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Enforcement Activities: FDA removes unapproved prescription ear drops

For years FDA has threatened to remove unapproved products (so-called DESI products) from the marketplace. Recently, the FDA took enforcement action against  several unapproved prescription ear drops.  What products will be next?  DESI producers can use the 505(b)(2) pathway to avoid such actions on their products. Let’s take a look at the recent action and show an example of  how to gain approval for a group of related DESII products.

The FDA published the Marketed Unapproved Compliance Policy Guide (CPG) in September 2011 describing how they intend to enforce their unapproved drug policy, including the exercise enforcement discretion with regard to drugs marketed in the United States that do not have required FDA approval for marketing (drugs marketed without approved NDAs and ANDAs) (CPG Sec. 440.100). However, the execution of this enforcement action has been limited. At the time of the CPG release, FDA estimated that in the United States approximately several thousand drug products are marketed illegally without required FDA approval. A dedicated FDA website was established where the Agency offers a number of resources, including updates on initiatives, and compliance actions as well as a decision tree that provides guidance to an overall approach to understanding how marketed unapproved drugs may be brought into compliance with requirements under the Federal Food, Drug, and Cosmetic Act. The specific role for approval via the 505(b)(2) regulatory pathway is included in this guide. As a result, these unapproved products represent unique opportunities for those willing to accept the challenge.

Once an unapproved marketed product is identified, taking enforcement action against the product typically involves one or more of the following: requesting voluntary compliance; providing notice of action in a Federal Register notice; issuing an untitled letter; issuing a Warning Letter; or initiating a seizure, injunction, or other legal proceeding. However, these actions appear to have been limited, likely because they are time-consuming and resource intensive efforts. Since publication of the FDA’s (CPG) for Marketed Unapproved Drugs, the FDA has taken compliance and enforcement actions against a number of companies that market unapproved prescription drugs. However, the primary focus has been on enforcement against classes of unapproved drugs, especially where there is a safety concern. This July, the FDA announced its intention to take enforcement action against companies that manufacture and/or distribute certain unapproved prescription ear drops labeled to relieve ear pain, infection, and inflammation. The unapproved prescription ear drops contain active ingredients such as benzocaine and hydrocortisone, and have not been evaluated by the FDA for safety, effectiveness and quality. Subsequently, in a Federal Register notice, the agency informed the companies that they must stop manufacturing these unapproved prescription otic products or be subject to enforcement actions, including seizure, injunction and/or criminal proceedings. The enforcement action against the unapproved otic products is a result of the FDA clearly giving higher priority to unapproved drug products with potential safety risks.

As indicated in the Federal Register notice, FDA has received at least five AE reports of allergic reactions to these otic drug products, including angioedema of the ear, eye, face, neck and/or mouth. A case of methemoglobinemia associated with the administration of an otic product containing benzocaine in an infant, which results in death was mentioned. Other less serious AEs associated with these products include contact hypersensitivity, pruritus, stinging, burning, and irritation.

Additionally, some sponsors have capitalized on pursuing development of drugs marketed in the United States that do not have required FDA approval for marketing – particularly those without safety risks. A number of these drug products have been marketed as “DESI” products for years but without formal approval – products that may be perfect for drug applications under section 505(b)(2).

A good example of such an opportunity is potassium chloride (KCl). Although a number of extended-release KCl products have FDA approval for marketing, a market need existed for an oral solution KCl which was being met via unapproved drug products. In light of this market opportunity, two KCl oral solution products were approved in the past year via 505(b)(2) drug applications: one for an oral solution and another for a powder for oral solution. FDA approved another 505(b)(2) application (NDA 206814; Pharma-Med Inc.) for Potassium Chloride Oral Solution available in two strengths (10% [20 mEq/15 mL] and 20% [40 mEq/15 mL]) on December 22, 2014. A second 505(b)(2) drug application (NDA 208019; Pharma Research Software Solution LLC) for Potassium Chloride for oral solution (pouch containing powder available in 1 strength [20 mEq]), a potassium replacement therapy typically for patients taking potassium-depleting diuretics was approved on August 19, 2015.  However, there are still a number of marketed unapproved prescription drug products for potassium chloride oral solution available on the market.  Once an approved product is marketed in such situations, FDA is expected to take enforcement action against all the remaining unapproved products, thus creating a de fact exclusivity for the approved product(s)

FDA normally intends to allow a grace period of roughly 1 year from the date of approval of the product before it will initiate enforcement action (e.g., seizure or injunction) against marketed unapproved products of the same type. However, the length of the grace period, if any, is solely at the discretion of the Agency. The grace period provided is expected to vary based upon a number of factors – in this instance, the most critical being: the effects on the public health of proceeding immediately to remove the illegal products from the market (including whether the product is medically necessary and, if so, the ability of the holder of the approved application to meet the needs of patients taking the drug).

Some see the estimated several thousand unapproved drug products being marketed illegally without required FDA approval (particularly “DESI” products) and the limited enforcement action as an opportunity. Because many of the unapproved products subject to FDA’s compliance guide have been marketed for lengthy periods of time, use of the 505(b)(2) regulatory pathway is often especially attractive. Since the product has been used for a long period, the likelihood it has been studied for one or several indications is quite good. These studies are very often published in the scientific literature, thus possibly providing a prospective applicant with the safety and efficacy data needed for a successful 505(b)(2) application. A copyright fee might be necessary for the published studies, but the cost is much less than that of conducting the studies de novo.


Stacey Ayres, PhD
Senior Director of Scientific and Regulatory Affairs

William Stoltman, JD
Senior Director of Quality Assurance / Compliance