A December 10, 2014 petition filed by Wiley Rein LLP on behalf of Acura Pharmaceuticals (here) asks the FDA to require Purdue to file an ANDA rather than a 505(b)(2) application for a duplicate version of an immediate release oxycodone tablet with abuse-deterrent properties.  The petitioner argues that,because the abuse-deterrent characteristics of the proposed Purdue product are similar to those of its Oxecta product, and because both products are pharmaceutical equivalents, that a firm should not be able to circumvent the listed patents on the Oxecta reference listed drug (RLD).

For those of you not familiar with Oxecta, it was the first abuse-deterrent immediate release oxycodone product approved by the Agency.  Oxecta  was originally approved on June 17, 2011 for both a 5 mg and 7.5 mg tablet. There are 5 patents listed in the Orange Book for the product.  Quite interestingly, FDA has not yet assigned a therapeutic equivalence (TE) code to the Oxecta product (at least for the 5 mg tablet) as there are other pharmaceutical equivalents approved for this strength.  It appears that the FDA is waiting to make a decision on TE until it is forced to do so (e.g., by a pending ANDA or 505(b)(2) when ready for approval).  Also of interest is that the Orange Book does not yet show a designation of RLD status for Oxecta, although, as the Acura petition points out, multiple ANDAs have been submitted to the Office of Generic Drugs (OGD) citing Oxecta as the RLD.

The actions requested in the petition (while complex in nature) point towards some of the decisions that FDA must make in regard to new 505(b)(2) submissions, ANDAs for “duplicate versions of a product, and issues related to substitutability of various abuse-deterrent products.

Acura asked FDA to:

  1. Require submission of a generic equivalent of Oxecta as an ANDA
  2. If FDA determines the product can be submitted as a 505(b)(2), require the NDA applicant to refer to Oxecta as RLD and make appropriate patent certifications to the cited patents on the RLD.
  3. If FDA has already accepted an NDA for filing and the applicant did not cite Oxecta as the RLD, require the NDA to be withdrawn and resubmitted with Oxecta cited as the RLD (theFood, Drug, and Cosmetics Act [FDCA] requires that if a 505(b)(2) or 505(j) application changes its RLD the application must be withdrawn and resubmitted). 

First question is-do you need to submit a pharmaceutically equivalent drug as an ANDA or is there some difference that would permit the submission as a 505(b)(2)?  Secondly, what is the basis of submission (what RLD) that a 505(b)(2) application must cite?  There appears to be conflicting FDA decisions on both of these issues.  Some petition responses (as noted in the Acura petition) require that a 505(b)(2) applicant to cite as the RLD the most similar product to an FDA approved product, but FDA has made other decisions that fly in the face of that decision (i.e. FDA’s decision to approve a Colchicine product and the  RLD selection n that 505(b)(2) NDA and how the reliance on an RLD may be used or judged as the basis for submission  (see post from FDA Law Blog on this issue ).  Acura wants FDA to require any ANDA or 505(b)(2) application to cite Oxecta as the RLD to require those applicant to certify to its listed patents and not be able to skirt that certification requirement by simply citing a different RLD as the basis of submission.

First, let’s look at the issue of whether a 505(b)(2) or ANDA is the appropriate mechanism for submission.  Quite simply put, if an applicant makes a change from that of the RLD that could not be submitted in an ANDA, then a 505(b)(2) application would be the appropriate filing vehicle.  For example, if the firm chose to submit additional strengths not approved in the Oxecta application, or if the labeling had to be significantly different due to differences in the abuse-deterrent characteristics of the proposed product, or if the firm used an inactive ingredient that had never been used for the oral route of administration or a previously approved inactive ingredient at higher levels than have ever been approved for use before, then a 505(b)(2) NDA would be appropriate.

Relative to the requirement for use of Oxecta as the RLD that must be cited in any ANDA or 505(b)(2) application, it is clear that a duplicate of Oxecta filed in an ANDA must cite Oxecta as the RLD (even though FDA has failed to update the Orange Book to provide the RLD designation to that product).  But as far as a 505(b)(2) application, the Agency has some flexibility and (as mentioned before) has reached different decisions based on the circumstance.  It is possible that some of the FDA’s decisions will be challenged in court, especially those where the FDA has split hairs relative to its position on similar issues.  So we will need to wait to see how this all plays out.   I was personally surprised by FDA’s decision in the colchicine case not to require the NDA applicant Hikma to avoid citing Colcrys (the first approved colchicine tablet ) as the RLD in its 505(b)(2) application, and so was the Colcrys applicant and thus as noted in the FDA Law Blog article above, the NDA holder did sue the FDA.

These decisions take into consideration some very complex and convoluted facts and must be handled on a case-by-case basis.  It will be up to the courts to determine whether in any of FDA’s actions are arbitrary or capricious.  Stay tuned and be careful if you are developing a unique strategy for submission.  Although not likely in this case, I must also point out that if a full 505(b)(1) application is submitted to the agency, then no patent certification or cited RLD are required in the application.