The Issue of Functionality – And a New Draft Guidance Hits the Street

Ever since the implementation of the Generic Drug User Fee Act (GDUFA), Guidance documents are flying out of FDA and landing faster than the planes at Atlanta’s busy Hartsfield airport.  One such Draft Guidance was posted yesterday on the FDA web site (here) entitled Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules.  While the specific issue addressed in this Guidance is clear, the general issue of something I like to call “functionality” is now being formally addressed through Guidance documents, as opposed to deficiency letters.

First, what is functionality?  Well, we know that for a generic product to be eligible for submission as an abbreviated new drug application (ANDA), it must have certain characteristics that make it the “same as” the reference listed drug (RLD) to which it refers in support of its ANDA filing.  These attributes demand the product be the same dosage form, strength, route of administration and contain the same active ingredient(s) as the RLD.  In addition, the product must be shown to be bioequivalent to and have the same labeling (with certain permitted exceptions) to the RLD.  However, over the past 5 years the Office of Generic Drugs (OGD) has been looking at other physical attributes of generic products that they believe may impact whether the generic products can be substituted at the pharmacy level and meet the patient’s expectation that the generic will perform, in all aspects, the same as the RLD.  Thus, the concept of functionality has evolved to be inclusive of the statutory and regulatory “sameness” requirements.

Let’s take a look at an example of what this might mean practically.   Say you are a patient who has been taking the same brand name product for the past 10 years and have had no trouble swallowing the medication.  Let’s also assume that the brand product is a capsule shaped, film coated tablet, with a total tablet weight of 300 mg.  Well, now a generic product gains approval and is rated as substitutable (AB rated) by the FDA; however, the generic version of the drug does not have a film coating, is round and its total tablet weight is now 750 mg.  If you as a patient were just able to swallow the film coated 300 mg tablet, and, now, when you walk into the pharmacy to get your refill and the pharmacist, due to state substitution laws, must dispense the generic version, when you get home what do you find?  Well, first of all, you see a tablet of a different shape that appears to be over twice the size of the brand name product you had been used to.  Your first impression may be, hey, if the tablet is twice the size, it must be a higher or different strength.  But, after calling the pharmacy and being reassured that the generic version (even though substantially larger) is the correct dosage strength, the next stop is the sink to get a glass of water so you can take your medication.  Remember, you, as the hypothetical patient in this example, were just barely able to choke down the 300 mg weight tablet and now you are faced with trying to swallow a tablet over twice the size and weight.  Not likely to happen!  So while you have in your hand a therapeutically equivalent product, you cannot swallow it.  So while the product may meet the “sameness” requirements for approval, if the patient cannot take it, it’s functionally is NOT the same and this obviously will mean that the patient will not have the same therapeutic effect from a product that cannot be swallowed.

So, now that you get the concept of “functionality” that FDA is inserting into the definition of “sameness” to describe a generic product, let’s take a look at the new Draft Guidance.

This document addresses the very issues we have discussed above and outlines that there may be significant importance to differences in physical attributes such as tablet or capsule size, shape, differences in dimensions, whether the tablet is film coated or not, and how some of these factors may impact transit time, and therefore, ultimately the safety and efficacy of the generic product.

In the Draft Guidance, FDA comments on how to judge what differences in size and shape may be permissible and outlines some suggested guidelines on those limits.  In addition, the Guidance suggests how applicants for generic products should set their quality target product profiles (QTPP) during drug development when taking the “functionality” between the generic and brand product into account.

While the Draft Guidance gives specific direction on dimensional aspects of the size difference of tablets and capsules that may be permissible and how to calculate such differences, it also provides the following narrative on shape influences:

“For any given size, certain shapes may be easier to swallow than others.  In vitro studies suggest that flat tablets have greater adherence to the esophagus than capsule-shaped tablets.  Studies in humans have also suggested that oval tablets may be easier to swallow and have faster esophageal transit times than round tablets of the same weight.  Patient compliance with medication regimens may be influenced by the size and shape of a tablet or capsule.”

After the passage of Hatch-Waxman in 1984, these functionality issues were seldom if ever considered in the review of an ANDA.  However, with various patents covering the brand drug that may dictate specific ratios of active and inactive ingredients that cause the generic firms to make products of differing sizes or shape to avoid patent infringement and/or in an effort to differentiate their product or to avoid a potential trade dress infringement problem, generic manufacturers have historically tried to make their products look different from their brand name counter parts.  But like many other approaches in business, if you wait long enough, everything seems to come full circle and the Draft Guidance now suggests that the ANDA applicant make an effort to achieve “… comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the Agency recommends that generic oral tablets and capsules intended to be swallowed intact should be of a similar size to their corresponding RLD.” And “[I]n addition to the size recommendations described above, we recommend manufacturing tablets and capsules that have a similar shape or have a shape that has been found to be easier to swallow compared with the shape of the RLD.  Evaluating and comparing the largest cross sectional areas of the RLD and generic product is one strategy to quantify changes in shape.”

Thus, generic manufacturers need to begin looking at “functionality” issues at the time of initial drug development, so they will not have to redesign their products prior to approval.  The Draft Guidance document discussed in this post does not cover already approved products, but the Agency notes that if it becomes aware of a specific problem it will ask the ANDA applicant to address it.