The afternoon sessions of the conference that I was able to attend included a discussion of Combination Products and Similarity, and two legal-based sessions, one on Approval Pathways for Complex Generics – 505(j) vs. 505(b)(2) and the other on Generic Drug Case Law.

The combination product similarity session described the various permutations of the sameness requirements for devices when part of a drug product. The issues associated with the critical design elements that differ from the reference listed drug (RLD) could constitute important differences that could preclude the submission or approval of the change in an ANDA. Minor changes may be permitted but the bottom line with a critical design element change is that “FDA expects that end users of generic combination products, including but not limited to lay-persons, such as patients, and/or caregivers, can use the generic combination product when it is substituted for the RLD without the intervention of the health care provider and/or without additional training prior to use of the generic.”  If such training or education is needed to support the change, then the change would likely not be permitted in an ANDA.

There were discussions about labeling differences and one questions raised by the audience asked if a change in labeling or the device to make it easier to use the product would be acceptable.  The advice from the panel was that the products must be the same and not better, but minor changes in labeling can be made under the permissible changes because the product is made by a different manufacturer, but those differences are limited. FDA’s advice was that if there are any differences in design or labeling proposed, that the firm either use a controlled correspondence or pre-ANDA meeting to get resolution prior to final development and well in advance of submission of the ANDA. Panel members also provided suggestions for FDA to include some examples of issues associated with human factor studies especially in the realm of virtual studies that may be required because of COVID or lack of patients or volunteers.

Note that biosimilar products are not constrained by device differences or label sameness like ANDAs.

The Complex Generic 505(j) v 505(b)(2) forum discussed the use of the (b)(2) process for products that differ in some aspect from the RLD.  Typically, parenteral or ophthalmic products may use an exception excipient in its formulation to avoid a patent issue and, because of regulatory restriction on what formulation differences can be made to these types of products, make the changed product ineligible for submission under 505(j) (as a generic).

The discussion quickly evolved into a fascinating discussion of therapeutic equivalence. The situation centered on a (b)(2) product that is a pharmaceutical equivalent and has been shown to be bioequivalent to the RLD and meets the other aspects (made under GMPs, meets compendial requirements) required to meet the criteria for a designation of therapeutic equivalence (TE) but, unlike generic approvals, the FDA does not automatically make the TE determination.

For the 505(b)(2) world, the sponsor must submit a petition to the FDA requesting that the product be given a TE rating. These petitions have taken years for the FDA to issue a response.  Why would an NDA product want to be rated as therapeutically equivalent? There are three major reasons.  First, they would be eligible for a waiver or refund of the some PDUFA user fees; second, they could be automatically substituted without health care provider interaction; and third, they would have an easier time achieving reimbursement through the Center for Medicare and Medicaid Services (CMS).

There is pending legislation to fix the petition problem and require FDA to make the TE determination at the time of approval of the 505(b)(2) application if the applicant is seeking such a determination.  Let’s see how that works out!

The last presentation I am reporting on for Day 2 is the Generic Drug Case Law session. Kurt Karst led a panel discussion of four cases that have particular importance to generic drugs. Since I have written blogs about three of the cases and the discussions, while Karst’s session was significantly more in depth, I will just refer you to the blog posts that describe three of the cases.

The first case is the Catalyst Pharmaceuticals v. FDA and Jacobus in an orphan drug exclusivity dispute and involves the issue of the same disease or condition requirement for granting ODE; the. The blog can be found here.

The second case is the Coreg case which is a skinny label case ; the blog can be found here.

The third case is the Genus Med. Techs., LLC v. FDA, 2021 and concerns what is a drug vs. what is a device; the blog can be found here.

The fourth case discussed related to Teva V FDA with regard to the issues of peptides and whether glatiramer (Copaxone) should have been one of the peptide products that were transitioned from a drug (NDA/ANDA) classification to a biologic (BLA) approval.  The basis of this case centered on Teva arguing that Copaxone met the definition of a protein, that is, a product with a recognizable and consistent array of amino acids. Teva sued FDA and the Court determined that, while Copaxone did have some common sequences of amino acids, the product is such a gimish, that it did not meet the definition of a protein.

That was the end of my Day 2 experience and quite a day it was!