On May 9, 2002, the U.S. Food and Drug Administration (FDA) issued a final rule banning the use of aloe (Aloe spp., Aloaceae) and cascara sagrada (Frangula purshiana (DC.) J.G. Cooper, Rhamnaceae; syn. Rhamnus purshiana DC.) as laxative ingredients in over-the-counter (OTC) drug products.1 Under the new regulation, the botanical ingredients "aloe," "aloe extract," and "aloe flower extract," as well as "cascara sagrada" (including "casanthrol," "cascara fluid extract aromatic," "cascara sagrada bark," "cascara sagrada extract," and "cascara sagrada fluid extract") are deemed not "generally recognized as safe and effective" (GRASE) for use as stimulant laxative ingredients in OTC drug products. The regulation is scheduled to become effective on November 5, 2002. After that date, any OTC drug product containing aloe or cascara sagrada and labeled for laxative use that is introduced into interstate commerce will be considered a "new drug" in violation of federal law. No recall of products already on the market or in distribution has been suggested.
In response, on June 10, the American Herbal Products Association (AHPA) and the International Aloe Science Council (IASC) filed a joint petition with FDA ("AHPA/IASC Petition") requesting that FDA stay (i.e., set aside) the effective date of the regulation and reconsider the status of the aloe and cascara sagrada ingredients.2 The AHPA/IASC Petition challenges FDA's final rule on both legal and scientific grounds, arguing that aloe and cascara sagrada ingredients cannot be deemed to be "new drugs" because they are GRASE based on readily available information. Although FDA regulations require the FDA Commissioner to "promptly review" such petitions, there is no time frame imposed upon the Commissioner to act.3
Overview of FDA's OTC Drug Review
The ban is part of FDA's OTC Drug Review, an ongoing administrative review process begun in 1972 to determine which active ingredients are GRASE for use in OTC drug products. Drugs that are generally recognized by qualified experts as safe and effective for their labeled uses are not subject to FDA premarket approval requirements applicable to "new drugs."4 Generally, only active ingredients used in OTC drug products in the United States prior to December 1975 were included in the Review. To facilitate the process, FDA divided OTC drugs into therapeutic classes and set up advisory panels to consider safety, effectiveness, and labeling (i.e., indications, warnings, and directions for use). In general, each panel prepared a report that was published by FDA in the Federal Register for public comment as an advance notice of proposed rulemaking. The reports set forth the conditions (i.e., active ingredients, therapeutic claims, and labeling) under which the panels believed the products are GRASE and not misbranded. This classification is known as "Category I." The panels also identified the conditions under which they believed OTC drugs are not GRASE (that is, "Category II"), or not classifiable because there were insufficient data at the time of the review to make a decision regarding safety or efficacy ("Category III").
Under the OTC Drug Review procedures, after consideration of comments to a panel report, FDA publishes a "tentative final monograph" (TFM), which has the legal status of a "proposed rule." After considering comments to the TFM, FDA issues a final monograph (final rule), which is eventually codified in the Code of Federal Regulations (CFR). OTC drugs that comply with the specifications of a final monograph are not "new drugs" and may be marketed without FDA approval of a new drug application.
FDA's review of laxative drug products
In 1975, FDA's Advisory Review Panel on OTC Laxative, Antidiarrheal, Emetic, and Antiemetic Drug Products recommended that aloe and cascara sagrada ingredients be classified GRASE for laxative drug use.5 In January 1985, FDA published a proposed rule (TFM) setting forth the conditions under which OTC laxative drug products are GRASE and not misbranded.6 In that TFM, the stimulant laxative ingredients "aloe" and "cascara sagrada ingredients" are classified as GRASE, that is, "Category I," for use in OTC drug products when labeled in accordance with the TFM, which mandates certain warning statements.
The 1985 TFM also classified "sennosides A and B" derived from certain senna (Senna alexandrina Mill., Fabaceae; syn. Cassia senna L.) sources (fruits and leaves) as GRASE for stimulant laxative OTC drug use.
In 1998, FDA proposed amending the TFM to reclassify aloe, cascara sagrada, and senna ingredients from GRASE ("Category I") to "Category III" (i.e., more data needed).7 FDA issued the proposed rulemaking apparently after considering data and information on the safety of bisacodyl, senna, and "two related" anthraquinone laxative ingredients, danthron and phenolphthalein. Formerly, phenolphthalein was the active ingredient in leading over-the-counter laxatives marketed by the pharmaceutical industry.8
The proposed reclassification was based on FDA's conclusion that aloe, cascara sagrada, and senna contain anthraquinone ingredients which require mutagenicity, genotoxicity and carcinogenicity tests to confirm safety. In a notice of proposed rulemaking published in the Federal Register on June 19, 1998, FDA indicated that the Center for Drug Evaluation and Research (CDER) Carcinogenicity Assessment Committee (CAC) "has recommended that the anthraquinone laxatives (aloe, cascara sagrada, and senna) and bisacodyl be tested in the standard battery of genotoxicity tests and under the test conditions by which phenolphthalein was found to be positive."9 At that time, FDA advised interested persons to consult with the agency concerning carcinogenicity testing requirements and protocols before initiating such testing. FDA also indicated that, if data were not provided or were deemed to be inadequate for aloe, cascara sagrada, and senna (and bisacodyl), the ingredients would be deemed not GRASE and placed in "Category II."10 In response, FDA received safety data only on senna (and bisacodyl) and has indicated that these ingredients will be addressed in a future issue of the Federal Register.
In issuing the May 2002 ban on the use of aloe and cascara sagrada in OTC laxative drugs, FDA concluded that, because interested persons (e.g., members of the pharmaceutical and dietary supplement industries) failed to submit new data from carcinogenicity studies for these ingredients, they are not GRASE. Thus aloe and cascara sagrada ingredients will not be included in the forthcoming final monograph for OTC laxative drugs. The FDA has determined that these ingredients should be eliminated from laxative drug products within 180 days of publication of the final rule (i.e., November 5, 2002), regardless of whether toxicology testing is undertaken in the future.11 While companies are encouraged to comply with the regulation immediately, products containing aloe and cascara sagrada may be marketed and distributed through November 4. Beginning November 5, existing inventory on market shelves may continue to be sold until it is gone, but no further distribution will be permitted.
The AHPA/IASCS petition
The AHPA/IASC Petition seeks a stay in the effective date of the regulation until FDA and a relevant Advisory Committee have reconsidered the action. Principally, the Petition argues that:
¥ the failure of interested persons to submit testing data requested by FDA does not invalidate the general recognition of safety and effectiveness of aloe and cascara sagrada confirmed by the Advisory Committee that initially reviewed the data;
¥ FDA does not have the statutory authority to unilaterally decide the requirements of general recognition of safety and efficacy; and
¥ aloe and cascara sagrada meet the legal standard for "general recognition of safety" established by FDA's own regulations which state: "a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use ... proof [of safety] shall include results of significant human experience during marketing ... ."12
AHPA and IASC also assert that FDA failed to consider relevant data and readily available information and conclusions of qualified experts, including information contained in AHPA's Botanical Safety Handbook, published in 1997.13 In addition, FDA apparently failed to consider relevant work by other notable expert bodies. The German Commission E lists both aloe and cascara sagrada as approved botanical drug ingredients for use in the treatment of constipation, according to certain use restrictions.14 Consumers are advised to obtain laxative effects through the use of bulk forming laxatives prior to use of aloe or cascara sagrada. The World Health Organization (WHO) also recognizes clinical data on aloe for the short-term treatment of occasional constipation,15 as do the monographs published by the European Scientific Cooperative on Phytotherapy (ESCOP).16
The Petition also cites an American Botanical Council publication, Herbal Medicine: Expanded Commission E Monographs, noting its review of evidence regarding cascara sagrada, the first Western use of which was reported by an Eclectic physician in 1877.17
The AHPA/IASC Petition also challenges FDA's rule under the Regulatory Flexibility Act, which requires an agency to consider regulatory options to minimize the economic impact of rulemaking on small businesses, if a rule will significantly impact a substantial number of them. The FDA, in both the 1998 proposed rule and final regulation banning aloe and cascara sagrada ingredients, determined this rulemaking would not have a significant economic impact on a substantial number of small entities. In its Petition, AHPA/IASC argue that FDA's determination is flawed because the agency did not consider the effects of the final rule on companies that manufacture and market dietary supplements containing aloe and cascara sagrada as laxative ingredients, as well as the effects on companies selling aloe as a food or dietary supplement product for non-laxative use. Previously, FDA has recognized that most of the manufacturers and distributors of dietary supplements meet the definition of a "small business."15
Currently, it is uncertain whether FDA will act on the AHPA/IASC Petition in a timely manner. However, FDA is not likely to revise the regulation to permit the use of aloe and cascara sagrada in OTC laxative drugs unless industry submits new data. Industry could submit to FDA new toxicological testing data or data concerning general recognition of safety as part of a citizen petition to amend the monograph. Under FDA procedures, the agency must act on such petition within 180 days.
Alternatively, new data concerning aloe or cascara sagrada could be submitted to FDA as part of a new drug application (NDA) to obtain prescription or OTC marketing status. This route appears highly unlikely due to the huge investment in time and money that such undertaking would require, particularly since these ingredients are not patentable. Moreover, although an "innovator" company can generally expect five years of marketing exclusivity for a drug approved by FDA under a NDA (regardless of any patent protection), this may not provide enough of a financial incentive to pursue the NDA route.
The final rule could have a far-reaching impact on the status of dietary supplements containing aloe and cascara sagrada that are sold for laxative effects, and possibly on other products that have not been proven safe by toxicological testing procedures despite long-term use. FDA fails to address these issues in its ruling. As a matter of law, it may be argued that FDA's final rule banning the use of aloe and cascara sagrada in OTC laxative drug products would not cover dietary supplements containing these ingredients. Still, it would appear that FDA's classification of aloe and cascara sagrada ingredients as not generally recognized as safe for OTC drug laxative use could form a basis for the agency to attempt to assert that the ingredients are not safe for dietary supplement or other food use.
Indeed, FDA has recognized an overlap between OTC drug claims and permissible structure-function claims for dietary supplements. In FDA's final rule concerning the permissible scope of structure-function claims for dietary supplements (implementing a provision of the Dietary Supplement Health and Education Act of 1994), FDA indicates that certain laxative-type claims may be made in dietary supplement labeling. A dietary supplement may include labeling claims indicating the product is intended to relieve "occasional constipation," which can arise from a variety of causes unrelated to disease.16
Importantly, FDA also indicates that a dietary supplement containing an ingredient covered by an OTC drug monograph, and bearing claims in labeling covered by the monograph, may be misbranded (that is, illegal) if material information required under the monograph is omitted from the labeling of the dietary supplement. In the final analysis, FDA's new regulation clearly implicates the status of aloe and cascara sagrada supplements sold for their laxative effects, and possibly other food and dietary supplement products. This is an issue that demands the attention of the dietary supplement industry, and, as the AHPA/IASC Petition argues, must be addressed by FDA.
Holly J. Bayne is an attorney based in Washington, D.C. at the Law Office of Holly Bayne, P.C., who specializes in advising companies on regulatory and business issues concerning food, dietary supplement, and botanical products.
1. 67 Federal Register 31125 (May 9, 2002).
2. Docket No. 78-N-036L, American Herbal Products Association and the International Aloe Science Council, Petition for Reconsideration and Petition for Stay of Action, Status of Aloe Ingredients and Cascara Sagrada Ingredients as Over-the-Counter Drug Active Ingredients ("AHPA/IASC Petition"). 2002 June 10.
3. 21 Code of Federal Regulations. Sections 10.33, 10.35.
4. 21 Code of Federal Regulations. Sections 321(p), 355.
5. 40 Federal Register 12902 (March 21, 1975).
6. 50 Federal Register 2124 (January 15, 1985).
7. 63 Federal Register 33592 (June 19, 1998).
8. FDA reopened the administrative record on danthron and phenolphthalein in the Federal Register of September 2, 1997 (62 Federal Register 46223), and discussed carcinogenic risk of these ingredients. When FDA announced that it planned to ban phenolphthaleins, Novartis reformulated Ex-Lax¨ to include sennosides as the active ingredient in its regular and maximum strength formulas. In a similar fashion, Schering-Plough reformulated Correctol¨. Bayer dropped Phillips' Gelcaps¨.
9. 63 Federal Register 33592 (June 19, 1998).
10. Common herbal ingredients such as, "prune powder," "prune concentrate dehydrate," Chinese rhubarb (Rheum palmatum L., and R. officinale Baill., Polygonaceae) and frangula or buckthorn (Frangula alnus Mill., Rhamnaceae; syn. Rhamnus frangula L.) are included among the list of "Category II" stimulant laxative ingredients. FDA did not determine these laxative ingredients are unsafe and/or ineffective, nor has it done so with respect to aloe and cascara sagrada. Rather, there were insufficient data in the administrative record to confirm safety and/or efficacy. These ingredients defaulted to "Category II" status according to FDA procedures. Both Chinese rhubarb and frangula are popular stimulant laxatives in Europe, approved by the German Commission E.
11. 67 Federal Register 31126 (May 9, 2002)
12. AHPA/IASC Petition at 3-5. See also 21 Code of Federal Regulations. Section 330.10(a)(4)(i).
13. AHPA/IASC Petition at 5-7. See also McGuffin M, Hobbs C, Upton R, Goldberg A, editors. American Herbal Products Association's Botanical Safety Handbook. Boca Raton (FL): CRC Press LLC; 1997. p. 7-8, 96, 177-9, 183.
14. Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins CW, Rister RS, editors. Klein S, Rister RS, translators. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin (TX): American Botanical Council; Boston (MA): Integrative Medicine Communication; 1998. p. 80-1, 104-5.
15. World Health Organization. WHO monographs on selected medicinal plants. Vol. 1 Geneva, Switzerland: World Health Organization; 1999. p. 33-48. Note: WHO differentiates aloe ("the dried juice of the leaves of Aloe vera ... or A. ferox ... and its hybrids... ." used for treatment of constipation) from aloe vera gel ("the colourless mucilaginous gel obtained from the parenchymatous cells in the fresh leaves of Aloe vera" traditionally used for external treatment of minor wounds and skin irritations).
16. European Scientific Cooperative on Phytotherapy. Monographs on the medicinal uses of plant drugs. Fascicule 5. Exeter, United Kingdom: ESCOP; 1997.
17. AHPA/IASC Petition at 6. See also Blumenthal M, Goldberg A, Brinckmann J, editors. Herbal Medicine: Expanded Commission E Monographs. Newton (MA): Integrative Medicine Communications; 2000.
18. AHPA/IASC Petition at 9-14. See also 60 Federal Register 67211 (Dec. 28, 1995).
19. 65 Federal Register 1000, 1015 (Jan. 6, 2000).