Generic Drugs | A Guidance on FDA Guidance

by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief

On November 1, 2017, we published a blog that addressed a large collection of newly issued guidance for the generic drug industry.  With this post, we continue with another three generic drug guidance that were issued recently.  Consistent with the previous collection, many of these find their roots in GDUFA legislation.  This time we address three guidance documents.  Regulatory affairs departments should carefully read the first two that include detailed specifics on who needs to pay what and when.  The last guidance addressed here should be read carefully by groups who develop filing strategy.  It appears most problematic and may not provide the relief or speed as it may have intended.

Assessing User Fees Under the Generic Drug User Fee Amendments of 2017″

This 36-page draft guidance dated October 2017 provides information regarding the FDA’s implementation of the Generic Drug User Fee Amendments, 2017 (GDUFA II).  GDUFA II implements changes from GDUFA I and this draft guidance provides information on the new fee structure and describes the various fees for which entities are responsible.  These fee changes are effective in FY2018 which begins on October 1, 2018.  Regulatory affairs staff should read this guidance carefully to ensure they are meeting the necessary GDUFA fee requirements.

GDUFA-I describes collection of four types of user fees:  backlog fees, drug master file fees, ANDA/prior approval supplement fees, and API/final dosage form (FDF) facility fees.  GDUFA-II eliminates the fees for filing of prior approval supplements and adds GDUFA program fees.  Also under GDUFA-II, firms that make both API and FDF will only be charged the FDF facility fee.  Facility fees apply only to facilities identified in approved applications, not for those identified in pending applications.  And, finally, CMOs will pay only one-third of the fee amount that would be paid by FDF facilities that are not CMOs.  Let’s look at each of the types of fees:

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  • BACKLOG FEES:  For all ANDA’s that were not tentatively approved but rather were in pending status on October 1, 2012, the firm owes an application backlog fee.
  • DRUG MASTER FILE FEES: This fee is owed by firms that own a Type II API DMF that is referenced in a filing on or after October 1, 2012.  This is a one-time fee, not an annual fee.
  • ANDA FILING FEES: These fees are due on the date the application is submitted to the FDA.  GDUFA II removed the fee for prior approval supplements.  Excluded from this fee are PET drugs, applications for a drug that will not be distributed commercially, or for serial submissions as described in the guidance (see Section VII.E.).  This section also addresses:
    • How refunds are addressed in instances of ‘Refusal to Receive’, ‘Withdrawals’, and ‘Inappropriate Receipts’.
    • How fees will be applied for resubmissions that correct deficiencies identified in the Refusal to Receive communication from the FDA.
    • Instances that are identified as exemptions from the application filing fee.
    • Fees that are due for API information that is not included by reference to a Drug Mater File.  As with the Drug Mater File fees above, this is a one-time fee, not one that is paid annually.  The FDA provides several examples of this type of fee.
    • Serially submitted ANDA fees are due “on the first working day after the day the relevant patent is listed in the Orange Book or, if the application is not submitted on that date, on the date the application is submitted.”
    • ANDA’s withdrawn prior to being received can receive a refund of 75% of the fee.
  • FACILITY FEES: These fees are due when a facility is identified in an approved application and they engage in the manufacturing or processing of an API or FDF.  A facility fee is not due for facilities that are identified in pending applications.  The fees are due on the first business day after October 1 of each fiscal year.  The various types of facilities who must pay fees include the following:
    • API’s fees are due when the facility is identified in an approved application or when a Type II API DMF is identified, also in an approved application.  An FDF facility owes a fee when it is identified in at least one approved generic drug application.
    • Some facilities are not required to pay facility fees.  Exceptions to facility fees include PET facilities, facilities that do not manufacture commercially distributed products and those whose only activity is to repackage, relabel, or test products.
    • For dual facilities that produce both API and FDF, they are only required to pay the FDF facility fee.  This represents a change from GDUFA I.
    • CMOs pay only 1/3 the facility fee of a FDF facility.
    • Fees include a foreign-facility differential of $15,000 applicable to all firms that must pay fees under GDUFA II.  This is meant to help defray the higher cost of foreign inspections.  Those sites that do not pay the differential include those located in territories and possessions outside the US.
    • Firms that are withdrawn from identification in approved applications no longer need to pay a fee.  Either the firm that references the facility may petition to have them removed or the facility itself may file the application with the FDA to remove itself from all applicable ANDAs.
    • Packagers and re-packagers are treated differently under GDUFA II.  Packagers must pay an FDF GDUFA fee, and re-packagers are not required to pay a user fee.  Packagers who work under contract are treated the same as when the activity is performed at a site owned by the applicant.
    • API and excipient mixtures are subject to FDF user fees except when the excipients are necessary to stabilize the API.
    • Atypical APIs are raw materials that are components of FDF that provide “…pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, and the ingredient is referenced in an approved ANDA.”  These firms may incur a facility fee.
    • Facilities that cease manufacturing no longer are required to pay user fees.  This occurs when the facility is withdrawn from applications or has ceased manufacturing of all APIs and FDFs (both generic and non-generic).  (NOTE:  This raises the question of whether a firm that ceases manufacturing of generic APIs and FDFs but continues to manufacture innovator drugs are subject to GDUFA fees in addition to PDUFA fees).
    • Multiple locations, for example separate buildings, owned by the same firm that are in ‘close proximity’ pay a single fee if their activities are ‘closely related to the same business enterprise’, operate under the same local management, and can be inspected by the FDA during a single inspection.
  • APPLICANT PROGRAM FEE: The fees are divided into three tiers of firms.  Small firms who have < 5 approved ANDAs, medium firms who have 6-19 approved ANDAs, and large firms who have > 20 ANDAs.  Multiple sections here address the specifics of these payments and classifications.

The remainder of the guidance addresses how to submit the fee payment, and the consequences for failure to pay each of the five specific fee types.  Finally, the guidance describes the appeals process, additional resources, and includes two appendices that are FDA forms.

Controlled Correspondence Related to Generic Drug Development’

This 17-page draft guidance addresses how generic drug manufacturers might submit communications to the FDA that request feedback on generic drug development.  When this guidance is finalized, it will replace a September 2015 guidance of the same title.  The September 2015 guidance was issued to support implementation of GDUFA I, and this guidance is published to addresses changes in the program of controlled communications that are part of GDUFA II.  The guidance defines and addresses both standard controlled correspondence and complex controlled correspondence.  As with the previous guidance, Regulatory Affairs departments are encouraged to closely read this document and the details it includes.

The guidance provides details and recommendations regarding the inquiries that the FDA considers to be ‘controlled correspondence’, the information that should be included in the correspondence, the types of information the FDA will provide in response to requests, and how requestors can ask for clarification of the FDA’s response.  Further, when the request is more appropriately addressed in another venue, the FDA will identify how the requestor should proceed.

The remainder of the guidance addresses how to submit the ‘controlled correspondence’ and its suggested content.  The guidance addresses the type of topics for the correspondence including requests about inactive ingredients, formulation, product quality, post approval submission requirements, and those topics that require review by groups in different areas of the FDA.  The guidance also addresses correspondence by review disciplines.  Overall, the FDA’s continued publication and revision of product specific bioequivalence guidance is important to address what is frequently a development discussion issue for generic drug manufacturers.  Increasing the number and scope of product specific BA/BE guidance may result in fewer ‘controlled correspondence’ requests.

‘ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence)’

This 15-page revised draft guidance identifies the process for generic drug manufacturers seeking a priority review to submit facility information prior to the entirety of the original ANDA or a prior approval supplement.  The original draft of the guidance was published in June 2017.  This revised guidance was necessary because of changes made in the user fee legislation with regard to ‘pre-submissions of facility information.’  It is worth noting that the pre-submission of facility information includes relevant sections of the ANDA, and it does not require submission in the format described in the original draft guidance.  The pre-submission is used to “support the application to determine whether an inspection is necessary.” 

It will be interesting to see how many firms take advantage of this option.  Personally, it looks like submission of a mini-ANDA 60-days prior to submission of the complete filing.  In my experience, many of the requested information arrives at the firm and are compiled and dropped into the submission very near to the time it is submitted to the agency.  If firms have the information for the pre-submission, they very likely have most of the information necessary to make the full submission.  I’m not sure if this option truly provides a lot of value for ANDA sponsors.  Time will tell, and, hopefully, the FDA will publish how many firms availed themselves of what seems to be fairly burdensome option!  If the FDA knew the name and location of the various facilities involved in manufacturing, testing, packaging, and BA/BE studies, they should be able to determine recent enforcement history and products made at the site and make decisions about the need for an inspection.  For example, it is not clear how having process validation information, specifications, and control of critical steps can be considered ‘facility information.

Priority ANDAs qualify for review within 8-months by pre-submitting “complete, accurate information regarding facilities involved in manufacturing processes and testing of the drug that is the subject of the application,” as outlined in this guidance, not later than 60 days prior to ANDA submission, giving FDA at least 60 days to determine whether inspection of a facility is necessary and, if so, begin inspection planning in advance of the ANDA receipt.”  The pre-submitted facility information must be unchanged in the original full ANDA submission.

The guidance identifies the eCTD section number and the specific information necessary for the pre-submission.  Although the title of this guidance addresses submission of ‘facility’ information, the requested information includes far more than simply facility information.  For example, the manufacturing process for the API and drug product must be provided along with validation information, process development, and batch analyses.  Also, BA and BE reports must be provided.

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