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FDA Issues Final Rule Banning Ephedra
ISSUE:
Page:
63-64
FDA Issues Final Rule Banning Ephedra

Sales of Ephedra Supplements Must Cease by April 12, 2004

By Rakesh M. Amin

On Friday, February 6, 2004, the United States Food and Drug Administration (FDA) announced that it was publishing its final rule banning the sales of all dietary supplements containing the controversial herb ephedra (Ephedra sinica Stapf, Ephedraceae) and any ephedra group alkaloids (e.g., ephedrine, pseudoephedrine).1 The final rule was published in the Federal Register on February 11, 2004, and will take effect sixty days following publication on April 12, 2004.2 The final rule is a culmination of FDA’s 1997 proposed rule requiring that warning labels be placed on dietary supplements containing ephedra.3 It also follows FDA’s December 30, 2003, consumer alert on the safety of dietary supplements containing ephedra and the agency’s notice to manufacturers of its intention to publish a final rule stating that dietary supplements containing ephedra alkaloids creates an “unreasonable risk of illness or injury” for consumers.4

The previous issue of HerbalGram (#61) contained an extensive article summarizing many of the issues dealing with FDA’s announcement in December of the proposed ban and the banning of ephedra by California, Illinois, and New York.5 The FDA’s ban follows the current trend of state legislation restricting the sale and use of dietary supplements containing ephedrine alkaloids. Currently three states, Illinois, California, and New York, have developed and placed into effect legislation outlawing the retail sale of dietary supplements containing ephedra and/or any of its alkaloids.6,7,8 The states do allow a narrow exception to an otherwise almost total ban on the sale of products containing ephedra. Illinois banned the sale of ephedra as a dietary supplement and does not allow an exception for healthcare practitioners like acupuncturists to use ephedra in their clinical practice.6 However, Illinois does permit the sale of FDA approved ephedrine alkaloid-containing products marketed under an over-the-counter (OTC) drug monograph or the prescription of ephedra alkaloid-containing drugs by conventional health professionals as explicitly approved by the FDA (i.e., for FDA-approved medical uses).6 California’s bill made sales of dietary supplements in California that contain any amount of “ephedrine group alkaloids” a crime as of January 1, 2004, effectively making any dietary supplement containing the herb illegal for any purpose unless sold by medical prescription.7 New York law prohibits the sale of dietary supplements containing ephedra and violators can face fines up to $500.00.8 The only exceptions to New York’s prohibition include the sale of the herb to licensed, certified, and accredited practitioners of Traditional Chinese Medicine (TCM) for appropriate purposes within the scope of their practice and for products that receive explicit safe and effective approval for their intended use according to the Federal Food, Drug, and Cosmetic Act or lawfully marketed under an OTC monograph.8 The new FDA ban preempts inconsistent existing state regulations that are more permissive but will not preempt those state regulations that are more stringent.

The FDA’s recent final rule came under the authority granted to it by the Dietary Supplement Health and Education Act of 1994 (DSHEA).9 Under DSHEA, the FDA determined that dietary supplements containing ephedra are “adulterated because they present an unreasonable risk of illness or injury under the conditions of use recommended, suggested or recommended in labeling, under ordinary conditions of use.”9 The FDA chose not to use or define the “significant risk of illness or injury” safety standard under DSHEA, relying instead on the “unreasonable risk” safety standard. The FDA concluded that “unreasonable risk represents a relative weighing of the product’s known and reasonably likely risks against its known and reasonably likely benefits. In the absence of a sufficient benefit, the presence of even a relatively small risk of an important adverse health effect to a user may be unreasonable.”9 The FDA determined a “reasonably likely benefit” is one that is supported by a meaningful totality of the evidence given the current state of scientific knowledge though not the level of information required for prescription drug approval.9

To meet its burden of proof, the FDA gathered and reviewed evidence concerning the following: (1) ephedra’s pharmacology; (2) peer-reviewed scientific literature on the safety and effectiveness of ephedra; (3) adverse event reports; and (4) an independent seminal report on the safety and efficacy of ephedra supplements issued by the RAND Corporation.10,11 Based upon the best available scientific data and the known pharmacology of ephedrine alkaloids, the FDA determined that dietary supplements containing ephedrine alkaloids do not provide a meaningful health benefit and the risks of use were not outweighed by the known or reasonable likely benefits.12 The FDA’s sweeping approach and ability to trump up safety concerns potentially places at risk all dietary supplements including herbals without strong and substantiated benefits. Therefore, it is essential for the industry to address both safety and effectiveness in product testing and to stay abreast of adverse events while striving for solid methodology and strong substantiation to prove a product’s effectiveness.

The FDA listed a range of botanicals containing ephedrine alkaloids that would be part of the ban: ma huang (the Chinese name for ephedra), country mallow (Sida cordifolia L., Malvaceae; also known as bala ), the Chinese herbban xia (Pinellia ternata [Thunb.] Makino, Araceae), and most members of the genus Ephedra that contain the ephedra alkaloids, e.g., E. sinica , E. equisetina Bunge, E. intermedia var, tibetica Stapf, and E. distachya L.

The ephedrine alkaloids that appear to be pharmacologically active in plants and which are covered by the ban include l-ephedrine, d-pseudoephedrine, 1-norephedrine, 1-methylephedrine, d-norpseudoephedrine, and d-methylpseudoephedrine. The final rule does not apply to conventional foods (such as herbal teas) that contain ephedrine alkaloids, nor does it apply to OTC and prescription drugs. The FDA also stated that most American species of ephedra do not contain ephedrine alkaloids (e.g., Mormon tea [E. viridis Coville,]) and are therefore not part of the ban.

The rule will also not affect preparations prepared under TCM because they are intended for episodic (e.g., temporary respiratory infections) rather than chronic use (e.g., long-term use for weight loss). Thus, Chinese practitioners wishing to sell ephedra-containing products will have to remove the “Dietary Supplement” statement of identity from the products they sell. However, TCM practitioners importing products containing ephedra may be subjected to heightened regulatory scrutiny from U.S. Customs and the FDA because it is uncertain whether pre-market approval and/or other documentation will be required.

There are several notable consequences of the FDA’s final rule.

First, manufacturers, retailers, and distributors selling ephedra supplements after April 12, 2004, will be subject to civil and/or criminal enforcement, and likely serious product liability exposure.

Second, all dietary supplements, not just ephedra, will now be subject to a risk/benefit safety analysis for the first time as opposed to only risk of injury analysis which was relevant in the past. The FDA’s risk/benefit analysis weighs the quality, persuasiveness, and seriousness of the presence of risks associated with the supplement against the quality and importance of the related benefits, with an emphasis on long-term health outcomes opposed to temporary measures such as feeling or looking better.12 The FDA indicated its determination did not rely on adverse event reporting because such reports are not indicative of a determination of unreasonable risk.12

Third, the FDA will act proactively and the industry can expect further rule-making instead of waiting for case-by-case enforcement when an ingredient safety issue arises. One of these proactive measures is indicated by the FDA adding a new section to the Code of Federal Regulations for “Dietary Supplements that Present a Significant or Unreasonable Risk.”2

Fourth, the FDA has substantially raised the bar on safety substantiation. It is significant to note for future safety studies that the FDA rejected the previously published ephedra safety trials because they were either too small or designed to detect serious effects in susceptible individuals. Warning labels, says FDA, are insufficient. The implications of this ruling with respect to the sale of other herbs are not clear. Since few herbs on the market possess the relatively strong pharmacological activity as ephedra, the stringent warnings that would have pertained to ephedra if FDA’s warnings previously proposed in February 2003 had stood are now moot.13 Finally, various state ephedra laws that conflict with the FDA’s final rule will be preempted.

Predictably, while many elements of the supplement industry accepted FDA actions, the FDA’s final rule has not received totally positive reactions and several companies in opposition continue to defend ephedra’s use. Metabolife International, Inc. issued a statement maintaining the safety of ephedra products “if taken as directed as a safe, inexpensive and effective means by which to support weight loss.”14 On the other hand, several manufacturers see the FDA’s ban as a way to remove a level of controversy over the industry. Nonetheless, this is the first time the FDA has ordered a ban on a dietary supplement ingredient, which is strong evidence that most of the popular dietary supplements on the market when taken according to suggested use and labeling or under ordinary conditions of use are safe.

On March 4, 2004, NVE Pharmaceuticals, Inc. (NVE) became the first dietary supplement company to sue the federal government for banning ephedra (NVE v. Dept. of HHS, et al. , 04 CV 00999). NVE filed suit against the Department of Health and Human Services (HHS) in the U.S. District Court for the District of New Jersey on the grounds the ban is in violation of the 1994 DSHEA law. NVE requests the Court to set aside the government ban thereby stalling the April 12, 2004 deadline and to consider new evidence challenging the government’s claims that ephedra can dangerously raise blood pressure.

Various trade associations of the dietary supplement industry—the Council for Responsible Nutrition, the National Nutritional Foods Association, and the Utah Natural Products Alliance— recently announced they will not challenge the FDA’s final rule banning dietary supplements containing ephedrine alkaloids.15 The associations noted that the agency’s action demonstrates that the DSHEA provides FDA with the legal authority to take strong evidence-based regulatory action. While the associations do not agree with every point in FDA’s justification of the final rule, they believe the FDA’s discussion of the rule indicates that the agency supports access to dietary supplements that are safe, beneficial, made to high quality standards, properly labeled, and in compliance with the law.

For more information on the FDA’s first-ever ban on the sale of a dietary supplement ingredient, visit http://www.fda.gov/ohrms/dockets/98fr/1995n-0304-nfr0001.pdf. Further inquiries or comments can be directed to Rakesh M. Amin at (312) 327-3382 or e-mail to Rakesh@amin-law.com.

Rakesh M. Amin is a registered pharmacist and attorney at Amin Law, LLC. He is also an adjunct professor teaching Food & Drug Law at the DePaul University College of Law.

References:

1. U.S. Food and Drug Administration. Sales of Supplements Containing Ephedrine Alkaloids (Ephedra) Prohibited, February 6, 2004. 69 Fed. Reg. 6788 (February 11, 2004). Available at <http://www.fda.gov/oc/initiatives/ephedra/february2004/>.

2. U.S. Food and Drug Administration. Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk, 69 Fed. Reg. 6788 (February 11, 2004). Available at <http://www.fda.gov/ohrms/ dockets/98fr/1995n-0304-nfr0001.pdf.>.

3. U.S. Food and Drug Administration. Dietary Supplements Containing Ephedrine Alkaloids, 62 Fed. Reg. 30678 (June 4, 1997).

4. U.S. Department of Health and Human Services. FDA Announces Plans to Prohibit Sales of Dietary Supplements Containing Ephedra: Consumers Advised to Stop Using Ephedra Products Immediately, December 30, 2003. Available at <http://www.hhs.gov/news/press/2003pres/20031230.html/>.

5. Blumenthal M. FDA announces ban on ephedra supplements: Federal move follows bans by California, Illinois, and New York. HerbalGram 2004; 61:54-5. See expanded version at <http://www.herbalgram.org/herbalgram/articleview.asp?a=2644>.

6. 720 ILCS 602, Ephedra Prohibition Act, Illinois General Assembly, May 28, 2003. Available at <http://www.legis.state.il.us/legislation/ilcs/ilcs2.asp?chapterID=53>.

7. California Senate Bill 582, Ephedrine Group Alkaloids, effective January 1, 2004. Available at <ftp://www.leginfo.ca.gov/ pub/bill/sen/sb_0551-0600/sb_582_bill_20030911_ enrolled.html>.

8. Laws of New York: Chapter 385, Bans the sale of dietary supplements containing ephedra; provides exemptions for non-prescription over the counter drugs approved or regulated by the FDA; further provides for criminal penalties, August 19, 2003. Available at <http://public.leginfo.state.ny.us/menugetf.cgi>.

9. 21 U.S.C.A. §342(f)(1)(A)(i)(ii), Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103rd Congress, October 25, 1994. Available at <http://www.fda.gov/opacom/laws/dshea.html>.

10. Shekelle P, Morton S, Maglione M, et al., Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based Practice Center, RAND, under Contract No. 290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022. Rockville, MD: Agency for Healthcare Research and Quality. February 2003. Available at <http://www.fda.gov/OHRMS/DOCKETS/98fr/95n-0304-bkg0003-ref-07-01-index.htm>.

11. U.S. Food and Drug Administration. FDA Issues Regulation Prohibiting Sale of Dietary Supplements Containing Ephedrine Alkaloids and Reiterates Its Advice That Consumers Stop Using These Products, FDA News, February 6, 2004. Available at <http://www.fda.gov/bbs/topics/NEWS/2004/NEW01021.html>.

12. U.S. Food and Drug Administration. Dietary Supplements Containing Ephedrine Alkaloids Final Rule Summary, February 6, 2004. 69 Fed. Reg. 6788 (February 11, 2004). Available at <http://www.fda.gov/oc/initiatives/ephedra/february2004/finalsummary.html>.

13. U.S. Food and Drug Administration. Dietary Supplements Containing Ephedrine Alkaloids; Reopening of the Comment Period, 69 FR 11996 (February 28, 2003). Available at <http://www.fda.gov/ OHRMS/DOCKETS/98fr/95n-0304-npr0003.pdf>.

14. Kanak, Yvonne ed., FDA Will Ban Ephedra Dietary Supplements, Food Drug Cosmetic Law Reports , No. 2145, (January 12, 2004).

15. Council For Responsible Nutrition. Supplement Trade Associations Respond to FDA Action on Ephedra – Associations Note DSHEA Provides Adequate Regulatory Authority, Press Release , Washington D.C., February 12, 2004. Available at <http://www.crnusa.org/shellnr021204joint.html>.