The Dietary Supplement Health and Education Act of 1994 (DSHEA)1 dramatically altered the legal and regulatory environment for dietary supplement and food manufacturers.2 Even though the passage of DSHEA has been almost uniformly favorable for the dietary supplement and food industries from a marketing perspective, the post-DSHEA environment has created a new set of legal and regulatory challenges.3 One challenge that has gained prominence during the past year has been the emergence of legal and regulatory issues — and in particular potential product liability issues — associated with potential interactions between herbs (present in dietary supplements and/or foods) and conventional drugs.
This article focuses on the legal and regulatory implications that may result from the allegation that a company "failed to warn" of such an interaction — and also provides guidance for companies to follow when crafting herb/drug interaction warnings. In general, whether to include an herb/drug interaction warning on a food or dietary supplement depends upon a variety of factors, including, but not limited to: (1) the likelihood of a potential interaction; (2) the potential severity of a potential interaction; (3) whether the interaction is well known by the general population or scientific community; (4) whether drug product labeling already warns against ingestion of the herb or dietary supplement; and (5) the level of the herb present in the dietary supplement.
Increased Focus on Herb/Drug Interactions
Due to the number of recent journal articles and government reports that have addressed potential herb/drug interactions, dietary supplement warning-related issues are now likely to take on greater importance. Below is a sampling of recent government statements and journal articles regarding herb/drug interactions. Although these statements and articles are not legally binding, and some of them have been quite controversial (and have not been adopted by industry), they nevertheless still reflect the emerging focus on this issue.
• In January 2000, the British medical journal The Lancet published a detailed article on herb-drug interactions.4 The article identified a wide range of herbs that have been reported to cause drug interactions.
• In 2000, the American Botanical Council published an extensive article on herb-drug interactions in HerbalGram, which also identifies actual and potential interactions on 49 commony sold herbs.5
• On February 10, 2000, FDA issued a "Public Health Advisory" to health care professionals entitled "Risk of Drug Interactions with St. John’s Wort and Indinavir and Other Drugs."6 The agency identified numerous potential interactions between St. John’s wort and various drug products. Subsequently, then-FDA Commissioner Jane Henney published a brief article in the Journal of the American Medical Association (JAMA) on the same topic.7 In addition, the Federal Trade Commission (FTC) has entered into consent decrees mandating the use of specific St. John’s wort drug interaction language.8
• In August 2000, The National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM), announced that it was finalizing preparations for a research project designed to identify potential adverse reactions between dietary supplements (including herbs) and drugs.9 More than $4 million in grants have been targeted for the research project, which is expected to take up to six years to complete.
• The Office of Inspector General of the Department of Health and Human Services (OIG) issued a report in April 2001 entitled "Adverse Event Reporting for Dietary Supplements: An Inadequate Safety Valve" (OIG Report). The OIG identified risks associated with certain dietary supplements, and emphasized risks associated with herb/drug interactions. The OIG report states: "Several recent studies have identified potentially dangerous interactions between drugs and herbs that can include synergistic effects, poisoning, or inactivation of one of the substances. In one recent study, researchers at the National Institutes of Health demonstrated that St. John’s Wort, typically used to enhance mood, could significantly compromise the effectiveness of antiviral drugs often prescribed to treat HIV infection."10
• The U.S. General Accounting Office (GAO) issued a report in September, 2001 to the U.S. Senate Special Committee on Aging, entitled "Health Products for Seniors: Anti-Aging Products Pose Potential for Physical and Economic Harm." The GAO also identified herb/drug interactions as one of the potential dangers associated with dietary supplement use, noting, "Since seniors take more prescription medicines on average than do younger adults, the risk of interactions among seniors may be higher. For example, evening primrose oil, garlic, ginkgo biloba, ginseng, glucosamine, and St. John’s Wort magnify the effect of blood-thinning drugs such as warfarin or coumadin. We also identified reports suggesting that ginkgo biloba may reduce the effects of seizure medications and glucosamine may have a harmful effect on insulin resistance."11
• U.S. Rep. Susan Davis (D-CA) introduced two dietary supplement related bills on October 9, 2001, to Congress. One of the bills, H.R. 3065, would require dietary supplement manufacturers to register with the FDA and submit adverse event reports to the agency. The bill would also require dietary supplement companies to report to the FDA all adverse experiences a company becomes aware of where "there is a reason to believe that a factor associated with the experience is the interaction of the dietary supplement involved with a drug … ."12
• On December 5, 2001, the NIH National Institute of Allergy and Infectious Diseases issued a news release13 indicating that researchers have found that garlic supplements can cause a potentially harmful side effect when combined with a drug commonly used to treat HIV/AIDS (saquinavir). The news release provides that "[i]n the presence of garlic supplements, blood concentrations of saquinavir decreased by about 50% among our study participants." The researchers noted that it is unclear how garlic supplements chemically disrupt the intake of the HIV/AIDS medication.14
• In March 2002, the White House Commission on Complementary and Alternative Medicine Policy issued its final report (WHCCAM Report) — which addressed potential dietary supplement/drug interactions. The report provides: "When information about substantial, documented risks does become available, as in the case of the potential interaction between St. John’s Wort (Hypericum perforatum) and certain prescription drugs, it should be included on the label of both the prescription drug and the dietary supplement. Labels should provide information about significant interactions with prescription or over-the-counter drugs, food, or other health products, as well as information about likely, significant risks to vulnerable populations such as children, the elderly, pregnant or nursing women, and those with certain health conditions or compromised immune systems."15
Product Liability Standards Associated with A "Failure to Warn"
Product liability actions in the U.S. are generally based upon three potential causes of action: (1) negligence, (2) strict liability, and (3) warranty (express or implied). Although different standards apply, each cause of action is nevertheless generally capable of addressing various types of product defects, such as manufacturing defects (defects in the production process for a specific batch of products), design defects (defects in intended product formulation) and marketing defects (including a failure to warn).16
Regardless of the product liability cause of action (e.g., whether it is based upon the theory of negligence, strict liability or warranty), the common elements of a product liability action based upon the failure to warn generally include: (1) whether the manufacturer knew or should have known of the potential danger, and (2) whether the manufacturer through labeling and/or educational efforts could have prevented or reduced the danger. The "duty to warn" generally consists of two duties. One duty is to provide adequate instructions for safe use and the other is to provide a warning regarding dangers. A warning provides information on the danger itself, whereas instructions for use provide information on how to use the product safely.
Finally, companies have a continuing duty to reevaluate claims and warnings. Many courts have held that manufacturers have a duty to provide warnings or dangers discovered after the product is initially sold (i.e., there is a continuing duty to warn).
Foods/Dietary Supplements: High Standard of Care
Since the early days of the common law, those engaged in the business of selling food intended for human consumption have been held to a high degree of responsibility for their products. Traditionally, under the theory of negligence, the standard of care for food and drinks has been the highest standard under the law.17 Courts in the U.S. have acknowledged, however, that many products cannot possibly be made entirely safe for consumption, and that any food or drug necessarily involves some risk of harm, even if only from over-consumption. Companies are generally not expected to warn against risks that a reasonable, informed person would have been aware of at the time of sale. In this regard, the Restatement, Second, of Torts section 402A18 provides that "a seller is not required to warn with respect to products, or ingredients in them, which are dangerous, or potentially so, when consumed in excessive quantity, or over a long period of time, when the danger, or potentiality of danger, is generally known and recognized. Again the dangers of alcoholic beverages are an example, as are also those foods containing such substances as saturated fats, which may over a period of time have a deleterious effect upon the heart."
For herbal dietary supplements and foods subject to potential drug interactions, therefore, a critical issue is whether a reasonable, informed person would be aware of the potential herb/drug interaction in the absence of label warnings. If a reasonable, informed person would not necessarily be aware of the herb/drug interaction, development and use of an appropriate warning in certain circumstances may avoid unnecessary product liability exposure.
FDA Food/Drug Interaction Warning Requirements for Prescription and OTC Drugs
As an initial matter, from a product liability perspective, FDA regulatory requirements applicable to prescription and OTC drugs have generally been deemed to provide minimum standards from a product liability perspective. Compliance with FDA regulatory requirements ordinarily does not shield a company from product liability causes of action.19 Nevertheless, compliance with industry standards and custom, and FDA regulatory requirements, will ordinarily minimize potential liability.
Prescription drug products20 are required, under FDA regulatory standards, to identify food/drug interactions on product labeling. Specifically, prescription drug labeling must contain "specific practical guidance for the physician on preventing clinically significant drug/drug and drug/food interactions that may occur in vivo in patients taking the drug."21 In addition, prescription drug advertising is also required to contain a "brief summary" that identifies important warnings (which may include food/drug interactions in certain circumstances).22
Effective April 1999, FDA altered the mandatory labeling requirements for OTC drugs, in part, due to concerns regarding OTC drug adverse events.23 The new OTC drug labeling regulations establish standardized format and content requirements for drug product labeling and require identification of drug/drug and food/drug interactions. Specifically, the revised OTC drug labeling regulations mandate numerous warnings, including but not limited to:
(1) "Do not use" warnings, which generally identify absolute contraindications for the drug product (regardless of whether a doctor or pharmacist is consulted) (e.g., "Do not use if you have diabetes");
(2) "Ask a doctor before use" warnings, which identify those situations where consumers should not use a product until a doctor is consulted (e.g., "Ask a doctor before use if you have glaucoma"); and
(3) "Ask a doctor or pharmacist before use if you are …" warnings, which identify all drug/drug and food/drug interaction warnings (e.g., "Ask a doctor or pharmacist before use if you are taking a prescription drug").24
FDA Food/Drug Interaction Warnings for Dietary Supplements
Except in a few situations, such as iron-containing dietary supplements and foods and supplements containing psyllium,25 the FDA does not mandate the content or format of warnings that must be included on foods or dietary supplements. Rather, the decision to include a dietary supplement or food warning is generally based upon Section 201(n) of the Federal Food Drug and Cosmetic Act, which requires companies to reveal material facts related to the consequences of product use.26 Specifically, the provision states, "If an article is alleged to be misbranded because the labeling or advertising is misleading, then in determining whether the labeling or advertising is misleading there shall be taken into account (among other things) not only representations made or suggested by statement, word, design, device, or any combination thereof, but also the extent to which the labeling or advertising fails to reveal facts material in light of such representations or material with respect to consequences which may result from use of the article to which the labeling or advertising relates under the conditions of use prescribed in the labeling or advertising thereof or under such conditions of use as are customary or usual."27
Importantly, according to DSHEA, inclusion of product warnings on a dietary supplement product is permitted and encouraged, but not required. Moreover, such warnings will not render a product "misbranded."28 Since the passage of DSHEA, FDA has emphasized the importance of the above provision. Perhaps due to the increase in the range of acceptable dietary supplement and "functional food" claims, FDA specifically indicated in its final rule addressing dietary supplement structure/function claims that dietary supplements (and foods) are required to contain appropriate warnings, including adverse event and interaction warnings. Specifically, FDA stated that "it is important to inform consumers about potential adverse effects or drug interactions for specific dietary supplement ingredients. In fact, dietary supplement labeling, like the labeling of other FDA-regulated products, is required to include all facts that are material in light of consequences that may result from use of the product or representations made about it … [emphasis added]. This provision is not intended in any way to preclude truthful adverse event or drug interaction information from appearing in a dietary supplement’s labeling."29
Dietary supplement and food companies must therefore evaluate adverse event and interaction-related issues in order to determine whether warnings should be included on product labeling or advertising. In order to make this assessment, it is often advisable for companies to: (1) monitor, on an ongoing basis, scientific developments regarding products they market; and (2) evaluate industry custom, including trade association statements regarding potential herb/drug interactions.30
Determining Whether to Include Herb/Drug Interaction Warnings if the Applicable Drug Already Warns against Ingestion of the Herb
If drug product labeling already warns against the ingestion of an herb present in a dietary supplement or food, an argument may be made that such a warning on the food or dietary supplement product would be redundant, unnecessary, and contrary to industry custom. Many food substances have the potential to interact with drug products — and drug product labeling historically has identified such interactions, whereas food labeling has not. Grapefruit and grapefruit juice, for example, are capable of interacting with a wide variety of drug products. Similarly, green leafy vegetables, and vitamins C, E, and K are known to interact with warfarin (an anti-coagulant).
According to industry custom, however, drug products warn against ingestion of grapefruit, grapefruit juice, certain vitamins, and/or green leafy vegetables — whereas food and dietary supplement labeling do not contain drug interaction information. As noted previously, however, the WHCCAM Report took the opposite approach. This is obviously a very complex, fact-dependent issue, for which companies must consult with qualified legal counsel.
Crafting Interaction Warnings
To the extent dietary supplement and food companies decide to include herb/drug interaction warnings on their products, traditional caveats applicable to development of OTC product warnings should be considered. The following are a sampling of caveats/guidelines that should be considered when crafting product warnings.
(1) Remember the target audience. OTC drug product warnings are intended to be read by consumers without any health professional intervention. Language should be clear, concise, and should avoid technical jargon to the extent possible.
(2) Provide appropriate details. Depending upon the situation, it may be necessary to inform consumers of the likelihood of the potential adverse event, as well as the severity of the potential event.
(3) Prominence can be as important as content. Even if the content of a warning is carefully crafted to reflect the target audience, and provides appropriate details, a warning can be deemed insufficient in the product liability context if it is not sufficiently prominent. Prominent placement of important product warnings is essential.
(4) If a product insert is used (and the insert identifies product warnings), depending upon the situation, it may not be advisable to merely include the disclosure "Read Insert Prior to Use" on the outer package label without also identifying the general warning on the outer package label.31
(5) Depending upon the situation, it may not be advisable to merely include the disclosure to consult a physician on the outer label — without providing additional warning-related language on product labeling.32
(6) Depending upon the situation, it may be advisable to phrase a disclosure as a contraindication rather than a general warning. For drug products, the FDA has distinguished between contraindications (situations where a product should not be used because the risk of use clearly outweighs any possible benefit) and general warnings (which describe potential serious adverse reactions and safety hazards, along with limitations imposed by them and steps that should be taken if they occur).33 In certain situations, it may be advisable to utilize "Do not use" language typical of most contraindications (e.g., "Do not use if you are taking cancer medication").
Dietary supplement and functional food companies must carefully evaluate product liability issues when crafting product labels, claims, and warnings. In determining whether to include an herb/drug interaction warning on product labeling, a variety of issues should be evaluated, including, but not limited to: (1) the likelihood of a potential interaction; (2) the potential severity of a potential interaction; (3) whether the interaction is well known by the general population or scientific community; (4) whether drug product labeling already warns against ingestion of the herb or dietary supplement; and (5) the level of the herb present in the dietary supplement.
The last factor deserves particular emphasis. Even if an herbal ingredient is capable of interacting with a drug, it should be determined whether the ingredient could cause such an interaction at the level included within the food or dietary supplement. Many foods and dietary supplements contain very low levels of certain herbal ingredients, and assuming the background science supports the conclusion that interactions do not occur at such levels (taking into consideration daily consumption patterns), an interaction warning might not be necessary.
Finally, due to the complexity of these issues, it must be emphasized that manufacturers and marketers of dietary supplement and food products must consult with legal counsel to address potential product liability issues with respect to herb/drug interactions. No article is capable of addressing the complexities of these issues, and therefore product-specific legal advice must be obtained.
Paul D. Rubin is a Partner in the Food and Drug Practice Group of Patton Boggs LLP, Washington D.C. He may be reached via e-mail at email@example.com.
1. Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103-417, 108 Stat. 4325 (Oct. 25, 1994).
2. See e.g., Pinco RG, Rubin PD. Ambiguities of the Dietary Supplement Health and Education Act of 1994. Food and Drug Law Journal 1995;51:383.
3. See e.g., Pape SM, Kracov DA, Rubin PD. Dietary Supplements and Functional Foods: A Practical Guide to FDA Regulation. Tampa (FL): Thompson Publishing; 2001.
4. Fugh-Berman A. Herb-drug interactions. Lancet 2000;355:134-8.
5. Blumenthal M. Interactions between herbs and conventional drugs: Introductory considerations. HerbalGram 2000;49:52-63.
6. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory, Risk of Drug Interactions with St. John’s Wort and Indinavir and Other Drugs. 2000, Feb. Available from: http://www.fda.gov/cder/drug/advisory/stjwort.htm. See also Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir Concentrations and St. John’s Wort. Lancet 2000;355:547-8. Jobst K, McIntyre M, St. George D, Whitelegg M. Safety of St. John’s Wort, Lancet 2000;355:575. It has been noted that many common foods and drinks also affect the cytochrome P-450 metabolic pathway. Grapefruit juice is an inhibitor of cytochrome P-450, whereas cruciferous vegetables, such as broccoli, cabbage, and Brussels sprouts, are cytochrome P-450 inducers (charcoal-grilled beef, red wine, and ethanol are also known to be cytochrome P-450 inducers).
7. Henney J. Risk of Drug Interactions with St. John’s Wort, JAMA 2000;283:13.
8. See Panda Herbal International, Inc. C-4018 and ForMore, Inc., C-4021 (Aug 3, 2001).
9. National Institutes of Health, National Center for Complementary and Alternative Medicine and National Cancer Institute. Botanical/Drug Interactions (news release). 2000 Aug. Available from: http://grants2.nih.gov/grants/guide/rfa-files/RFA-AT-00-004.html.
10. Department of Health and Human Services, Office of Inspector General. Adverse Event Reporting For Dietary Supplements, An Inadequate Safety Valve. OEI-01-00180, April 2001.
11. General Accounting Office. Health Products for Seniors, "Anti-Aging" Products Pose Potential for Physical and Economic Harm. GAO-01-1129, September 2001.
12. To Amend the Federal Food, Drug and Cosmetic Act to require the manufacturers of dietary supplements register with the Food and Drug Administration, to require the submission to such Administration of reports on adverse experiences regarding such supplements, and for other purposes, H.R. 3065, 107th Cong., 1st Sess. (2001).
13. National Institutes of Health, National Institute of Allergy and Infectious Disease. News Release, Garlic Supplements Can Impede HIV Medication. 2001, Dec. Available from: http://www.nih.gov/news/pr/dec2001/niaid-05.htm.
14. See e.g., Piscitelli SC, Burstein, AH, Welden N, Gallicano KD, Falloon J. The effects of garlic supplements on the pharmacokinetics of Saquinavir. Clin Infect Dis 2002 January 15;34(2):234-8.
15. Issued by the White House Commission on Complementary and Alternative Medicine Policy, Department of Health and Human Services, 2002 March 22.
16. See e.g., Jennings v. BIC Corp., 181 F.3d 1250, 1255 (11th Cir. 1999) (applying Florida’s strict products liability law); Arkansas-Platte & Gulf Partnership v. Dow Chemical Co., 886 F. Supp. 762 (D. Colo. 1995) (noting that Colorado’s general products law imposes a duty on the manufacturer to act reasonably in design, manufacture, and sale of a product).
17. See e.g., Eisenbeiss v. Payne, 25 P.2d 162 (Ariz. 1933).
18. American Law Institute. The Restatement of The Law Second, Torts 2d. St. Paul (MN); 1986. Section 402A.
19. See e.g., Woodell v. The Proctor & Gamble Mfg. Co., No. Civ. 3:96-2723-H, 1999 WL 624527 (N.D. Tex. Aug. 16, 1999); Barry v. Don Hall Labs., 642 P.2d 685 (Or. Ct. App. 1982); Michael v. Warner/Chilcott, 579 P.2d 183 (N.M. Ct. App. 1978).
20. Unlike OTC drug products, prescription drug products are generally protected under the "learned intermediary" doctrine, which holds that a prescription drug manufacturer ordinarily only has a duty to warn a physician or healthcare professional of product risks, rather than the ultimate consumer. See Sterling Drug, Inc. v. Cornish, 370 F.2d 82, 85 (8th Cir. 1966). In a recent case in New Jersey, however, the New Jersey Supreme Court refused to apply the "learned intermediary" doctrine to a prescription drug company due to the company’s use of "direct-to-consumer" (DTC) advertisements. Rather, the New Jersey Supreme Court established a rebuttable presumption that the duty to warn consumers is satisfied by compliance with FDA regulations. Perez v. Wyeth Labs., 734 A.2d 1245, (N.J. 1999). At the present time, it is unclear how the proliferation of DTC advertising, Internet claims, and FDA Medication Guides (an FDA-approved form of patient package inserts, 21 C.F.R. Part 208) will influence the judicial application of the learned-intermediary doctrine.
21. Drug interactions, 21 C.F.R. Sect. 201.57(f)(4)(i) (2001).
22. Prescription-drug advertisements, 21 C.F.R. Sect. 202.1 (2001).
23. Format and content requirements for over-the counter (OTC) drug product labeling, 64 Fed.Reg. 13253 (March 17, 1999), codified at 21 C.F.R. Sect. 201.66 (2001). An emerging issue is the extent to which FDA’s OTC drug labeling requirements may preempt state regulation of OTC drugs. Section 751 of the Federal Food, Drug, and Cosmetic Act (FFDCA) preempts states from issuing labeling regulations that conflict with FDA OTC drug labeling requirements — but specifically indicates that Federal preemption does not affect product liability actions. Specifically, the FFDCA states: "No Effect on Product Liability Law. Nothing in this section shall be construed to modify or otherwise affect any action or the liability of any person under the product liability law of any state." Section 751(e) of the FFDCA.
24. Content requirements 21 C.F.R. Sect. 201.66(c)(5) (2001).
25. Food labeling warning and notice statements, See 21 C.F.R. Sect. 101.17 (2001).
26. The Federal Trade Commission (FTC) has also focused its attention on dietary supplement and functional food safety – and in particular the importance of disclosing material facts to consumers in product advertising (the FTC’s jurisdiction over dietary supplements and foods is for the most part limited to product advertising as opposed to labeling). In its guidance document entitled "Dietary Supplements: An Advertising Guide for Industry," the FTC provides a number of examples where dietary supplement advertising should be qualified to reflect adverse event information.
27. Sect. 201(n) of the Federal Food Drug and Cosmetic Act, Pub. L. No. 75-717, 52 Stat. 1040 (1938).
28. Sect. 10 of DSHEA provides: "A dietary supplement shall not be deemed misbranded solely because its label or labeling contains directions or conditions of use or warnings." Section 403(s) of the FFDCA.
29. Regulations on Statements Made for Dietary Supplements Concerning the Effect of the Product on the Structure or Function of the Body, 65 Fed.Reg. 1000 (January 6, 2000).
30. With regard to herbal products sold in the U.S., it may be prudent to review documents prepared by the American Herbal Products Association and American Botanical Council. See e.g., McGuffin M, Hobbs C, Upton R, Goldberg A. American Herbal Product Association’s Botanical Safety Handbook. Boca Raton, FL: CRC Press, 1997; Blumenthal M, Goldberg A, Gruenwald A, Hall T, Riggins CW, Rister RS (eds.), Klein S, Rister RS (trans.). The Complete German Commission E Monographs: Therapeutic Use of Herbal Medicines. Austin, TX: American Botanical Council, 1998.
31. See e.g., Woodell v. The Proctor & Gamble Mfg. Co., No. Civ. 3:96-2723-H, 1999 WL 624527 (N.D. Tex. Aug. 16, 1999).
32. See e.g., Torsiello v. Whitehall Labs., 398 A.2d 132 (N.J. Super. Ct. App. Div. 1979).
33. Contraindications and Warnings, 21 C.F.R. Sects. 201.57(d) and (e) (2001).