Two Watch Outs That May Cost You Dearly!

In trying to read the tea leaves at the Office of Generic Drugs (OGD) and discussing issues that really worry both OGD and industry, I have come across two issues that you need to stay on top of, one during the approval process and the other just after ANDA approval, to avoid a potential delay in approval that you did not see coming or a potential change in the way OGD does business relative to ANDAs subject to the valuable 180-day exclusivity provisions of the Act.

The first is rather straightforward.  Make sure the DMF holders cited in your firm’s pending ANDAs are aware of the need to notify the ANDA holder of any changes they make.  Some firms have been blindsided lately because DMF holders have failed to notify the ANDA applicant of an amendment made to the DMF prior to ANDA approval.  As the ANDA moves through the final review, one thing that OGD checks is whether any amendments have been submitted to the DMFs referenced in their applications since the DMF was last reviewed.

We all know that DMF holders are supposed to notify ANDA applicants of changes that may need to be reported to the ANDA (as stated in 21 CFR 314.420(c)), but if the firm does not know, how can the applicants decide if they need to amend their ANDA?  So, potentially, at the end of the final review process, just before putting ink on that approval letter, OGD notes that an amendment that had not yet been reviewed by FDA, had been submitted to one or more DMFs, and guess what – your approval letter gets rewritten, and now, instead of an anticipated approval, the firm receives a complete response letter which obviously will significantly delay obtaining approval.  This might not have happened pre-GDUFA and OGD might have just reviewed the DMF amendment to see if it could impact their decision to approve the ANDA, but now, under GDUFA rules, there is a time penalty for this additional review and you are likely to get a letter asking how the DMF amendment impacts your product.  Depending on the number of tiered amendments you have already submitted to the ANDA, your GDUFA clock will be reset once you amend the ANDA and, if the number of amendments exceeds the 5th minor, then you are off the GDUFA clock altogether.

Let the buyer beware – make certain the DMF holders cited in your application are aware that they must notify you and any changes made to the DMF, and you as the ANDA holder must determine the actions you need to take to provide notice to your application!

The second issue deals with the OGD’s ability to accurately determine the start of 180-day exclusivity.  For those of you that may be new to the ANDA rules of the road, the 180-day exclusivity is awarded to the first applicant(s) that submit a substantially complete ANDA that contains a challenge to an existing patent (commonly referred to as a paragraph IV challenge) that is listed in the Orange Book for the reference listed drug upon which the ANDA relies is basis for submission.  This permits a 180-day window during which no subsequently filed applicant can obtain approval.  A very valuable commodity!

Prior to the Medicare Modernization Act (MMA) in 2003, there were two triggers to start the 180-day exclusivity period – a final court decision or first commercial marketing.  However, the provisions of the MMA eliminated the court decision trigger, and instead, provided for certain forfeiture provisions of 180-day exclusivity to keep firms from “parking” their exclusivity.  The MMA left the first commercial marketing as the only trigger for 180-day exclusivity.

Because of the importance of the commercial marketing trigger, the “first” ANDA applicant(s) eligible for 180-day exclusivity are required to provide notice to the FDA of the date they begin commercial marketing (21 CFR 314.107(c)(4)).  So where is the problem?   OGD has indicated that some firms that are granted 180-day exclusivity fail to provide timely notification to OGD of their first commercial marketing of the product; thus, OGD cannot determine the expiration of such 180-day period to enable it to approve subsequent applications.  The problem is exacerbated when the FDA might be able to approve a subsequent applicant’s ANDA, but cannot calculate the 180-day period because they were never informed of its start date due to the failure of the first applicant to provide the required notice.  So what is FDA’s remedy?  Well, that same regulatory citation, 21 CFR 314.107(c)(4), that requires such notice to be provided to FDA also has some interesting language that, to date, I don’t believe FDA has used.  It states: “If an applicant does not promptly notify FDA of such date [the date of first commercial marketing], the effective date of approval shall be deemed to be the date of commencement of first commercial marketing.”   Wow – imagine a firm that begins commercial marketing two months after the effective date of approval, fails to notify FDA of the date of first marketing and FDA then applies this provision of the regulations and deems the 180-day to have begun two months earlier – the application holder would then really only have the benefit of 4 months of protections, rather than the full 6months it was due.

To date, I am not aware of an instance where the FDA has invoked this regulatory provision, but I understand they are thinking about it because of previous issues where firms did not provide prompt notice.  So what is the moral of this story – Be certain to notify the FDA PROMPTLY of the commencement of first commercial marketing when you are a “first” applicant entitled to 180-day exclusivity because all subsequent applicants will be the first to point out your failure to notify to FDA.