Generics: FDA´s final Guidance for Handling Amendments to Submissions

The U.S. Food and Drug Administration recently published its final guidance on ANDA Submissions — Amendments to Abbreviated New Drug Applications. According to the FDA the guidance is intended to explain how the review goals established as part of the Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II) apply to amendments to either abbreviated new drug applications (ANDAs) or prior approval supplements (PASs). In addition, the guidance describes classifications for amendments and categories and explains how amendment submissions may affect an application’s review goal dates.

The guidance finalizes the October 2017 draft guidance ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA and supersedes the December 2001 guidance Major, Minor, and Telephone Amendments to Abbreviated New Drug Applications and the July 2014 draft guidance ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA, both of which will be withdrawn. The 2001 amendments guidance contained descriptions of major and minor amendments. Excerpted text from that guidance, specifically, the sections describing major and minor amendments is contained in an Appendix.

Each submission to an application under review will be considered by FDA as an amendment. The submissions will be classified based on the content submitted and issued a goal date consistent with that classification. The types of amendments and review goals only apply to submissions that have been received for assessment. Information Requests (IRs) and Discipline Review Letters (DRLs) neither stop the review clock nor add to the GDUFA II goal. If a response to an IR or DRL contains information not requested by FDA, or if FDA determines that the information provided requires a more thorough assessment, FDA will classify the submission as a major or minor amendment with a corresponding goal date. Any amendment submitted should identify on the first page that it is an amendment. FDA will issue the applicant an acknowledgment letter to confirm submission of the amendment. Most acknowledgment letters will be issued before the assessment of that amendment begins. Therefore, the acknowledgment letter will not state whether a preapproval inspection (PAI) is required but will instead state two possible goal dates: the goal date with an inspection and the goal date without.

Changes to Classifications
All initial amendment classifications and any changes to those classifications will be made at FDA’s discretion. Furthermore, the FDA may change its initial classification. If the agency determines that a PAI is required for any facility referenced in the ANDA during the assessment of an unsolicited or minor amendment, FDA will classify the submission as a major amendment and set a review goal of 10 months from the submission date. Applicants may request reclassification of their major amendment status via a teleconference with FDA.

CATEGORIES and GOALS

Major and minor amendments were originally described in the 2001 amendments guidance. Now, further description of these amendments in consistency with the 2001 amendments guidance is provided. In addition, FDA has developed a non-exhaustive list of examples of major deficiencies, which is available in Appendix A. FDA says an "appendix containing examples of minor deficiencies is not included in this guidance because, in general, deficiencies not classified as major will be classified as minor deficiencies".

Major Amendments (based on a determination by FDA that the content of the information or data provided will require extensive assessment) are for example:

• Manufacturing a new batch of drug product for any reason (e.g., a composition change or reformulation, a change in the source of a drug substance, a change in the manufacturing site, the need for a new bioequivalence (BE) study, a new in vitro study for a specific product, a change in a major manufacturing process, a new strength of the product, unacceptable impurities or impurity levels, unacceptable excipients found during assessment, failed stability data, or a change in the container-closure system (other than solid oral dosage forms));
• Performing a new BE study whether or not related to the manufacture of a new batch or different formulation of the drug product;
• Developing new analytical procedures and providing full validation data.

Goals:

• ANDA and PAS amendments subject to standard review:
  FDA will review 90% of standard major ANDA amendments within 8 months (PAS amendments: 6 months) of the amendment submission date if a PAI is not required. If a PAI is required 90% will be reviewed within 10 months of the submission date.
• ANDA and PAS amendments subject to priority review:
  FDA will review 90% of priority major ANDA amendments within 6 months (PAS amendments: 4 months) of the amendment submission date if a PAI is not required. If a PAI is required 90% will be reviewed within 8 months of the amendment submission date when the applicant submits a complete and accurate PFC (pre-submission facility correspondence) no later than 60 days prior to the amendment submission date and the PFC remains unchanged at the time of the amendment submission. Finally, FDA will review 90% within 10 months of the amendment submission date if a PAI is required and the applicant fails to submit a complete and accurate PFC no later than 60 days prior to the amendment submission date or information in a complete and accurate submitted PFC changes.

Minor Amendments
The 2001 amendments guidance included minor problems regarding GMP (good manufacturing practices) as an example of a minor deficiency. FDA’s current thinking is that, in general, any GMP or facility deficiency is, in fact, a major deficiency. Therefore, minor amendments (those not classified as major or are a response to a deficiency that could be adequately resolved through an information request (IR) or discipline review letter (DRL) and typically require less extensive assessment by FDA) are for example in response to:

• Minor deficiencies in the drug master file (DMF);
• Incomplete dissolution data;
• Labeling deficiencies that have not been adequately addressed in response to an information request.

Goals: FDA will review 90% of standard and priority minor ANDA and PAS amendments within 3 months of the amendment submission date.

Unsolicited Amendments

An unsolicited amendment is an amendment with information not requested by FDA, except for those amendments considered routine or administrative and that do not require scientific assessment. If an unsolicited amendment contains information that addresses any of the major deficiencies, the unsolicited amendment will be classified as major.

Goals:
Review of an unsolicited ANDA or PAS amendment submitted during the review cycle will be performed by the later of either
- the goal date for the original submission being amended, or
- the goal date assigned under the review goals for standard and priority ANDAs/PASs.
Between review cycles the review will be performed by the later of
- the goal date for the subsequent solicited amendments, or
- the goal date assigned under the review goals for standard or priority ANDAs/PASs.

Appendix A contains a non-exhaustive list of examples of deficiencies that FDA may consider major. During either the course of submission assessment or the inspection of any facility referenced in a submission, data integrity issues related to any discipline(s) below may be found. If FDA, through further investigation or follow up, determines that the data supporting the submission are unreliable, FDA may consider the issue a major deficiency:

• Pharmaceutical Quality Deficiencies (e.g. Failure to provide adequate analytical procedures or method validation which would require significant new procedure development; Major change in drug substance or drug product manufacturing process with inadequate supporting data; API batch inadequacies that require manufacture of a new API batch)
• BE Deficiencies
• Risk Evaluation and Mitigation Strategies (REMS) Deficiencies
• Labeling Deficiencies (e.g. labeling differs from the last approved labeling)

Appendix B contains the excerpt of text from the 2001 amendments guidance describing major and minor amendments.
The following examples of deficiencies would result in a major amendment.

• Manufacture of a new batch of drug product (with supporting information) for any reason; for example:
  • Composition change or reformulation
  • Change in the source of a drug substance
  • Change in manufacturing site
  • Need for a new bioequivalence study
  • New in vitro study for a specific product
  • Change in major manufacturing process
  • New strength of the product
  • Unacceptable impurities or impurity levels
  • Unacceptable excipients found during the review
  • Failed stability data
  • Change in the container-closure system
• New BE study that is not related to manufacture of a new batch of the drug product
• New analytical methods and full validation data
• In rare cases, the sterility assurance and/or microbiology reviews, rather than chemistry, may determine the major amendment designation (for example, when extensive validation work is necessary).

Minor amendments often consist of deficiencies that are outside the control of the applicant or deficiencies that are more easily addressed than those in a major amendment. Some examples include:

• Deficiencies in the drug master file (DMF)
• GMP Problems
• Incomplete dissolution data
• Labeling deficiencies that have not been adequately addressed
• Sterility assurance and/or microbiology issues that would likely take less than a full day to review. However, the microbiology designation is determined by the chemistry review.