In July 2018 the United States Food and Drug Administration (FDA) issued a final guidance document titled, “ANDA Submissions–Amendments to Abbreviated New Drug Applications under GDUFA–Guidance for Industry.” A guidance document represents the recommendations of the FDA, but is not legally binding.

The Guidance Document explains how amendment submissions may affect an application’s review goal dates (i.e., the time it will take FDA to respond to an ANDA Amendment). Amendments to an ANDA will be designated as “standard” or “priority,” and classified as “major” or “minor.” FDA assigns a goal date depending on the above designation and classification, and other factors, such as whether a facility inspection will be required.

The guidance applies to ANDAs that are submitted after October 1, 2017. Key concepts include:

A.            The type of amendment being submitted

1) Major amendments – When the content or data provided by an ANDA applicant in response to a deficiency cited by the FDA will require extensive assessment by the agency.

2) Minor amendments – Those responses to deficiencies that require less extensive assessment by the FDA.

In the Complete Response Letter (CRL) FDA sends the ANDA applicant, the agency will advise whether the amendment response will be classified as major or minor.

3) Unsolicited amendments – The ANDA applicant may also submit an amendment that is not prompted by an FDA-noted deficiency. The amendment will be characterized as major or minor depending on its content.

B.            What other factors impact review timing?

1) Is the ANDA subject to standard or priority review?

The FDA can grant an ANDA priority review status when there are no more than three approved drug products listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book), and where there are no patents or regulatory exclusivities that prevent approval of the ANDA. ANDAs including patent challenges under the Hatch-Waxman regime that can result in a first generic offering may become eligible for priority review. Other criteria for priority review designation are provided in the Manual of Policies and Procedures – Center For Drug Evaluation and Research, MAPP 5240, 3 Rev. 4 (November 9, 2017)¹. Unless an ANDA is given priority status, it is assigned standard review status.

2) Has the ANDA applicant submitted timely and accurate pre-submission facility correspondence (PFC) (i.e., Information regarding the facilities involved in the manufacturing and testing of the ANDA drug)?

The ANDA applicant should submit its PFC at least 60 days prior to the submission of its ANDA and confirm that the PFC is accurate at least 60 days prior to the date of submission of each ANDA amendment.

3) Will the FDA reclassify the submitted amendment from minor to major?

The FDA can change and amendment’s classification from minor to major if the submission creates an issue that requires extensive review by the Agency

4) Are there any changes to the drug master file (DMF) referenced in the ANDA?

Any changes that could impact the safety, efficacy, quality or substitutability of the drug product can be considered by The FDA as unsolicited amendments subject to the timing guidelines in Part D.

C.            Practical recommendations

We recommend the following be implemented as part of your regulatory responsibilities:

1. Understand whether your ANDA has been designated as receiving priority or regular review (and, if appropriate, request priority review at the time of submission)
2. Review CRLs to determine if the amendment will initially be classified as major or minor
3. Avoid submission of unsolicited amendments unless believed necessary for approval
4. If the ANDA is subject to Hatch-Waxman litigation and is a first filer application, factor in the expected FDA response time to achieve a timely tentative approval
5. If the ANDA is subject to Hatch-Waxman litigation, factor in the expected FDA response time to satisfy all regulatory review obligations prior to the expiration of any litigation or regulatory stay periods
6. When requesting final approval, do so at least 90 days before the date that final approval is desired and, unless absolutely necessary, do not make any changes to the ANDA
7. Use a standard first page for all ANDA Amendment submissions that addresses the points in Section E

D.            Timing guidelines for FDA’s response to ANDA Amendments

FDA’s goal is to assess and act on 90 percent of the ANDA Amendments in accordance with the following:

1. Major amendments subject to standard review:
   1. If, because of the amendment, there is no pre-approval facility inspection needed: eight months from submission of the ANDA Amendment
   2. If, because of the amendment, there is a pre-approval facility inspection needed: 10 months from submission of the ANDA Amendment
2.  Major amendments subject to priority review:
   1. If, because of the amendment, there is no pre-approval facility inspection needed: six months from submission of the ANDA Amendment
   2. If, because of the amendment, there is a pre-approval facility inspection needed AND the PFC has been properly filed, has been properly maintained and contains current and accurate information²: eight months from submission of the ANDA Amendment
   3. If, because of the amendment, there is a pre-approval facility inspection needed AND the PFC has not been properly filed and maintained, or the facility information needs to be updated in the amendment with current and accurate information: 10 months from submission of the ANDA Amendment
3. Minor amendments subject to standard or priority review: three months from submission of the ANDA Amendment
4. Unsolicited amendments submitted during a review cycle: FDA will respond by the later of either: (1) the goal date for the original submission or solicited amendment being amended; or (2) The goal date assigned under the review goals for standard and priority review ANDAs
5. Unsolicited amendments submitted between review cycles: FDA will respond by the later of either: (1) the goal date for the subsequently solicited amendments; or (2) the goal date assigned under the review goals for standard or priority review ANDAs

E.            What wording should be used when submitting ANDA Amendments?

Any amendment should be clearly identified on the first page of the submission, which should also include the following information, as appropriate:

• A statement indicating whether the amendment is unsolicited or in response to an assessment from FDA
• The discipline from which the Information Request/Discipline Review Letter was issued or the disciplines from which the CRL was issued
• The amendment classification (major or minor) as identified in a CRL
• If unsolicited, the amendment classification proposed by the applicant
• A statement indicating that the application should be designated as priority (including a justification for that designation)
• A statement indicating that the applicant is requesting priority review for the amendment (including a justification for that request)
• A statement indicating if and when a PFC was submitted in preparation for the amendment
• A statement indicating if the amendment is addressing a change in the DMF
• A statement indicating whether the amendment contains any manufacturing or facilities changes  

References

[1] https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM407849.pdf

[2] The information contained in the most recent PFC submission is at least 60 days old and no changes were required in the ANDA Amendment.

About the Author

Andrew M. Solomon is an Esquire at Polsinelli PC. Polsinelli is an AmLaw 100 firm with more than 800 attorneys in 20 offices.