DMFs from a GDUFA Perspective

Huyi Zhang, Ph.D DMF Review Staff/OGD/OPS/CDER

Orlando, FL March 27, 2014

Outline

• GDUFA Year One Accomplishments

Completeness Assessments

Available for Reference List

DMF Complete Response Letters

DMF No Further Comment Letters

10-day Teleconferences

• Expansion of the DMF Staff

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Completeness Assessments: FY 2013 Numbers

• 1, 797 DMF user fees paid (2,144 by Feb 2014, 347 in 5 months of FY14)

– Projected number was 700 for FY2013

• 1, 707 CA review cycles performed

• 1,164 DMFs are complete (65%) (1658 by Feb 2014, 77.3%)

• 1, 432 DMFs have completed at least one CA review cycle (80%)

• 842 Eligible for Administrative CA (47%)

• 955 required a Full CA (53%)

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Completeness Assessments: FY 2013 Backlog

• Define backlog as a DMF unassigned for the initial full CA cycle

• 1, 432 of the 1, 797 DMFs have completed at least one CA review cycle

• 137 DMFs currently assigned and initial cycle is under review (172 by Feb 2014)

• 184 DMFs pending assignment (backlog is 10% of the total workload) (66 by Feb 2014)

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Factors Impacting Timelines and Backlog

• Large overall number of DMF Payments (about 2.5 times the projected number)

• Large bolus of payments initially and at close of FY (almost 600 in the first two months, 300 in September due to FY2014 fee increase)

• Limited review resources 5

Composition of the current CA Backlog

• Backlog is primarily made up of DMFs with no risk of causing a Refuse to Receive (RTR) for an ANDA due to the “risk based” prioritization scheme

• Of the 184 backlogged CAs on September 30, 2013, 176 or 96%, were not associated with an ANDA submission (zero risk)

• Only 8 (4%) were associated with a non-expedited ANDA submission undergoing filing review.

• None were associated with an expedited ANDA submission undergoing filing review. (unassigned DMFs were not associated with any ANDA submission by Feb 2014)

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Completeness Assessment Priorities

• Guiding principle – Reduce the risk to ANDA sponsors for being RTR due to the DMF not being “Available for Reference”

• Tiered “risk based” prioritization scheme

Priority (#) Sorted by…. Used for…. Expedited

(113; 12%)

ANDA Submission Date (earliest first)

DMFs associated with ANDA/PAS in queue for OGD filing review that DLPS/RSB has identified as expedited.

Referenced

(337; 35%)

ANDA Submission Date (earliest first)

DMFs associated with a ANDA/PAS in queue for an OGD filing review (non-expedited)

Normal

(504; 53%)

DMF Fee payment date (earliest first)

DMFs which have paid the fee but are not yet referenced by a GDUFA submission. Low

High

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Current Prioritization of CAs

• Previous priority scheme remained in place for DMFs which pay the fee by December 31, 2013.

• After that date DMF holders and ANDA sponsors will take on more responsibility for planning a viable submission strategy.

• This scheme is current in place for the rest of FY2014

Priority Sorted by…. Used for…. Expedited ANDA Submission Date

(earliest first) DMFs associated with ANDAs in queue for filing review that DLPS/RSB has identified as expedited.

Normal DMF Fee paid date (earliest first)

DMFs which have paid the fee that are not associated with an expedited ANDA. Low

High

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Future Prioritization of CAs • Starting in Cohort Year 3 (FY 2015) on October 1, 2014 DMFs must be

“Available for Reference” at the time of ANDA submission or they will be Refused to Receive (RTR).

• This is a major shift compared to Cohort years 1 and 2 where RTRs only resulted for “incomplete” DMFs after a DMF had at least an initial CA review and the holder had an opportunity to respond.

• ANDA applicants and DMF holders need to plan ahead for this change!

• Starting in Cohort year 3 the DMF fee should be paid a minimum of 6 months ahead of ANDA submission to ensure the CA is done and the DMF is available for reference. The sooner you pay the fee and get the CA the better!

• DMF holders need to be aware of the ANDA submission timelines and respond to CA incomplete letters quickly!

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Completeness Assessment Timelines

• Average time from payment to completion for an administrative CA: 19 days

• Average time from payment to completion of the first cycle for a full CA October thru April: 83 days

• Average time from payment to completion of the first cycle for a full CA May thru September: 69 days

• DMFs Complete on the first cycle (Full CA): 132 (14%) (217, 20% by Feb 2014)

• Average response time to first Incomplete Letter: 45 days

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Completeness Assessment Timelines • Will continue to improve going forward

– Decreasing trend in workload

– Clearing of the initial and September bolus

– Additional review resources and experience with the process

Type of CA Priority Typical time to assignment (Spring 2013)

Typical time to assignment (Now)

Administrative Any Priority Two to Four weeks Two to Four weeks

Full Expedited Two to Four weeks Two weeks

Full Referenced Eight to Ten weeks Four to six weeks

Full Normal Twelve weeks plus Eight weeks

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Keys to a Smooth CA Process • Submit a complete DMF (use the checklist)

• Update older DMFs that might not meet the standard (amend or provide a complete update)

• Respond to Incomplete letters as soon as possible (RTRs have resulted from slow responses)

• Maintain good communication between ANDA sponsor and the DMF holder

• Pay the DMF fee as early as possible!

– 6 months ahead of ANDA submission

• Follow instructions on the cover sheet to send email notification of a response to the chemist

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The Available for Reference List

• List is now published in a searchable/sortable MS Excel format.

• “Holder” and “Subject” fields are as they appear in the official archive

• “Completeness Assessment Review Date” field is the date the DMF was first deemed complete and became eligible for the list

• Any changes to these fields can only be made if the DMF holder submits an amendment to the DMF requesting the change

• The amendment must be signed by the DMF Holder and not an agent

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The Available for Reference List

• Comprehensive list of all Type II DMFs for APIs that have paid the DMF fee and passed a Completeness Assessment

• Updated list has been posted on the FDA website on a weekly basis since12/19/2012 (41 lists posted in FY2013; 1,237 DMFs on the list) (63 lists posted by Feb 2014; 1,658 DMFs on the list)

• Once the DMF is on the list you remain on the list unless fee payment is withdrawn or the DMF has a status other than “active”

• All questions regarding the contents of the list should be sent to: DMFOGD@fda.hhs.gov

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DMF Complete Response Letter • Created a new letter template and process called the DMF

Complete Response to comply with GDUFA requirements for DMF deficiency communications

• In use for all Type II DMFs for APIs since mid-October 2012.

• Modeled after the ANDA Complete Response

• Chemistry Deficiencies (if applicable)

• Microbiology Deficiencies (if applicable)

• Facilities information

• Letters reflect the compliance status of facilities at the time the letter issues

• Deficiencies from any related consults are included under the discipline that requested the consult

• 277 DMF CR Letters issued in FY2013 (498 by Feb 2014) 15

DMF No Further Comments Letter

• The Commitment letter states:

• “FDA will issue the DMF holder a letter to indicate that the DMF does not have any further open matters as part of the review associated with the referencing ANDA.”

• Issued at the time of approval of the ANDA, not when the DMF is first deemed adequate

• Not to be construed as an indication of any future status of the DMF (i.e. not equivalent to an approval letter)

• Goal to issue within 30 days of the ANDA action letter

• 493 NFC letters were issued in FY2013. Most within two to three weeks of the approval action. (613 by Feb 2014)

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“10 day” Teleconferences

• 30 minute teleconference for first cycle deficiency letters to discuss the contents of the letter

• To qualify, a written request must be received by FDA within 10 days of receiving the deficiency letter

• Contact information for requesting these teleconferences is included at the end of the DMF Complete Response letter

• Details of the process will be covered by our PM, Kun Shen

• There are limits of one teleconference per DMF holder per month

• 11 T-con requests in FY2013 (22 by Feb 2014)

• We would like to see DMF holder’s use this more often!

17

Expansion of the DMF Staff in FY2013 and 14

• DMF Staff has hired 14 new reviewers as a result of GDUFA resources since October 2012.

• All are on board and most have completed initial reviewer training.

• DMF Staff is now divided into five teams and is about the same size as a traditional CMC review division.

• The DMF Staff has 27 chemists and 2 PMs in FY13 (currently 34 chemists and 3 PM by Feb 2014)

• For FY 2014 DMF Staff will hire 19 additional chemists and 2 additional PMs

• Support for all 16 ANDA Teams

• Support for DMFs referenced in supplements

• Support for drug substance information included in the ANDA

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The DMF Fee under GDUFA

Due for Type II DMFs for the API referenced by an initial letter of authorization by an ANDA submission on or after October 1, 2012

Required upon the first reference on or after October 1, 2012 Paid only once during the DMF lifecycle Is triggered when the DMF reference is included in the following

ANDA submissions: – Original ANDA – An amendment to an ANDA – A Prior Approval Supplement (PAS) – An amendment to a PAS

A DMF fee can be paid before it is due and we strongly encourage

you to do this!

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BACKUP SLIDES

The DMF Fee under GDUFA

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When A DMF fee is not Required

For ANDAs that are part of the backlog For submissions not part of GDUFA (INDs, NDAs, CBE 0/30

supplements) For any non-Type II DMF (Type IV DMF for an excipient) For any Type II DMF that is not referenced as the API

– DMFs for API intermediates – DMFs for drug product manufacturing intermediates

For submissions reporting a change to the DMF that had established a relationship to the ANDA before GDUFA – PAS that reports a manufacturing process change for the API – Amendment that reports a new API manufacturing site

Issuing an updated Letter of Authorization that does not establish a new relationship to the ANDA submission – Change in DMF ownership prompts LoAs updated with new

letterhead

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Fee Payment and the Filing of ANDAs

Under GDUFA the goal of the DMF holder is to get the DMF to “Available for Reference” status

Only ANDA submissions which reference DMFs for APIs that are

“Available for Reference” can be accepted and filed by FDA Under GDUFA, an “Available for Reference” DMF must meet two

requirements: – The DMF fee must be paid – The DMF must pass the Completeness Assessment

Payment of the DMF fee is the trigger that automatically places the DMF in queue for the Completeness Assessment

The consequences to the referencing ANDA for failure to pay the fee

and failure to pass the Completeness Assessment are different

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Consequences for the ANDA when the DMF is not “available for reference” How fee Payment impacts filing:

– Fee payment status check is performed by OM within several days of the ANDA being submitted to FDA

– ANDA sponsor will receive a notification from OM (Office of Management) that the DMF fee is due and given 20 calendar days to pay.

– After 20 days the ANDA submission will be Refuse to Receive and the entire ANDA application fee will be forfeited.

– If all fees are paid (including the DMF fee) the ANDA is placed in queue at OGD for the comprehensive filing review and the DMF is automatically placed in queue for the Completeness Assessment

How the Completeness Assessment impacts filing:

– When the OGD filing review decision is ready to be made the DMF must be Available for Reference (i.e. passed the CA)

– OGD filing review process can last several months based on priority and workloads

– The CA review process can also last several months based on several factors

– If not, the ANDA is Refuse to Receive by OGD and a 75% refund of the ANDA submission fee can be granted.

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DMF Fee Payment Process

– Fee collection is processed in FDA for GDUFA by OFM (Office of Financial Management) and OM (Office of Management)

– Two cases: • Paying DMF fees for DMFs which are not yet filed with FDA • Paying DMF fees for DMFs which are already filed with FDA

– Amount of the fee for GDUFA year 2 (Oct 1, 2013 to Sep 30, 2014) is $31,460.

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Case 1: Pay the DMF fee for a DMF that has not yet been filed (file and pay)

2

DMF Holder requests a pre-assigned DMF

number from FDA*

1

FDA assigns a DMF# and communicates it to the holder

*For information on how to request a pre-assigned DMF#, see the DMF website at: www.fda.gov/Drugs/.../DrugMasterFilesDMFs/default.htm

Case 2: Pay the DMF fee for a DMF that has already been filed (pay only): Skip this step since you already have a DMF#.

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1. DMF Holder logs into iStore and provides requested information (DMF# required)

2. System generates the appropriate user fee cover sheet with the required fee. 3. DMF Holder pays the required fee using the cover sheet (Note that partial

payment is not acceptable).

DMF Holder Logs into OFM User Fee

System (i-Store)

User Fee Coversheet

Generate User Fee Coversheet

1 2 3

OFM User Fee System

Complete Payment

With Assigned DMF Number, DMF Holder Pays User Fee Through OFM User Fee System (i-Store)

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With DMF User Fee Paid, DMF Holder Submits the DMF Document

DMF Document

DMF User Fee Coversheet

(Form 3794)

Holder submits DMF to FDA’s Central Document Room

1

Submits DMF

2

Document Room Receives DMF

FDA Central Document Room

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Submitting Documentation

Note the following for Case 1 (pay then file):

• DMF User Fee Coversheet (Form 3794) must be included in the submission.

• File in Section “1.1 Forms” in FDA Regional Information

Note the following for Case 2 (pay only): • Submit DMF User Fee Coversheet (Form 3794) separately to

the DMF as a stand-alone amendment (not within an annual update or other amendment)

• Clearly indicate on the cover letter that the submission is the User Fee Cover Sheet.

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Case 1: FDA Performs Administrative Review of DMF Application (Not to be confused with the completeness assessment)

1 DMF

Application

FDA performs Administrative Review of submitted DMF

If DMF is administratively complete, FDA sends the Filing Acknowledgement to

holder and DMF is Active

DMF Status: Active

2a

If DMF is not administratively complete, FDA sends a letter to firm identifying issues. DMF is not Active until issues

are resolved.

2b

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CDER/OM (Office of Management) confirms User Fee payment and sets the status for the DMF

OM sees that DMF has paid DMF fees

1

DMF record indicates the Fee has been paid

Fee Status: MET

2

Set User Fee status

Once the user fee status is “Met” OGD can perform the completeness assessment.

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