Inspections, Compliance, Enforcement, and Criminal Investigations
Bayer HealthCare LLC 27-Oct-2008
Department of Health and Human Services
Public Health Service
Rockville MD 20857
October 27, 2008
Mr. Gary S. Balkema
Bayer HealthCare L.L.C.
36 Columbia Road
Morristown, New Jersey 07962
Dear Mr. Balkema:
This letter concerns "BAYER ASPIRIN With HEART ADVANTAGE" (Bayer Heart Advantage), which is marketed by your firm as a combination over-the-counter (OTC) drug dietary supplement product. According to the package labeling, each caplet (tablet) contains, among other ingredients, 81 mg of aspirin and 400 mg of phytosterols. The product is prominently labeled as containing these ingredients (e.g., "BAYER ASPIRIN" and "ASPIRIN PLUS CHOLESTEROL LOWERING PHYTOSTEROLS"). It is also clearly labeled as an "ANALGESIC/PHYTOSTEROL SUPPLEMENT." The labeling also prominently describes this product as the "The Only Product That Contains ... • Aspirin, to protect your heart by keeping your blood flowing freely [and] • Phytosterols, to help lower bad cholesterol ......"
Immediately preceding the "Supplement Facts" panel appearing on the package labeling and bottle label are directions for daily use ("Directions: For phytosterols, adults and children 12 years and over, take one caplet twice a day with meals ...." Regarding the phytosterols in Bayer Heart Advantage, the carton labeling also includes a health claim about phytosterols and reduced risk of heart disease (see 21 C.F.R. § 101.83) stating: "DIETARY SUPPLEMENTS OR FOOD CONTAINING AT LEAST 400MG PER SERVING OF FREE PHYTOSTEROLS, EATEN TWICE A DAY WITH MEALS FOR A DAILY TOTAL INTAKE OF AT LEAST 800 MG, AS PART OF A DIET LOW IN SATURATED FAT AND CHOLESTEROL, MAY REDUCE THE RISK OF HEART DISEASE BY LOWERING BLOOD CHOLESTEROL. EACH BAYER ASPIRIN WITH HEART ADVANTAGE DUO-CAP CONTAINS 400MG OF FREE PHYTOSTEROLS." In addition, the package labeling also bears a "Drug Facts" panel, which states that the product is used" • for the temporary relief of minor aches and pains ... [and] • ask your doctor about other uses for Bayer Aspirin with Heart Advantage," and provides directions for those uses, i.e., "Directions ... • talk to your doctor about regimen use of aspirin ... [and] • for pain, adults and children 12 years and over: take 4 caplets, not to exceed 4 caplets in 24 hours ...."
These and other statements related to this product's intended uses also appear on retail shelf promotional material for this product. Other statements include: "More heart protection with: • Aspirin, proven to help reduce the risk of a heart attack by up to 32% in appropriate patients
•Phytosterols, to help lower LDL (bad) cholesterol"; "Aspirin helps prevent blood clots and can cut the risk of a heart attack by up to 32%"; "By lowering cholesterol, phytosterols can help prevent plaque buildup."
Regarding the use of Bayer Heart Advantage as a source of aspirin, the Drug Facts panel states that the analgesic is intended to treat pain. However, other statements and representations on the package suggest that Bayer Heart Advantage is also intended for long-term daily use in preventing heart attacks and lowering cholesterol, and therefore in preventing and treating cardiovascular disease and hypercholesterolemia. Moreover, the labeled directions for adult analgesic use specify a daily dosage of "4 caplets, not to exceed 4 caplets in 24 hours," which falls within the range of the dosages listed in the professional labeling for aspirin for cardiovascular-related indications (see 21 C.F.R. § 343.80), but is well below the dosages that are listed in the tentative final monograph1 for internal analgesics for adults and children 12 and over (325 mg to 650 mg every four hours or 325 to 500 milligrams every 3 hours or 650 to 1,000 milligrams every 6 hours, not to exceed 4000 mg in 24 hours, or as directed by a doctor). See 53 FR 46204 at 46257.
As labeled, Bayer Heart Advantage is a "drug" under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321(g)(1)(B)), because it is intended to be used as an internal analgesic and to mitigate, treat, or prevent disease (specifically, heart disease and hypercholesterolemia), and under section 201(g)(1)(C) of the Act (21 U.S.C. § 321(g)(1)(C)) because it is intended to affect the structure or function of the body.
Notwithstanding your attempt to market this product as a combination drug-dietary supplement, the presence of aspirin in this product, with its intended uses as an analgesic and to mitigate, treat, and prevent heart disease, renders the entire product a drug. The phytosterols in this product could be marketed separately as a dietary supplement if the claims, "Plus Cholesterol Lowering Phytosterols" and "Phytosterols, to help lower bad cholesterol," were removed and no other cholesterol-lowering claims were made, except as provided for in 21 C.F.R. § 101.83 as part of an explanation of the mechanism by which phytosterols reduce the risk of heart disease. However, when, as here, a drug and a dietary ingredient are combined into a single dosage form, the combination becomes a "drug" under section 201(g) of the Act (21 U.S.C. § 321(g)).
Although the package labeling for Bayer Heart Advantage bears a health claim for phytosterols and the reduced risk of coronary heart disease, as described under 21 C.F.R. § 101.83, the presence of this claim does not exempt the product from regulation as a drug if it meets the definition of a drug in section 201(g)(1) of the Act (21 U.S.C. § 321(g)(1)) for other reasons. Moreover, the claims "Plus Cholesterol Lowering Phytosterols" and "Phytosterols, to help lower bad cholesterol" on the package labeling are not health claims under 21 C.F.R. § 101.83, but rather claims to treat, mitigate, or prevent hypercholesterolemia and coronary heart disease. These conditions are diseases as defined in 21 C.F.R. § 101.93(g)(1). See 21 C.F.R. § 101.93(g)(2)(ii); 65 FR 1000, 1016-1019 (2000). Accordingly, these claims render the phytosterols in your product a drug under section 201(g)(1)(B) of the Act (21 U.S.C. § 321(g)(1)(B)).
There is no provision in the Act, as amended by the Nutrition Labeling and Education Act of 1990 (NLEA) or by the Dietary Supplement Health and Education Act of 1994 (DSHEA) that exempts any part of your product from the scope of section 201(g) of the Act (21 U.S.C. § 321(g)).2 Under section 201(g)(1)(D) of the Act (21 U.S.C. § 321(g)(1)(D)), the phytosterols used in combination with the aspirin in Bayer Heart Advantage are also drugs, even in the absence of any claims that the phytosterols treat, mitigate, or prevent hypercholesterolemia or heart disease, because the phytosterols are components of the finished drug product. See 21 C.F.R. § 210.3(b)(3). And, based on the labeling claims attributed specifically to the phytosterols in this product (e.g., "Phytosterols, to help lower bad cholesterol ...," "DIETARY SUPPLEMENTS ... CONTAINING AT LEAST 400MG PER SERVING OF FREE PHYTOSTEROLS ... MAY REDUCE THE RISK OF HEART DISEASE BY LOWERING BLOOD CHOLESTEROL" and "By lowering cholesterol, phytosterols can help prevent plaque buildup ..."), they are also "active" drug ingredients within the meaning of 21 C.F.R. § 201.66(b)(2).
Moreover, based on the combination of active drug ingredients (i.e., aspirin and phytosterols) and their combined labeled use in mitigating, treating, or preventing cardiovascular-related diseases, as described above, Bayer Heart Advantage is a new drug within the meaning of section 201(p) of the Act (21 U.S.C. § 321(p)) and 21 C.F.R. § 310.3(h), because it is not generally recognized as safe and effective for its labeled uses. Bayer Heart Advantage is not subject to the Food and Drug Administration's (FDA's) OTC Drug Review, because no product formulated with these active ingredients and labeled for these intended uses has previously been commercially marketed, and the Agency has never proposed that such a product be included in that Review.3 Thus, the current marketing of Bayer Heart Advantage violates section 505(a) of the Act (21 U.S.C. § 355(a)), because it is a new drug and it is not the subject of an approved new drug application.
In addition, Bayer Heart Advantage is misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)) because it does not bear adequate directions for its intended uses, i.e., for preventing heart attacks and preventing/treating heart disease in general. "Adequate directions for use" is defined in 21 C.F.R. § 201.5 as "directions under which the layman can use a drug safely for the purposes for which it is intended." Thus, if an indication requires the supervision of a practitioner licensed to prescribe drugs, adequate directions for use cannot be written for an OTC product for that indication. See U.S. v. Articles of Drug, 625 F.2d 665, 672-673 (5th Cir. 1980). Indeed, with regard to aspirin, when the Agency finalized the regulations for the professional labeling for aspirin (21 C.F.R. § 343.80) (63 FR 56802, 56809) (Oct. 21, 1998), it explicitly rejected a comment recommending that FDA allow consumer-directed OTC labeling for aspirin for various cardiovascular indications, stating:
"The Agency considers the conditions and uses of aspirin that are the subject of this final rule to require the supervision of a physician (or other practitioner licensed to prescribe drugs) to ensure safe use ... It is not possible, in OTC drug product labeling, to provide adequate directions and warnings to enable the layperson to make a reasonable self assessment of these factors [relating to the need for drug therapy and its safety for these purposes]."
As described in 21 C.F.R. § 343.80, cardiovascular indications accordingly are permissible only in the professional labeling for aspirin. Under that regulation, manufacturers are not permitted to disseminate labeling for their OTC aspirin products to lay consumers for cardiovascular-related indications.
Bayer Heart Advantage is also misbranded under sections 502(f)(2) and 502(a) of the Act (21 U.S.C. §§ 352(f)(2) and (a)) because its labeling does not bear adequate warnings and is misleading. Warnings that appear within the "Drug Facts" panel are both inconsistent and incompatible with the directions elsewhere on the labeling that recommend the daily consumption of Bayer Heart Advantage as a source of dietary phytosterols (i .e., "Directions: For phytosterols, adults and children 12 years and over, take one caplet twice a day with meals ..."). Furthermore, the placement of warnings within the perimeter of the "Drug Facts" panel, and the separate "Supplement Facts" panel and directions for use that do not include those warnings, suggests that the information in the "Drug Facts" panel pertains only to the uses of the product listed in that panel, and that such warnings are not relevant when using the product for the phytosterols component. Thus, these labeled warnings are not adequate, and are misleading because they are undermined by the inconsistent and incompatible language pertaining specifically to the phytosterols component. The Agency is concerned that persons using your product to supplement their diet may overlook or disregard the importance of these warnings, or may be unsure as to their relevance when there are no such warnings associated with the supplement portion of the labeling, and that adverse events may occur as a result. Specific examples of this include:
(1) Your product labeling specifies a ten-day use limit under the "Warnings" heading in the "Drug Facts" panel (i.e., "Stop use and ask a doctor if ... • pain gets worse or lasts more than 10 days"), but this warning appears only within the "Drug Facts" panel of the retail package. Its placement within the perimeter of the "Drug Facts" panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling: "For phytosterols, adults and children 12 years and over, take one caplet twice a day ....", without any limitation on duration indicated.
(2) Your product labeling warns against use by children and teenagers, to prevent Reye's Syndrome (i.e., "Warning[ ] ... Reye's syndrome: Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness reported to be associated with aspirin."), but this warning appears only within the "Drug Facts" panel of the retail package. Its placement within the perimeter of the "Drug Facts" panel suggests that it applies exclusively to the analgesic use discussed in that panel. It is contradicted by the statement elsewhere on the labeling: "For phytosterols, adults and children 12 years and over, take one caplet twice a day ....", without any warning that there are circumstances where it is not appropriate for children and teenagers to take the product.
The concerns with the two warnings listed above also apply to the following warnings within the perimeter of the "Drug Facts" panel:
(1) the warning against use by those who are allergic to aspirin;
(2) the warning regarding use by those who consume alcohol;
(3) the warning regarding use by those who may have stomach problems, bleeding problems, ulcers, or asthma;
(4) the warning regarding use by those who may be taking prescription drugs for anticoagulation, gout, diabetes, or arthritis;
(5) the warning to stop use if an allergic reaction occurs, redness or swelling is present, or ringing in the ears or loss of hearing occurs; and
(6) the warning against use when pregnant or breast-feeding.
Moreover, Bayer Heart Advantage is misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)) in that the directions for daily supplement use (i.e., "Directions: For phytosterols, adults and children 12 years and over, take one caplet twice a day with meals ...") are misleading when juxtaposed with the "Drug Facts" directions for use (i.e., "Directions ... for pain, adults and children 12 years and over, take 4 caplets, not to exceed 4 caplets in 24 hours") and with the ten-day use limitation under the "Warnings" heading in the "Drug Facts" panel, as described above. Thus, these statements on the labeling send consumers a mixed message about the purpose of the product and the duration for which it can be safely used. Because these two different directions for use are inconsistent and contradictory, Bayer Heart Advantage fails to bear adequate directions for use in this regard and, therefore, is also misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)).
We acknowledge your August 18, 2008, letter to Gerald F. Masoudi regarding Bayer Heart Advantage. In that letter, you assert that both FDA and the Federal Trade Commission have encouraged direct education of the public about the cardiovascular benefits of aspirin, and that a ban on cardiovascular claims in consumer labeling for Bayer Heart Advantage would violate Bayer's rights under the First Amendment. We would like to briefly address your assertions.
With regard to your first point, whether or not FDA or FTC have encouraged Bayer (or other aspirin manufacturers) to engage in direct to consumer advertising about the benefits of aspirin for cardiovascular disease, we are not aware that FDA has ever encouraged an aspirin manufacturer to market an OTC aspirin product with consumer labeling concerning its intended use for any cardiovascular indication, nor are we aware of any statements by FDA suggesting that it would be legally permissible to market such a product. FDA's regulation regarding the professional labeling for aspirin (see 21 C.F.R. § 343.80), as the title of the regulation indicates, makes clear that the cardiovascular indications are to be included solely in labeling directed at healthcare professionals, and not in labeling for the general public. In any event, Bayer Heart Advantage does not contain aspirin alone, but aspirin in combination with phytosterols. To the best of our knowledge, the Agency has made no statement sanctioning either the OTC use of or OTC advertising for a combination aspirin/phytosterol product for cardiovascular indications; therefore, any past statements by the Agency regarding direct to consumer advertising for cardiovascular uses of aspirin are inapplicable to your product.
With regard to your second point, FDA believes that the Agency's objections to your marketing of Bayer Aspirin with Heart Advantage would pass muster when analyzed under the test for restrictions on commercial speech set forth by the Supreme Court in Central Hudson Gas & Electric Corporation v. Public Service Commission, 447 U.S. 557 (1980).
First, as noted in your letter, commercial speech that is false or misleading, or that concerns illegal activity, is not protected by the First Amendment and may be banned. Even if specific cardiovascular-related claims are protected by the First Amendment, your labeling is false or misleading for the reasons set forth above, and therefore is not protected by the First Amendment.
Second, we note that your argument, taken to its logical conclusion, would necessitate the abolishment of both the new drug approval process and the OTC Drug Review, because it would allow the marketing of human drug products without regard to whether such products meet either of the applicable statutory standards for legal marketing. Although the determination above that the labeling for your product is false or misleading obviates the need for FDA to address the other three prongs of Central Hudson, the new drug approval process and the OTC Drug Review are clearly permitted under the final three prongs of the Central Hudson test, including for the
1) The Government's Interest is Substantial - The ultimate objective of the new drug approval process and the OTC Drug Review is to protect the public. The recipients of drugs that have not been demonstrated to be safe, effective, or properly labeled not only
suffer economic losses, but more importantly, rely to their detriment on a drug product which did not go through the requisite regulatory review, and could prove harmful.
2) The Drug Approval Process and the OTC Drug Review, Including the Associated Labeling Requirements, Directly Advance the Government's Substantial Interest - The new drug approval process and the OTC Drug Review both advance the government's interest by excluding unsafe and ineffective drugs from the market, increasing patient and health care practitioner knowledge, and preventing unscrupulous firms from misleading consumers.
3) The Drug Approval Process and the OTC Drug Review, Including the Associated Labeling Requirements, are not More Extensive than Necessary to Serve the Government's Interest - In the Central Hudson decision the Supreme Court suggested that prescreening arrangements for commercial speech could be constitutional alternatives to commercial speech bans if they included adequate procedural safeguards. The new drug approval process and the OTC Drug Review both include numerous procedural safeguards to prevent arbitrary rejection of claims, and to ensure that FDA reviews the application with appropriate speed. In addition, Congress has already tried more limited regulatory schemes, such as the Food and Drugs Act of 1906, and the Federal Food, Drug and Cosmetic Act as originally enacted in 1938, and has found them to be wholly inadequate in protecting the public.
The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products, nor are the arguments raised here regarding them exhaustive. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct the referenced violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Your reply should be directed to Kevin M. Budich, Compliance Officer, at the following address:
Food and Drug Administration
CDER/Office of Compliance
Division of New Drugs & Labeling Compliance
OTC Drugs Team
10903 New Hampshire Ave.
Silver Spring, MD 20993
If you have any questions about the content of this letter, you may contact Mr. Budich at 301-796-3304 or email@example.com.
Deborah M. Autor, Esq.
Office of Compliance
Center for Drug Evaluation and Research
1 Although a final OTC drug monograph for internal analgesics has not yet issued, 324 mg of aspirin (4 tablets, 81 mg each) is such a low daily dosage that it has never been considered as part of the Agency's OTC Drug Review for adult pain relief. See 42 FR 35346 (July 8, 1977) and 53 FR 46204 (November 16, 1988).
2 In addition, the presence of aspirin in Bayer Heart Advantage excludes this product from the definition of a "dietary supplement" under section 201(ff)(3)(B) of the Act (21 U.S.C. § 321(ff)(3)(B)), because a new drug application for aspirin was approved under section 505(a) of the Act (21 U.S.C. § 355(a)) before any marketing of aspirin as a dietary supplement or as a food. FDA approved a new drug application for aspirin, marketed under the name "Measurin," on June 25, 1965. To the best of FDA's knowledge; aspirin has not been marketed as a dietary supplement or other food to date.
3 FDA issued a Tentative Final Monograph (TFM) for OTC intern al analgesics in the Federal Register on November 16, 1988 (53 FR 46204). However, that TFM does not describe the combination of phytosterols with aspirin for either pain relief or the mitigation, treatment, or prevention of cardiovascular disease.