FDA Publishes Proposed Rule to Revise the Requirements for Combination and Co-Packaged Rx and OTC Products

In what appears to be an effort for FDA to harmonize their treatment of combination or co-packaged prescription or over-the-counter drug products, the Agency has published a 70 page Federal Register Notice addressing this issue.

The proposed rule notes that “[U]nder proposed § 300.53, two or more active ingredients may be combined in a fixed-combination or co-packaged drug or included as a combination in an OTC monograph when two requirements are met.”

“First, under proposed § 300.53(a)(1), each active ingredient must make a contribution to the effect(s) of the combination, enhance the safety or effectiveness of an active ingredient, or minimize the potential for abuse of an active ingredient. Second, under proposed § 300.53(a)(2), the dosage of each active ingredient (amount, frequency of administration, and duration of use) must be such that the combination is safe and effective and provides rational concurrent therapy.”

FDA also recognizes that “[b]ecause there are some products for which it would be unfeasible or medically unreasonable or unethical to meet the requirements of this proposed rule, proposed § 300.60 would give FDA the authority to grant a waiver of some or all of the requirements of the proposed rule at the request of an applicant or interested person or on its own initiative.”  The waiver provisions outlined in the proposed rule give FDA sole authority to act on a waiver request and the provisions are fairly tight.

As identified in the regulations, “[c]ombinations of active ingredients described in an OTC drug monograph may be marketed without prior Agency approval. Those combinations that are not described in a proposed tentative final monograph (TFM) or OTC monograph must either be added to the applicable OTC monograph or be approved under the NDA or abbreviated new drug application (ANDA) provisions in section 505 of the FD&C Act before they may be marketed in the United States.”

In addressing the issue of co-packaged drugs (which the Agency has not really opined on officially before), “[t]he Agency interprets the act of shrink-wrapping or otherwise packaging two products together, in the absence of any alternative explanation for the packaging such as “convenience” or “value” pack, to be an implied claim that the products are intended to be used together for a common or related therapeutic purpose. In the case of a dietary supplement co-packaged with a drug, the co-packaging implies that the dietary supplement is intended to be used for a therapeutic purpose, and the dietary supplement will be considered a drug under the FD&C.”  Such combinations must be approved through a new drug application or a petition to the OTC monograph for inclusion of the new combination (and, yes, co-packaging two drug products together or a dietary supplement and a drug make the co-packaged drug a combination product and a new drug).

In the absence of another explanation, such as the “convenience kit,” packaging two products together makes an implied claim that they are safe and effective when used together.  Without proper approval, these products are considered unapproved drugs under section 505(a) of the FD&C Act.  Without approved labeling, such products would also be considered misbranded under section 502 of the FD&C Act, including under section 502(n).

The Agency does recognize that “[i]n some cases, however, OTC drugs are packaged together for convenience, such as a “travel kit” or “convenience kit” that includes an antiperspirant, an internal analgesic, toothpaste, sunscreen, and/or a sleep aid. In other cases, OTC drugs might be packaged together as two or more shrink-wrapped cartons to be sold as one unit identified as a “special value” or “value pack.” These individual drugs are not intended to be used together for a common or related therapeutic purpose. Therefore, these types of kits do not meet the proposed definition of co-packaged drug and would not be subject to the requirements of this proposed rule.”

It is interesting to note that this is the first time the FDA has made an official distinction of a ”convenience kit,” relative to the definition of a co-packaged drug product.  While FDA’s long-standing policy has not changed, this clarification may open the way to a consistent FDA enforcement policy.  It could also signal FDA’s intention to begin enforcement action where previous enforcement has been lax.

FDA outlines a waiver provision by saying that “[f]inally, it is important to note that it is not always a requirement that a fixed-combination formulation be used in a factorial study. The data from a factorial study in which the individual active ingredients are administered separately can be relied upon to support an application for a fixed-combination drug if the study data is linked to a fixed-combination formulation by a bioavailability study.”  However, carefully read carefully the section on waivers, as there must be sufficient information to inform any FDA decision.

This document is long and complex, and as mentioned, while it outlines FDA long-standing policy, the intent and driver of the proposed rule is not totally clear.  Maybe it’s because more and more companies are playing fast and loose with co-packaged products without obtaining approval, or it could just be that FDA wants everyone on the same page.