By Lou Caputo
The FDA recently issued its Final Rule concerning good manufacturing practice requirements for combination products. For those engaged in the dietary supplement industry and familiar with combination products, it comes as no surprise that there is no mention of dietary supplements in the Final Rule. The Rule stands as another reminder, however, that there remains no defined set of circumstances under which the agency will determine that any drug/dietary supplement combination product is permissible. In fact, it has been over three years since the Food and Drug Administration sent its last Warning Letter concerning an over-the-counter drug/dietary supplement combination product. That Letter, addressed to Procter and Gamble, discussed two of P&G’s products: “Vicks DayQuil Plus Vitamin C” and “Vicks NyQuil Plus Vitamin C.” That Letter not only later served as an evidentiary basis for a supposed state-law claim against P&G for making false and misleading claims, See Loreto v. Procter & Gamble Co., 737 F. Supp. 2d 909, 913 (S.D. Ohio 2010), but it also removed any doubt about the FDA’s current position concerning drug/supplement combination products, which is that the agency disapproves of them.
On May 30, 2000, the FDA issued a response to a question concerning the regulatory status of OTC drug/dietary supplement products. The FDA called the product in question a “combination product,” noting that such products “raise a number of significant public health and policy issues.” The FDA further expressed that it had to “determine under what conditions these combination products can be marketed in accordance with the…FDCA.” It cautioned that, “Until the agency has carefully considered these issues…FDA strongly recommends that firms refrain from marketing products that combine or co-package drug and dietary supplement ingredients.” The letter advised that the FDA would pursue “appropriate measures” against any company that sold a combination product in violation of the FDCA. In 2001, the FDA made good on that promise, sending two Warning Letters to manufacturers of such products.
In 2002, as required by the Medical Device User Fee and Modernization Act of 2002, the FDA’s Office of Combination Products (OCP) was established. The Office is tasked with, among other things, developing “guidance and regulations to clarify the regulation of combination products.” The OCP’s website makes clear that, “A product that combines a drug and a dietary supplement (without including a device or biological product)” is not an authorized “combination product as defined in 21 CFR 3.2(e).” Combination products are defined under Chapter 21 of the Code of Federal Regulations. Under § 3.2(e), there are four categories of products that, when combined and/or marketed together, can be considered a permissible “combination product.” These include:
- A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
- Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
- A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
- Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
The failure to reference combination dietary supplement/drug products has led parties to ask the agency about its formal position on such combinations. On May 29, 2008, in a letter to the FDA Assistant Commissioner for Policy, the American Herbal Products Association directly sought “clarification” about FDA’s policy on such products. The AHPA sought this guidance with reference to a new product introduced by Bayer Healthcare: “Bayer Aspirin With Heart Advantage.” Citing the FDA’s prior Warning Letters concerning these products, the AHPA wrote “AHPA is asking whether FDA’s policy on this subject has or has not been modified. In either case, AHPA is requesting that FDA announce the current policy forthwith so neither the public nor the regulated industry is confused by the introduction of this new product by Bayer Healthcare.” The AHPA and Bayer received FDA’s answer five months later when the FDA sent two Warning Letters to Bayer, one concerning “Bayer Aspirin With Heart Advantage” and another for “Bayer Women’s Low Dose Aspirin + Calcium Tablets.”
In 2009, the FDA sent Procter and Gamble a Warning Letter. For the first time, the agency specifically announced that, “FDA’s position on the regulatory status of OTC drug products that combine drug ingredients with dietary ingredients in a single dosage form for drug indications has been described in four previously issued Warning Letters.” The P&G Letter was in many ways similar in form and substance to the agency’s previous Letters, and the result was of course the same. There was simply no way that the FDA would find that such products could be properly marketed.
Aside from any remaining debate about whether a functional ban on such products exists, the FDA has explained the (seemingly insurmountable) hurdles that a manufacturer faces if it wishes to market a combination dietary supplement/drug product. Below are just a few examples.
First, FDA takes the position that each product will invariably make a claim that it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man, which will render the entire product a “drug” under 21 U.S.C. § 321(g)(1)(B). FDA does not address whether use of a disclaimer would mitigate this problem. For example, the product could include the following disclaimer on the label and in labeling: “X nutrient contained in this product is not for the treatment, mitigation, or prevention of any disease but is supplied to provide support for healthy immune system function.”
Further, the ingredient that is the marketed as the dietary supplement will also likely be considered a drug because it is a component of such a finished product. 21 U.S.C. § 321(g)(1)(D). That position is not required by the FDCA but is an interpretation the agency prefers, largely due to an intra-agency bias against dietary supplements and in favor of a high wall separation between substances deemed therapeutic through drug approval and substances deemed a subset of foods, such as dietary supplements.
Second, the dietary supplement component ingredient may also not be included in the final monograph for the particular drug at issue. For those unfamiliar, a monograph is the document that sets out the approved standards that an OTC drug must follow. Such monographs describe, among other details, the active ingredients and their respective amounts that are allowed for a particular product. Looking to the FDA’s letter to P&G, the agency explained that the final monograph at issue did not allow for the inclusion of Vitamin C, and, therefore, the combination product “lack[s] general recognition of safety and effectiveness.” That position, of course, elevates form over substance because a consumer could obtain over the counter both the OTC drug and the nutrient and consume both; what then justifies prohibition of the combination when the two are otherwise lawfully sold OTC and not deemed unsafe or interactive in ways that create safety risks.
Third, because both the drug and dietary supplement components may be considered active drug ingredients, the final combination products may be deemed “new drugs” as defined by 21 U.S.C. § 321(p). If the manufacturer has not submitted a new drug application, which has been approved, the products will be considered an unapproved new drug and in violation of the FDCA. This is an attempt by FDA to bootstrap supplements into the drug approval regime. Again, would not a disclaimer suffice to establish that the nutrient is not intended to treat, mitigate, or prevent disease?
Fourth, such products are susceptible to claims of being misbranded pursuant to 21 U.S.C. § 352 on any number of grounds. Because the product’s label does not identify the dietary supplement component as an active drug ingredient, the product may be considered misbranded. Additionally, as in the case of P&G’s products, if the manufacturer chooses to list the dietary supplement component as an “inactive ingredient,” the FDA may also allege that it is misbranded. In its 2008 Letter to Bayer Healthcare, LLC, the FDA notes that the product at issue is misbranded because there is a lack of adequate warnings, and the warnings that are included are “inconsistent and incompatible” with other directions on the labeling. The FDA further commented that the comprehensive dosage recommendations were incompatible, causing the labeling to be misleading, and therefore meaning that the product misbranded.
Since the P&G letter, there have been no further Warning Letters sent to companies concerning such combination products. It is not hard to imagine why. The Warning Letters reveal a very strong FDA bias against combination OTC drug/dietary supplement products and numerous bases for legal action against those who manufacture and distribute such products. That is unfortunate given that OTC drug/dietary supplement combination products could provide significant benefits for consumers and reduce the inconvenience and cost associated with buying multiple products. The FDCA does not prohibit such combinations and there appear to be obvious means to avoid consumer misperception concerning the role of nutrients in such products through, for example, the use of disclaimers. Moreover, in the absence of evidence that a particular nutrient alters the therapeutic efficacy of the active drug ingredients, there would appear no public safety issue justifying FDA action to restrict the development of this combination market.