“Size Matters,” Says FDA, When it Comes to Generic Drug-RLD Sameness

By Kurt R. Karst –

In what appears to be a further sign of FDA’s efforts to clamp down on differences between brand-name Reference Listed Drugs (“RLDs”) and their proposed generic counterparts, FDA’s Office of Generic Drugs (“OGD”) is now looking more closely at tablet size differences.  The increased scrutiny may be intended to address, at least in part, criticism about some generic drugs not acting the same as their brand-name counterparts (see our previous post here). 

OGD recently issued letters to companies with pending ANDAs for one product, stating that the applications are not approvable because of tablet size differences when compared to the corresponding strengths of the RLD.  According to the letters:

The larger tablet size poses greater potential safety issues such as choking, tablet arrest, and prolonged transit time, which could result in esophageal injury and/or pain.  The larger tablet size also raises product efficacy concerns due to patients’ inability or unwillingness to swallow the larger tablets. . . .  Therefore, from a clinical standpoint, this product is unacceptable for approval as a generic and we recommend that you redesign your product to be closer in size to the relevant strengths of the RLD.

The legal basis for FDA’s decision is not stated in the letters, but may be based on FDC Act § 505(j)(4)(H), which states that FDA shall approve an ANDA unless the Agency finds that:

information submitted in the application or any other information available to the Secretary shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included.

Unfortunately, the letters do not provide any guidance on what is an acceptable size difference between a proposed generic and its corresponding RLD, leaving ANDA sponsors with several questions, including whether OGD is taking a one-size-fits-all approach (i.e., a set, permissible size difference applicable to all generics) or a case-by-case approach.  Absent guidance on an acceptable size difference, ANDA sponsors will be stumbling around in a dark room, unable to make informed decisions on how to redesign their products.  Such concerns are heightened when there is a patent on the RLD that covers size (or shape).  And what about drug products already on the market?

OGD gave a heads-up that the Office would be looking more closely at tablet size (as well as shape and color) during a presentation at the October 2011 GPhA/FDA Fall Technical Conference.  According to Dr. Vilayat Sayeed, Director, Division of Chemistry III., OGD, draft guidance is in the works and will published to address concerns about generic tablet size, shape, and color compared to the RLD.  Clearly, FDA has decided to move forward with its policies before issuing guidance. 

Once published, FDA’s guidance on tablet size, shape, and color will join a host of other recent guidances that address generic drug sameness issues.  In January 2011, FDA issued draft guidance titled “Size of Beads in Drug Products Labeled for Sprinkle” after OGD issued several refuse-to-receive letters to generic drug applicants who had proposed products with fewer beads (e.g., mini-tablets) than in the RLD product, making sprinkling the product on food an impossibility, according to FDA.  In the guidance, FDA suggests a maximum bead size of 2.0 mm for drug products labeled for sprinkle based on information demonstrating that food is chewed to approximately 2 mm in median particle size before swallowing.  More recently, in August 2011, FDA issued draft guidance, titled “Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation,” in which the Agency discusses the need for consistent scoring between a generic product and its RLD.

Ratcheting up ANDA standards may be one way for OGD to gain better control of the ANDA review queue, particularly with the likely enactment of the Generic Drug User Fee Act (“GDUFA”) in 2012 (see our previous posts here and here).  Among other things under GDUFA, FDA will agree to certain staged performance goals and will commit to substantially reducing the ANDA backlog.  In addition, the draft version of the “Generic Drug User Fee Act Program Performance Goals and Procedures” states that by the end of year 1 of the program “FDA will develop enhanced refusal to receive standards for ANDAs and other related submissions.”  FDA is supposed to, under the agreement with the generic drug industry, publish those standards in advance of implementation.  The enhanced standards, which we understand are intended to provide more clarity as a whole for less experienced filers and to improve agency efficiency, are not related to topics such as tablet size.

Additional Reading:

• New England Journal of Medicine – Why Do the Same Drugs Look Different? Pills, Trade Dress, and Public Health