The U.S. Food and Drug Administration (FDA) published its proposed rule on fixed-combination and co-packaged drugs, which relates to both prescription and over-the-counter (OTC) drug products and to combinations of active ingredients under consideration for inclusion in an OTC monograph. The proposed rule will not apply, however, to “individual natural-source drugs, which are drugs derived from natural raw materials, even though those drugs may contain multiple ingredients derived from the same source.” Under this proposed rule, there would no longer be separate provisions for OTC fixed-combinations or co-packaged drugs. Instead, the proposed rule will “harmonize the requirements for prescription and nonprescription products and make them consistent with long-standing Agency policy.” The deadline for submitting comments on this proposed rule is March 22, 2016.

The proposed rule defines a fixed-combination drug as “a drug in which two or more active ingredients are combined at a fixed dosage in a single dosage form.” These fixed-combination drugs “involve deliberate combinations of distinct, single active ingredients, either produced synthetically or isolated and purified from a natural source.” Fixed-combination drugs do not include whole blood, individual or pooled transfusible blood components, pooled plasma products or plasma derivatives from human or animal sources. Co-packaged drugs are defined in the proposed rules as “a product that contains two or more separate drugs in their final dosage forms that are intended to be used together for a common or related therapeutic purpose and that are contained in a single package or unit.”

Under the proposed rule, the following two requirements must be met before two or more active ingredients may be combined in a fixed-combination or co-packaged drug or be included as a combination in an OTC monograph: (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” and (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 provide rational concurrent therapy,” defined as “medically appropriate treatment for a patient population defined in the drug’s labeling.”

To meet these requirements, applicants seeking approval of a combination “must state the intended use of each active ingredient in the combination.” This is true even for ingredients that may not be considered active ingredients in other contexts in order to ensure that the therapeutic purpose of each ingredient is claimed. Additionally, applicants “must provide sufficient evidence to demonstrate that their products meet the requirements of § 300.53(a), including evidence demonstrating the contribution of each active ingredient to the effect(s) of the combination.” The amount and type of data required to make this demonstration will vary. The statement and evidence specified in the proposed rule “must be provided in an NDA or a BLA or, if an interested person seeks to include the combination in an OTC monograph, in a submission under part 330.”

The proposed rule does provide for potential waiver of its provisions if the following conditions are met:

(1) There is a reasonable rationale for the combination of the individual active ingredients, and compliance with any of the requirements of § 300.53 would be infeasible or medically unreasonable or unethical; or (2) the product contains all or a subset of the known or probably components in the same ratio as a natural-source drug or a waived product, provided the product is intended for the same conditions of use as the natural-source drug or the waived product; there is a reasonable basis to conclude that the product would provide a comparable clinical effect to the natural-source drug or the waived product; and, for products containing large molecules (macromolecules), the ingredients have the same principal molecular structural features and overall mechanism of action.