Earlier this year the FDA announced its intention to issue a rule on fixed-dose combinations and co-packaged products. On December 23, FDA issued its proposed rule, with comments due by March 22, 2016. The rule outlines revisions to its regulations on prescription and nonprescription fixed-combination and co-packaged drugs as well as combinations of active ingredients under consideration as part of an over-the-counter (OTC) monograph.
FDA proposes that active ingredients must make a contribution to the effect of the combination, minimize potential for abuse of an active ingredient, or enhance the safety/effectiveness of an active ingredient. The dosage of active ingredients must be safe and effective, providing concurrent therapy. The agency says the proposal is largely intended to remain consistent with longstanding FDA policy.
This does not apply to individual natural-source drugs, but does apply to prescription and OTC fixed-combination and co-packaged drugs that are subject to approval under a new drug application or biologics license application, along with combinations of active OTC ingredients. Furthermore, applicants will be required to provide proof that demonstrates their products meet evidence requirements that demonstrate the contribution of each active ingredient. There is no set amount of data required and FDA says the type of information needed may vary on a number of factors such as the therapeutic intent of the combination.
This could include a number of different options, including controlled clinical trials showing a contribution of each active ingredient to the claimed effect and/or controlled studies that show an effect of each active ingredient on a pharmacologic parameter or biomarker considered predictive of the therapeutic effect. Other options include in vitro data, animal model data, and clinical pharmacology data. FDA recommends the use of a factorial study for a combination of active ingredients to show the combination is more effective than all possible active ingredient combinations. When this is not possible, FDA says different approaches may be employed to demonstrate the contribution of active ingredients to the effect of the combination by identifying a population where the added effect of an active ingredient can be established.
FDA also notes the growing interest in the development of investigational drugs for use in combination as individual agents labeled for use with one another or as a fixed-combination or co-packaged drug. “There is particular interest in such development for targeted cancer and anti-infective therapies. In contrast to fixed-combinations or co-packages of previously approved drugs, new investigational products are not well-characterized. Therefore, this type of development is inherently more complex and requires studies to characterize not only the combination, but also the individual agents to the extent necessary and feasible,” FDA writes, noting previous guidance from 2013.
The proposed rule additionally notes that for some products it would be unreasonable or unethical to meet the proposed requirements. To address this, FDA proposes granting a waiver of some or all requirements of the proposed rule at applicants’ or interested persons’ request or the agency’s own discretion. Products for which FDA expects to grant waivers include traditional medicinal products composed of multiple parts of animals, traditional medicinal products composed of substances derived from more than one type of natural source, traditional botanical products composed of multiple botanical raw materials in fixed ratios, and cellular and gene therapies. The agency further expects to waive the requirements of this proposal for some allergenic products. An example includes allergy patches that are applied to the surface of skin and determine the specific cause(s) of the condition.