Regulation and Compliance

On July 9, 2012, the Generic Drug User Fee Act (GDUFA) was passed by the US Congress (1). The Act, to be implemented from Oct. 1, 2012, is designed to streamline the generic-drug review process and has been welcomed by the pharmaceutical industry. However, there have been a lot of unanswered questions regarding the general outcome of GDUFA and how it will impact the industry.

The GDUFA agreement includes application fees for original Abbreviated New Drug Applications (ANDAs), prior approval supplements (PAS), and Type II Drug Master Files (DMFs) for APIs. Based on the fee structure, Type II DMFs will account for 6% and the API manufacturing facilities will account for about 14% of the GDUFA fees, respectively (2). To fulfill the GDUFA requirements and to streamline the DMF review process, the FDA Office of Generic Drugs (OGD) has established a DMF Review Team, with a future possibility of a division, which will be dedicated to review of API information submitted in Type II DMFs. With all the changes in the Type II DMF review processes that are covered in the GDUFA legislation and given the fact that there is currently a lack of adequate information available to the industry, there have been many industry questions and speculations regarding the impact of GDUFA on the submission and review of Type II DMFs. This article attempts to provide clarification to some frequently asked questions regarding the fate of DMFs under GDUFA.*

Q. What will be the difference in DMF review once GDUFA is implemented?

A. GDUFA legislation requires the following for the Type II DMFs:

• Type II DMFs pay a one-time fee when referenced under GDUFA

• DMFs must be deemed "available for reference" by the Health and Human Services (HHS) Secretary

• DMF deficiency letters must address issues from all relevant disciplines, including inspections (complete response)

• DMF holders will be issued a letter stating that there are no further comments (new type of letter) when the ANDA, referencing the DMF, is approved.

Q. We have an old DMF in the Center for Drug Evaluation and Research (CDER) that has been referenced by an NDA. Do we need to pay a fee under GDUFA?

A. No, DMF fees were negotiated under GDUFA and apply only to ANDAs, submitted after Oct. 1, 2012 and not NDAs. So, if there is no ANDA in CDER that references your DMF, paying of the GDUFA fee is not necessary.

Q. We have an old DMF in CDER which has been referenced by many ANDAs. Do we need to pay a GDUFA fee now?

A. No, you do not need to pay a GDUFA fee for DMFs referenced in ANDAs before Oct. 1, 2012. However, a one-time fee will be due for your DMF, upon first reference (triggered by a letter of authorization) after Oct. 1, 2012. In other words, if a new ANDA submitted after Oct. 1, 2012 references your DMF, the one-time GDUFA fee will have to be paid.

On the other hand, if a company decides to pay a fee without being referenced by any new ANDA, the OGD's DMF review team will review your DMF for completeness and your DMF information will be listed in a FDA monitored, publicly available database as a DMF which has paid GDUFA fees and is considered "complete" by OGD.

Q. What is the "completeness assessment" we have been hearing about and who will decide if the DMF is "complete?"

A. "Completeness assessment" refers to a preliminary assessment of the DMF to assure that all the required information is present in the application for a full scientific review at a later date. The need for a "completeness assessment" of a DMF arose from the poor quality of DMF submissions to the agency, the lack of pertinent information for full scientific evaluation. This assessment is expected to assure that the DMF holders have submitted relevant information in all the sections and subsections of the CTD and thus reduce the number of review cycles and deficiencies cited for the DMFs. The "completeness assessment" requirements for Type II DMFs will be very similar to the "filing" requirements for ANDAs. This assessment will be done by chemistry reviewers in the DMF review team of OGD.

Q. We were told that DMF deficiencies will be communicated in complete response letters. What does this mean?

A. GDUFA goals clearly state that the FDA will issue a letter detailing all identified deficiencies, rather than discipline specific letters, for all DMFs, including those under review at the time of enactment of the implementing legislation.

This will, however, result in minimal changes to the current process. GDUFA applies to only Type II DMFs for APIs, which are in most cases stand-alone documents with Chemistry, Manufacturing, and Controls (CMC) information only. The only discipline other than chemistry, which is sometimes involved in review of a Type II DMFs is the Division of Microbiology. Under the GDUFA criteria of "Complete Response" for the Type II DMFs, the format of the deficiency letter will change and the chemistry and microbiology deficiencies will be provided concurrently, where applicable. Only limited reference may be made to facility inspections. It is also the expectation of OGD that the DMF holders provide complete response to the deficiency letter, covering all the questions.

Q. Does GDUFA provide opportunities for DMF holders to meet or interact by any other way with OGD regarding deficiencies cited?

A. Yes, GDUFA goals state that when requested by a DMF holder within 10 business days of FDA issuing a first cycle DMF deficiency letter, FDA will schedule a 30 minute teleconference with a limit of one teleconference per DMF holder per month. A simple interpretation of this complex statement is that after a DMF holder receives the first deficiency letter related to their DMF, they may call the related Project Manager within 10 working days and request a 30-minute meeting with the reviewer to clarify the deficiencies. However, in these meetings, the reviewers will only discuss the deficiencies related to the specific DMF.

Q. Will DMF holders receive an approval letter when the DMFs become adequate?

A. No, DMFs will not receive any kind of "approval letter" when deemed adequate. However, GDUFA requires that a letter be issued to the DMF holder at the time of approval or tentative approval of an ANDA, which references the particular DMF. The scope of this letter will be very narrow and will only indicate that there are no further deficiencies related to the specific ANDA, which is being approved. DMF holders will be reminded that the status of the DMF may change to "inadequate", based on the review of any updates to the DMF, which in the agency's opinion, can have an adverse effect on the drug substance and drug product quality and safety.

Q. Our firm is not referencing a DMF but rather providing all the information regarding the drug substance in the ANDA itself. Do we need to pay any fees?

A. Yes, GDUFA states that ANDAs, which include the drug substance information will need to pay an additional fee, equivalent to the DMF fee.

Q. We have been told that a Question-Based Review (QbR) document is being prepared for DMFs. When will this be implemented?

A. Yes, the OGD is in the process of preparing a QbR for DMFs, which will likely be implemented in 2013. However, this step will only apply only to Type II DMFs that are referenced by ANDAs. OGD is expected to communicate more information to industry regarding how DMF QbR will be implemented.

Conclusion

It is expected that the implementation of the GDUFA goals related to Type II DMFs by the agency will lead to a more streamlined review of the DMFs, lead to better communication between the DMF holders and the reviewers, which can, in turn, result in quicker resolution of the DMF related deficiencies for the ANDAs. APIs are the most crucial components of a drug, which determines its efficacy and safety. Thus, assurance of better quality of the API though more scrutiny, and consistent communication between OGD and DMF holders may lead to lesser product concerns and stronger public confidence in generic drugs.

Addendum

Since this paper was accepted for publication and finalized, two draft guidance documents were published by the FDA regarding the GDUFA fees on Aug. 22, 2012, which provide information regarding the fee structure and also self-identification of facilities. The following draft guidance documents and the related federal register notice are to be found at the website, http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm313983.htm: Draft Guidance for Industry on Generic Drug User Fee Amendments of 2012: Questions and Answers, and Draft Guidance for Industry on Self-Identification of Generic Drug Facilities, Sites, and Organizations; Availability.

References

1. FDA, Generic Drug User Fee Amendments of 2012 (Aug. 10, 2012), www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm

2. FDA, Human Generic Drug Performance Goals and Procedures Fiscal Years 2013 through 2014 (July 17, 2012), www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm282513.htm.

3. Aloka Srinivasan, PhD, "DMF (Type II) Review Team in the Office of Generic Drugs," presentation at the GPhA Fall Technical Conference, Oct. 4, 2011.

* Disclaimer: The views herein do not claim to represent those of FDA.