FDA Issues Proposal on Prescription and OTC Fixed-Combination and Co-Packaged Products

December 30, 2015

By Riëtte van Laack

On December 23, 2015, FDA issued a proposed rule amending the regulations for prescription and over-the-counter (OTC) fixed-combination products, co-packaged drugs, and combinations of active ingredients under consideration for inclusion in an OTC monograph. The 20-page proposal is intended to harmonize the rules for fixed-combination prescription and OTC drugs. For purposes of the proposed rule, the term “drug” includes biological products but does not include medical devices. FDA does not provide information on the intent and driver for the proposed rule.

The proposed rule creates a single set of regulations for prescription and OTC combination drugs, and codifies, what FDA asserts, is FDA’s existing policy on the type of studies needed to show that the combination drug requirements are met. In addition, the proposed rule clarifies the application of FDA’s requirements regarding fixed-combination drugs to certain natural source drugs and addresses the issue of co-packaging. It further establishes the circumstances under which FDA may waive the requirements for a particular drug or biological product.

Under the proposed rule, fixed-combination and co-packaged drugs will be generally recognized as safe and effective when three criteria are met:

  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;
  2. the combination of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and
  3. the dosage of each active ingredient must be such that the combination is safe and effective and provides “rational concurrent therapy.

“Rational concurrent therapy” constitutes a “medically appropriate treatment for a [defined] patient population” which “can benefit from all of the active ingredients at the specific doses present, given for a similar duration of treatment, and not be adversely affected by receiving them in combination.”

Fixed-combination drugs can provide convenience, therapeutic benefit, and even economic benefit to patients. However, there also are potential disadvantages, such as a lack of flexibility in adjusting the dosage of each active ingredient to individual needs and the potential overexposure or unnecessary exposure to a particular ingredient.

FDA proposes to define “co-packaged drug” 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.” In the absence of another explanation for the co-packaging, such as “convenience,” a “travel kit” or a “value pack,” the act of shrink-wrapping or otherwise packaging two products together constitutes an implied claim that the co-packaged products are intended to be used together for a common or related therapeutic purpose. Unless the co-packaged product has been approved or falls within a final or tentative final monograph, the product is an unapproved new drug. FDA groups fixed-combination and co-packaged drugs together because, according to the Agency, co-packaged drug products can “raise concerns” that are similar to those associated with fixed-combination drugs.

In line with previous actions against such products, FDA takes the position that co-packaging of a dietary supplement and a drug is an implied claim that the dietary supplement is intended for a therapeutic purpose, and, therefore, the dietary supplement will be considered a drug under the FDC Act. Apparently, in FDA’s world, there is no alternative explanation (e.g., convenience) for this type of co-packaging.

The proposed rule does not apply to products such as whole blood, individual or pooled transfusible blood components, pooled plasma products, plasma derivatives from human or animal sources and to individual natural-source drugs, (which are drugs derived from natural raw materials), even though such drugs may contain multiple ingredients derived from the same source.

FDA would be authorized to grant a waiver from all of the proposed requirements because for those products for which it would be unfeasible or medically unreasonable or unethical to meet the requirements of the proposed rule. According to FDA, the types of products for which a waiver would be appropriate include traditional botanical products composed of multiple botanical raw materials in fixed ratios; traditional medicinal products composed of multiple parts of animals;  traditional medicinal products composed of substances derived from more than one type of natural source and cellular and gene therapies.

The comment period closes March 22, 2016.