October has so far seen a flurry of guidance publications focused on generic drugs.  It’s unusual to see so many guidance on one kind of product published almost simultaneously — though the device area seems to be making the same effort!  Many of the generic drug guidance are published to implement requirements in the Generic Drug User Fee Act (GDUFA I or II).  Two of the guidance documents are final, and one is a MAPP; the others are drafts available for comments that the FDA will consider prior to finalizing.  In addition, the FDA published thirty-two (32) new draft bioequivalence guidance and nineteen (19) revised guidance to assist in the development of generic drugs.  We won’t cover the bioequivalence guidance here, but if you operate in the generics area, please look at them.  Let’s take each of the others in turn to briefly see what they cover.


Completeness Assessments for Type II API DMFs Under GDUFA

GDUFA I specifies that, effective October 1, 2012, DMF holders must pay a DMF fee when first authorizing the reference of the DMF in a generic drug application, and the API DMF must undergo a ‘completeness assessment.’  The completeness assessment checklist is provided as an appendix to the guidance.  The FDA suggests that six (6) months be allowed for the DMF completeness evaluation prior to submission of the ANDA with which it is associated.

Although the requirement for the ‘completeness assessment’ is new, previous DMF evaluations were conducted using the checklist in the guidance appendix.  Thus, this does not appear to represent a change in actual processes or expectations.

DMFs for complex APIs should also provide data to ensure ‘sameness’ of the API.  Additional information on ‘sameness’ may be found in the product specific bioequivalence guidance on the FDA’s website.  If this information is not provided, the FDA will deem the DMF to be incomplete.

GDUFA IV goals for completeness reviews for 90% of Type II API DMFs are within 60 days of the date of DMF submission or DMF payment fee, whichever is later.

ANDA Submissions – Prior Approval Supplements Under GDUFA

GDUFA I was signed into law in July 2012 and established fees for submissions of ANDAs, PASs, certain DMFs, annual facility fees, and a one-time fee for ANDAs that were pending at the time the law was signed.  GDUFA II was signed into law recently and eliminates the fee for PASs — a significant change from GDUFA I.

GDUFA IV did not change the criteria for submission of PASs, CBEs (CBE-0 or CBE-30), or annual reports from that which was previously required by the regulations.  The governing regulations are 21 CFR 314.70, 314.71 and 314.97.  Briefly, changes are classified as ‘major’ which requires submission and approval of a PAS; ‘moderate’ which includes submission of CBE-0s or CBE-30; and ‘minor’ which can be described in the annual report.

This guidance does not describe the criteria used to determine how a change should be categorized, but rather provides details on the performance goals for the PAS submissions.  GDUFA performance goals provide performance targets for PASs submissions in FY2018 through FY2022.  It also removed the tiered system of amendments to pending submissions.  The GDUFA action dates depend on whether the FDA needs to conduct an on-site inspection before approving the supplement.  In general, the need for an inspection may add 4 months to an initial GDUFA date compared to a supplement where an inspection is not deemed necessary.

The guidance identifies the administrative information that needs to be submitted with the supplements.  It also addresses ‘grouped supplements’ where multiple changes are being made.  MAPP 5015.6 provides additional clarity on this topic, and firms are encouraged to discuss this type of option with the FDA.  Also, Appendix A provides a flow chart for GDUFA II supplements.

Receiving and Processing a Request for Voluntary Withdrawal of an Approved NDA

This item from the FDA Manual of Policies and Procedures (MAPP5220.1) describes how requests for withdrawal of an approved ANDA are to be requested and processed.  An ANDA holder remains responsible for legal and regulatory requirements until a notice is published in the Federal Register that the approval of the ANDA has been withdrawn by the FDA.  Until this time, the ANDA holder is responsible for post approval reporting requirements and user fee payments.

If a sponsor wishes to have the ANDA withdrawn and no longer manufacture or market the drug, they should submit:

  • A request to withdraw the ANDA including a Form FDA 356h for each ANDA
  • A cover letter identifying that the ANDA has full approval
  • A statement that they request withdrawal of the approved ANDA(s).

The firm must reference the relevant regulation for this voluntary withdrawal request, 21 CFR 314.50(c).  The FDA will withdraw the ANDA along with any amendments and approved/pending supplements to the application.  If the ANDA holder changes their mind prior to the publication of the withdrawal in the Federal Register (or prior to the date of withdrawal specified in the FR announcement), they may petition to have the voluntary withdrawal request rescinded.  If the request is made after the effective date of withdrawal identified in the Federal Register, they will be notified by the FDA that the request is denied.


ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA

One of the guidances above addressed performance goals for GDUFA reviews of prior approval supplements.  But the guidance did not address the criteria for submission of amendments.  This 32-page draft guidance ‘describes amendment classifications and categories and explains how amendment submissions may affect an applications’ GDUFA II review goal dates.’  When finalized this guidance will replace a December 2001 guidanceMajor, Minor, and Telephone Amendments to Abbreviated New Drug Applications.’  This draft supersedes the draft guidance from July 2014 ‘ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA.’  Management of amendments submitted prior to October 1, 2017 is also described.

This guidance simplifies the classification of amendments from a multi-tier system to a standard vs priority and major vs minor system.  The guidance includes a full discussion of administrative issues and how GDUFA review dates and actions may modify these dates.  Appendix A of the guidance lists major deficiencies that may be identified upon either review or inspection.  The FDA addresses identification of data integrity issues during review or inspection and states that ‘If FDA, through further investigation or follow up, determines that the data supporting the submission is unreliable, FDA may consider the issue a major deficiency.’

Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA

As part of GDUFA II, the FDA committed to develop a program to assist those developing generic drugs that are complex products.  The program includes meetings during the drug development process, pre-submission meetings, and mid-review-cycle meetings between sponsors and the FDA. The GDUFA II Commitment Letter defines complex products to include:

  • “Products with complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of [active pharmaceutical ingredients], naturally sourced ingredients); complex formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels); or complex dosage forms (e.g., transdermals, metered dose inhalers, extended-release injectables);
  • Complex drug-device combination products (e.g., auto-injectors, metered dose inhalers); and
  • Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement.”

The 20-page guidance addresses how these meetings may be requested and the information to be included in the request.  Each of the meeting types, product development/pre-submission/mid-cycle review is addressed in turn.  Also covered are submissions of each type of pre-meeting package, meeting minutes, and resolution of disputes about meeting minutes content.  It will be interesting to see how this effort is implemented.  Stay tuned, I’m sure it will be a work in progress.

ANDA Submissions – Refuse-to-Receive Standards:  Questions and Answers

Thirty-five (35) questions are addressed in the draft guidance.  The questions address areas of DMFs, quality, bioequivalence, and clinical.  When the FDA makes a refusal-to-receive decision, it means that the ANDA does not include the necessary information to ‘permit a substantive review.’  This draft guidance references previous guidance including final, revised final, and another revised final guidance from 2014 – 2016.

GDUFA I required the FDA to develop standards that would guide their refusal-to-receive decisions.  The intent was to minimize starting review of ANDAs where serious remediation must occur during the review process.  This is inherently inefficient for both the firm and the FDA because it impacts the time for review and approval.

The thirty-five questions are grouped into the following categories (number of questions):   Scope (1), Responding to Deficiencies and RTR Determinations (9), General Deficiencies (4), Drug Master File Review and Deficiencies (3), Stability Data (2), Packaging Configurations (1), Batch Records (2), Over-the-Counter Drug Products (2), Inactive Ingredients (2), Impurity Data (1), Dissolution Testing (1), Scoring and Conditions of Use (1), Bioequivalence and Clinical deficiencies (6).

ANDAs for Certain Highly Purified Synthetic Peptide Drug Products that Refer to Listed Drugs of rDNA Origin

This draft guidance is written to assist potential applicants to determine when they may submit an ANDA, rather than an NDA, for a synthetic peptide drug product that ‘refers to a previously approved rDNA peptide drug product.’  Specifically, the guidance addresses five peptide drug products:  glucagon, liraglutide, ebiratide, teriparatide, and teduglutide.  The FDA defines peptides to have forty or fewer amino acids.

Whether the application should be an ANDA rather than an NDA will largely depend on the impurity profile which may impact immunogenicity, safety, or efficacy.  Current advances in technology for synthesis and characterization of peptides have advanced to the point where the FDA ‘…now believes it is possible for an ANDA applicant to demonstrate that the active ingredient in a proposed generic synthetic peptide is the same as the active ingredient in the RDL that is of rDNA origin and demonstrate that such products are pharmaceutical equivalents.’  Note, this is not biosimilarity of the active ingredient, but rather the “sameness” active ingredient.

Applicants are encouraged to contact the FDA if they plan to develop this type of product.  It will be interesting to watch this area develop and see when the generic product of this type is approved.

Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA

This guidance is developed to support performance commitments identified in GDUFA II regarding the schedule and conduct of efficient meetings in response to a Complete Response Letter (CRL).  This guidance states that the FDA will only grant these post-CRL meetings for the applicant to ‘seek clarification concerning deficiencies identified in a CRL.’  These meetings are apparently not the place and time to dispute the CRL classification, provide new information, or agree upon a path forward from the CRL.  Those would be the subject of other communications and meetings.

The guidance provides the GDUFA II time-goal for scheduling of the meetings, content of the meeting request, and communications in response to these requests from the FDA.  Section V.A and B respectively address when a request for this type of meeting will be denied and when it will be granted.  The guidance also addresses documentation of the meeting and how disputes about meeting minute content will be resolved.


The FDA has been quite active in publishing guidance for generic drugs that support commitments in GDUFA I and GDUFA II.  I would expect more to come in other areas as well while the FDA works diligently to meet commitments made in response to this and other user fee legislations, PDUFA, MDUFA, and Biosimilar User Fees.

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