FDA Issues GDUFA ANDA Amendment and PAS Guidances Explaining Implementation of Some of the More Complex Provisions of the User Fee Agreement

By Kurt R. Karst –      

Earlier this week, and just a day after the second anniversary of the 2012 FDA Safety and Innovation Act that, among other things, includes the Generic Drug User Fee Amendments (“GDUFA” ), FDA announced the release of two draft guidance documents that explain how the Agency (and the Office of Generic Drugs in particular) intends to implement the rather complex ANDA amendment and Prior Approval Supplement (“PAS”) provisions and performance metric goals contained in the Program Performance Goals and Procedures (“Commitment Letter”) accompanying GDUFA.  The draft guidances, along with pre-recorded webinars (here and here) and slides (here and here), come less than three months before the October 1, 2014 date when GDUFA goes into full effect, and when the generic drug industry will be forever changed.

The amendment and PAS provisions of the Commitment Letter – and the amendment provisions in particular – are not for the faint of heart.  You’re left scratching your head after the first readthrough of the Commitment Letter wondering how this system is going to work, but by the tenth readthrough things begin to start sinking in.  And the two new draft guidances – ANDA Submissions – Prior Approval Supplements Under GDUFA and ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA – go a long way to elucidate how the submission system will work under GDUFA, and provide several very helpful real-world examples.

Let’s start with a few basics from GDUFA and the Commitment Letter, and some concepts shared among both draft guidances before moving on to some specifics from each draft guidance:

• ANDAs are now categorized according to cohort year (i.e., FY 2015, FY 2016, FY 2017).  PASs are also identified by the fiscal year of submission, but the term “cohort year” is not specifically used to refer to a particular submission year.
• Once an original ANDA is in a particular cohort year based on the original submission date made through FDA’s electronic gateway (see our previous post here), dates of submission of an amendment to that original ANDA do not change the cohort year.   In other words, if you submit your original ANDA in FY 2015, that application will forever be a cohort year 3 ANDA.  The same holds true for a PAS fiscal year submission. 
• FDA agreed to review and act on 60% of original ANDA submissions within 15 months from the date of submission for the year 3 cohort (FY 2015); 75% of original ANDA submissions within 15 months from the date of submission for the year 4 cohort (FY 2016); and 90% of original ANDA submissions within 10 months from the date of submission for the year 5 cohort (FY 2017). 
• FDA agreed to review and act on 60% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2015; 75% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2016; and 90% of complete PASs that do not require inspection within 6 months from the date of submission, and within 10 months from the date of submission that require inspection for receipts in FY 2017. 
• Acting on an original ANDA and PAS includes issuance of a Complete Response (“CR”) letter, an approval letter, a tentative approval letter, or a refuse-to-receive action.
• The date of submission of an original ANDA or PAS is calculated in months beginning on the receipt date of arrival of the submission in the electronic submission gateway.  For example, if a complete PAS (not requiring an inspection) is submitted on November 3, 2014, the 6-month GDUFA goal date for FDA review and action is May 2, 2015.  Note that this calculation differs from the goal date calculation under the Prescription Drug User Fee Act.
• The 15-month and 10-month base period action dates for cohort year 3-5 ANDAs can change (i.e., are incremental and can be recalculated to a longer period/date) based on the type and number of amendments submitted to FDA and how they are tiered (i.e., Tier 1, Tier 2, and Tier 3).  Similarly, the 6-month and 10-month base period action dates for PASs can be recalculated.  GDUFA established certain review goals for the various types and tiers of amendments that are fully explained (with examples) in the draft guidances.

ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA:  The draft guidance delves into the details of the various categories of amendments to an original ANDA or PAS.  The number, classification, and tier group of amendments can affect FDA’s goal date for acting on an original ANDA or PAS, as well as the need for an inspection.  Amendments to an original ANDA or PAS are classified as solicited, unsolicited, or administrative.  Solicited amendments are identified as major, minor, or as an Easily Correctable Deficiency (“ECD”).  Unsolicited amendments are identified as delaying and non-delaying.  In addition, amendments are grouped as Tier 1, Tier 2, or Tier 3.  Together, they result in the matrix below from the draft guidance.

A solicited amendment is a submission made by an applicant in response to a CR letter.  The classification of such an amendment as major or minor (or as an ECD) is largely a matter of FDA discretion.  Nevertheless, FDA applies the following general principles, which are further explained with examples in appendices to the draft guidance:

• “Major amendments contain a substantial amount of new data or new information not previously submitted to or reviewed by FDA, requiring, in FDA’s judgment, a substantial expenditure of FDA resources.  In general, the type, quantity, or complexity of data contained in a major amendment requires a lengthy review by FDA, and consults from other divisions or offices may be required to complete the review.”
• “FDA review of a minor amendment requires, in FDA’s judgment, fewer FDA resources than are necessary to review a major amendment, but more than are necessary to review the information submitted in response to an ECD.”
• “FDA review of information submitted in response to an ECD requires, in FDA’s judgment, a modest expenditure of FDA resources.  An applicant should be able to respond to an ECD quickly as the applicant should already possess or be able to quickly retrieve the information needed for an adequate response to an ECD.”

Unsolicited amendments, which are either delaying (Tier 1) or non-delaying (Tier 2), are submitted on an applicant’s own initiative and not in response to a CR letter.  As FDA explains, “[d]elaying amendments address actions by a third party that would cause delay or impede application review or approval timing and that were not a factor at the time of submission. ”  Thus, for example, “if a [citizen petition] requests certain [bioequivalence] data be submitted to support an ANDA for a particular drug product and FDA grants that petition, an ANDA applicant may submit the [bioequivalence] data reflected in the [citizen petition] response prior to FDA’s request of the data from the ANDA applicant.”  In contrast, non-delaying amendments “are unsolicited amendments that contain information that is not requested by FDA and is not the result of changes to the RLD or USP monograph, changes to the RLD labeling, a REMS and REMS modification, or generic approval requirements reflected in citizen petition responses issued by FDA.”  Finally, administrative amendments “are routine in nature and do not require scientific review.”  They do not fall within the tier matrix, and therefore do not affect GDUFA action dates.

The draft guidance also provides instructions for applicants that want to challenge FDA’s classification of an amendment by requesting reconsideration:

• “If an applicant is requesting reconsideration of a CR amendment, the applicant will submit a written request for a post-CR-letter meeting within 10 business days from issuance of the CR letter. . . .  The division will issue a decision about the request for reconsideration and notify the applicant of the decision within 10 business days from the date of the meeting.”
• “If an applicant wishes to request reconsideration of a change in classification that occurred after submission of the applicant’s CR amendment, the applicant should submit a request for reconsideration within 10 business days from issuance of the goal letter. . . .  The division will notify the applicant of the decision within 10 business days from the date the request for reconsideration was received.”

ANDA Submissions – Prior Approval Supplements Under GDUFA:  This draft guidance, which should be read in conjunction with the first draft guidance, addresses various topics in relation to PASs to approved ANDAs, including how the GDUFA performance metric goals apply to a PAS subject to the refuse-to-receive standards, a PAS that requires (or does not require) an inspection, and PAS amendments.  (It bears noting that the statutory and regulatory criteria for submitting information to an ANDA as a PAS – or as a changes being effected supplement, or as an annual reportable change – based on a major, moderate, or minor change were not altered by GDUFA.  These reporting criteria should not be confused with FDA’s categorization of amendments as major or minor.) 

Most ANDA sponsors have experienced at some point in time a delay in the approval of a submissions to FDA because of an “expired” inspection.  But FDA explains in the draft guidance that in some cases the Agency will cut sponsors some slack:

FDA intends to continue the practice of using a risk-based assessment in determining the need for an inspection, guided by a 2-year cycle for finished dosage product sites and a 3-year cycle for API sites and consideration of the type of finished product or API in the application.  Practically, this means that in making decisions about pending supplemental applications for which FDA does not have current inspection information within the time period indicated, FDA may use previous FDA inspection information and/or use inspection information from another regulatory authority as appropriate.  If FDA determines that an actual inspection is not required, the goal date would be revised from 10 months to 6 months.

The draft guidance also explains FDA’s approach to so-called “grouped supplements” – i.e., “multiple supplements (typically five or more) submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application.”  FDA says that each supplement in the group is considered an indivdual submission assessed a separate PAS user fee (with generally the same GDUFA goal date).  Alternatively, an ANDA sponsor may want to consider submitting a PAS with a comparability protocol outlining the change and the support for it.  “Once the PAS is approved, the agreed-upon reporting category could be used.  Thus, at the time the PAS containing the comparability protocol is approved, FDA can designate, where appropriate, a reduced reporting category for future reporting of changes covered by the approved comparability protocol (e.g., from a PAS to a CBE-30 supplement).”  This means that while the GDUFA performance metric goals and applicable user fees would apply to the initial PAS, they would not apply to future supplements submitted under the reduced reporting category.  What a deal (or not), depending on what’s more important to you – time or money.  (Though time is money, no?)