appeal the agency stated that it does not believe that the court’s ruling applies to dietary supplements containing more than 10 mg of ephedra (per daily dose).18 Second, the FDA may seek to obtain a stay of the trial court’s order while the appeal is pending; in effect, this would place all of the litigants in the same position as they were before the lawsuit was filed. Third, depending on the outcome of the appeal, it is highly likely that the FDA and the Department of Justice will take the position that the decision is not binding outside of Utah and may take the position that it is only applicable to the Plaintiffs in this lawsuit. In addition, this ruling has no effect on several states (New York, Illinois, and California) which have enacted laws banning sales of all ephedrine-containing dietary supplements. The court’s decision also does not affect the ban on importation of ephedra, which may effectively prohibit some manufacturers from resuming production of their product due to lack of sourcing for the raw materials.
It is important to keep in mind also that the court has ruled only on those products containing ephedrine alkaloids equivalent to 10 mg or less per daily dose, which is considered to be low-dosage forms as evidenced by existing products prior to the enactment of the Final Rule. Manufacturers must be careful to comply with this ruling as the FDA still has the ability to enforce against products containing more than 10 mg per day as per the Final Rule. The trial court’s ruling on the validity of the Final Rule is not grounded on the number of milligrams in a unit; the decision of the trial court states only that the FDA has failed to meet its burden of proof as required by 21 U.S.C. 342(f), which requires an affirmative demonstration of significant or unreasonable risk at a particular dosage level, and that the FDA failed to meet the government’s burden for Plaintiffs’ product containing 10 mg or less of ephedra per daily dose. The trial court was not making a determination of the safety of Plaintiffs’ product or other ephedra-containing products, but simply remanded its decision to the FDA for further rulemaking consistent with its decision that the Agency had failed to meet its burden of proof according to the statute.
In any event, this decision has caused much controversy on both sides of the issue. Some proponents of the dietary supplement industry are cautiously optimistic about the decision as many believed that the FDA misinterpreted the intent of DSHEA. The Final Rule was seen by many as a forecast for stricter regulation of other dietary supplement products in the same manner as that instituted by the promulgation for the ephedrine-containing dietary supplements. In fact, Plaintiffs in this case have been quoted as saying that the company’s reason for filing the suit was not based on its ephedrine product alone but because of the potential effect on many of its other products, referring to the legal basis upon which the FDA banned the sale of ephedra.19 Anti-supplement critics and activists in medical groups, Congress, the media, and elsewhere are condemning the court’s decision and many have renewed their attacks on DSHEA and the dietary supplement industry as a whole, stating that DHSEA needs to be re-evaluated and/or changed to give proper enforcement power to the FDA in an industry that is dismissed by many as “unregulated.”20,21<
On May 17, 2005, prior to the FDA’s appeal, three dietary supplement industry associations sent a joint letter to the FDA about the court’s decision, requesting the Agency to promptly address the issues raised in the decision.22 In its letter, the American Herbal Products Association (AHPA), the Council for Responsible Nutrition (CRN), and the National Nutritional Foods Association (NNFA) indicated that these organizations have cautioned their member companies that the ruling is limited as it applies to low-dosage ephedra-containing products only and have advised these companies to refrain from any commerce associated with ephedrine-containing products at this time.
More information on the ephedra safety issue is available in previous issues of HerbalGram.23,24
1. Nutraceutical Corp. and Solaray, Inc. v. Lester Crawford, D.V.M., Acting Commissioner, U.S. Food and Drug Administration, et al, No. 2:04CV409TC (C.D. UT). Available at: http://www.utd.uscourts.gov/reports/204cv409-28.pdf.
2. Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule, 62 Fed. Reg. 30,677 (June 4, 1997) (to be codified at 21 C.F.R. pt. 111).
3. Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part, 65 Fed. Reg. 17,474 (April 3, 2000) (to be codified at 21 C.F.R. pt. 111).
5. Federal Food and Drug Administration, Consumer Alert: FDA Plans Regulation Prohibiting Sale of Ephedra-Containing Dietary Supplements and Advises Consumers to Stop Using These Products. Available at: http://www.fda.gov/oc/initiatives/ephedra/december2003/advisory.html.
6. Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk; Final Rule, 69 FR 6788 (February 11, 2004) (to be codified at 21 C.F.R. pt. 119).
7. Federal Food, Drug and Cosmetic Act A4402(f)(1)(A)[21 U.S.C. A4342(f)(1)(A)](2004).
8. Supra note 1.
10. Supra note 4.
12. SEC v. Chenery, 332 U.S. 194 (Sup. Ct. 1947).
13. Blair Connelly & Shane H. Freedman, Federal Court Overturns Ban on Ephedrine-Containing Dietary Supplements. Available at: http://www.npicenter.com/anm/anmviewer.asp?a=12200&print=yes.
15. Supra note 2.
16. Supra note 1.
17. Nutraceutical Corp. and Solaray, Inc. v. Lester Crawford, D.V.M., Acting Commissioner, U.S. Food and Drug Administration, et al, No. 2:04CV409TC (C.D. UT).
18. American Herbal Products Association. AHPA Update: AHPA advises against sale of all ephedra dietary supplements. Available at: http://www.ahpa.org/update_05_0426.html.
19. Amin RM. Federal Court Overturns FDA Ban on Ephedra at Low Doses. Available at: http://www.herbalgram.org/ default.asp?c=FDAephedra.
20. Time to Ban Ephedra [editorial]. New York Times, April 21, 2005.
21. Mooney C. Unnatural Law: A 10-year-old law on herbal supplements is endangering consumers. The Prospect. April 25, 2005. Available at: http://www.prospect.org/web/page.ww?section= root&name=ViewWeb&articleId=9591.
22. Letter to Lester M. Crawford, D.V.M., Ph.D., Acting Commissioner, Food and Drug Administration with copy to Michael Leavitt, Secretary of Health and Human Services. Available at:http://www.ahpa.org/05_0517_Crawford.pdf.
23. Blumenthal M. FDA Proposes Strong Warnings for Ephedra, Releases Independent RAND Report on Ephedra Safety and Efficacy. HerbalGram 2003;No. 58:68-70. Available at: http://www.herbalgram.org/herbalgram/articleview.asp?a=2500.
24. Blumenthal M. FDA Announces Ban on Ephedra Supplements: Federal Move Follows Bans by California, Illinois and New York. HerbalGram 2004;No. 61:54-55. Available at: http://www.herbalgram.org/herbalgram/articleview.asp?a=2658.