usfda-generic drug user fee act_a complete review

7/29/2019 Usfda-generic Drug User Fee Act_a Complete Review

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Useni Reddy Mallu et al., IJSID, 2012, 2 (5), 117-131

International Journal of Science Innovations and Discoveries, Volume 2, Issue 5, September-October 2012

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USFDA-GENERIC DRUG USER FEE ACT: A COMPLETE REVIEW

Useni Reddy Mallu* and Anand K

Dept. of Chemistry, Sri Krishnadevaraya University, Anantapur, AP, India

INTRODUCTION

INTRODUCTION

ISSN:2249-5347

IJSID

International Journal of Science Innovations and Discoveries An International peerReview Journal for Science

Research Article Available online through www.ijsidonline.info

Received: 19-08-2012

Accepted: 18-10-2012

*Corresponding Author

Address:Name:

Dr. Useni Reddy Mallu

Place:

Sri Krishnadevaraya University

Anantapur, AP, India.

E-mail:

[email protected]

ABSTRACT

USFDA has implemented several types user fee acts for human and animal

medicines, bio-Similar, colors, exports, tobacco and medical devices. After several

discussion and negotiations with Generic Pharmaceutical Association (GPhA), USFDA has

recently implemented Generic Drug User Fee Act (GDUFA) for Generic Drugs. GDUFA key

goals are Safety, Efficacy and Access. From the GDUFA implementation, USFDA will get the

funds approx. $1.5billion over the 2013 to 2017 financial years from the generic players.

The main intention to implement the user fee is to increase the number of reviewers in

USFDA team, speed up the facility inspections and approval process of all types of

applications including the prioritization of the paragraph-IV.

Keywords: USFDA, Generic Drug User Fee Act (GDUFA) amendments 2012, Drug Master

File (DMF), ANDA, and GDUFA cover sheet.


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INTRODUCTION

Scope: This article is intended to provide basic information and general pathway required to adopt during filling of ANDA by

the generic industries.

Purpose: The purpose of this article is

Educate readers on basics of the GUDFA

Enable readers to understand the difference between traditional ANDA and GUDFA adopted ANDA filling.

Summarize a wide documents related to GUDFA published by public USFDA cder domain website.

Background:

FDA has User Fee programs (UFP) to fulfill its mission of protecting the public health and accelerating innovation in

the industry. The collected fees are used to provide the safety and effective medicines to the patients. FDA has user fees for

human and animal drugs, medical and mammography devices, color additives, exports and tobacco products. The Division o

User Fees (DUF) is responsible for the overall management of the program, Office of Financial Management (OFM). The OFM

has collecting the user fee from manufacturer.

USFDA has implemented about thirteen user fee acts for protecting health and providing safety, efficacy medicines for

humans and animals. The lists of user fee acts are represented below.

1. Animal Drug User Fee Act (ADUFA)

2. Animal Generic Drug User Fee Act (AGDUFA)

3. Bio similar User Fee Act (BsUFA)

4. Color Certification (CERTS)

5. Exports Certificate (Exports)

6. Family Smoking Prevention and Tobacco Control Act (Tobacco)

7. Food Safety Modernization Act (FSMA)

8. Freedom of Information Act Fees

9. Generic Drug User Fee Act (GDUFA)

10. Mammography Quality Standards Act (MQSA)

11. Medical Device User Fee and Modernization Act (MDUFMA)

12. Prescription Drug User Fee Act (PDUFA)

13. Tobacco Product Fees

GENERIC DRUG USER FEE ACT (GDUFA)

Pharmaceutical industry has grown rapidly by submitting the number of DMFs and ANDAs. FDA has the more backlog

of Type-II DMF, ANDA applications and inspections (domestic and foreign). In the year 2010, FDA has initiated the discussions

with Generic Pharmaceutical Association (GPhA) and finally the USFDA has implemented the user fee for generic drugs

through GDUFA amendments 2012. Figure-1 to 5 represents increasing the Type-II DMFs and ANDAs application submissions

backlog details and inspections in the last 10 years (The below figures are copied from the public FDA websites).


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Figure-1: Continued growth in the ANDA submissions in the last ten years.

Figure-2: Type-II DMF submissions for USFDA approval in the last ten years.


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Figure-3: Pending ANDAs at USFDA in the last six years.

Figure-4: FDF inspections in the last ten years.

Origin of GDUFA:

2010: Initiation of USFDA discussions.

2011: FDA has conducted the meetings with GPhA for negotiations and Implementing, drafting the GDUFA.

2012: On July 9, 2012, GDUFA was signed into law by the President. GDUFA draft Guidelines released on Sep-2012.


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Figure-5: API facilities inspections by USFDA in the last ten years.

Why GDUFA is required?

The purpose of GDUFA is to provide additional funds to USFDA to supplement the traditional annual funding

appropriated by Congress. User fee for generic drugs provides the funding to achieve the same surveillance inspection

frequency for both domestic and foreign manufacturers to insure that all industry participants in the U.S. generic drug system

are held to consistent good manufacturing practice (GMP) standards. The three strong scopes of GDUFA are:

Figure-6: GDUFA Key Goals

Safety: Ensure that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held

to consistent high quality standards and are inspected biennially, using a risk-based approach, with foreign and domestic

parity.

Access: Expedite the availability of low cost, high quality generic drugs by bringing greater predictability to the review

times for ANDAs, amendments and supplements.


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Transparency: Enhance FDAs ability to protect Americans in the complex global supply environment by requiring the

identification of facilities involved in the manufacture of generic drugs, active pharmaceutical ingredients, and improving

FDAs communications and feedback with industry in order to expedite product access.

GDUFA Goals:

USFDA have a proposal for increasing the facility inspections, speed up the review process, increasing the data base

management, immediate response letters to the applicant and special focus on paragraph-IV submissions. The main goals of

GDUFA are,

Backlog API DMF and ANDAs review

Speed up the review process for all submissions

Increase the facility inspections (Domestic and Foreign)

Increase the Regulatory Research

Prioritization of Paragraph-IV submission

Maintenance of DMFs in the OGDs external website

Letter to DMF-holder when all deficiencies have been addressed

When requested by a DMF holder within 10 days of receiving a first-cycle deficiency letter, the agency will grant a 30

minute teleconference to the DMF holder.

Perform relevant research on BE of locally acting products, effects of excipients on permeability and absorption, post-

marketing surveillance and physicochemical characterization of complex drug substances

GDUFA FEE:

Generic drugs play in providing more affordable, therapeutically equivalent medicine, the Generic Drug User Fee

program is designed to keep individual fee amounts as low as possible to supplement appropriated funding to ensure that

consumers continue to receive the significant benefits offered by generic drugs which provided more than $824 billion dollars

in savings to the nations health care system in the last decade alone.

FDA has tentatively finalized the user fee for generics. Under GDUFA the generic player need to pay the fee to the FDA

agency for Type-II DMF and ANDA submission and facilities. The detailed fee applicability and fee structure has represented in

the table-1; Figure-7.


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Application Fees:

Backlog fees:

Backlog fees are in year 1 [(Year 1 Oct 1, 2012 to Sept 30, 2013) for ANDAs pending review at the date of program

implementation] and ANDA and Post-Approval Study (PAS) fees, as well as DMF first reference fees in all years.

Facility Fees:

Both finished dosage form manufacturer and API facilities with a modest fee differential reflecting the added costs of

overseas inspection.

Source of Fees:

Fees will be derived from both applications and facilities in a 30%-70% split. Fees will be split between finished

dosage form manufacturers and active pharmaceutical ingredient manufacturers in an 80%-20% split.

GDUFA Fee agreement:

As per the GDUFA agreement all API, Finished Dosage Forms (FDF) facilities and applicants of DMF, ANDA are need to

pay the user fee. Details of GDUFA fee agreement are,

Funding level = inflation adjusted $299M/year

Fees for Applications and Facilities

Applicants Facilities

Applications in the backlog (year 1 only) Drug master file fee ANDA and prior approval supplement (PAS) filing

fee

Involved in manufacture of generic drugs,whether Active Pharmaceutical Ingredient (API)or Finished Dosage Form (FDF), domestic orforeign.

Exemption from fees: Positron Emission Tomography (PET) drugs

Individual fees calculated/published upon implementation and Order of magnitude lower than PDUFA fees

Critical splits:

80% from finished dosage form manufacturers, 20% from API manufacturers

70% from facility fees, 30% from application fees

In year 1, $50M from backlog fee, so above splits are slightly different

Figure-9: GDUFA user fee partition


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Total revenue for 2013 is as follows,

Table-1: USFDA total revenue for FY 2013

Fee type % as per the GDUFA After partition from $ 299

Backlog Fee ------ $ 50

ANDA/PAS 24% $ 59.8

DMF 6% $ 14.9

API Facility 14% $ 34.9FDF Facility 56% $ 139.4

Total Value 100% $ 299

Table-2: User fee details as per the GDUF Act

Backlog Fee

Requirement Payment frequency

1styear statutorily directed revenue targetand method of calculating individual fee

Effective date

Pending ANDA applications as on Oct-1, 2012 without a tentative approval

Once $50 million divided by the total No. of OriginalANDAs pending on Oct-1, 2012

Oct-31st2012

Details: Any original ANDA that has not been withdrawn, tentatively approved, or approved by September 28, 2012, is

considered pending and is subject to a backlog fee.

The backlog fee will be determined based on the number of original ANDAs pending at the start of the business day onOctober 1, 2012. In accordance with GDUFA, FDA will divide $50 million by the number of original ANDAs pending toarrive at the amount of the individual one-time backlog fee, which will be due for each pending original ANDA.

Absent withdrawals, there could be 3,000 pending original ANDAs on October 1, 2012. A number of these applicationsare old and incomplete and may be withdrawn by applicants prior to October 1, 2012 to avoid incurring the backlogfee.

The ANDA applicant should notify the Office of Generic Drugs (OGD) in writing with the request to withdraw theapplication. To avoid the backlog fee, written notification must be received by September 28, 2012.

One-time calculation for FY13 and remains in effect for FY14-17.Fee = $50 Million / number of ANDAs in backlog population(Example: If backlog population = 2000 ANDAs, then fee is $25,000 for each ANDA).

DMF Fee

Requirement Payment frequency 1styear statutorily directed

revenue target and methodof calculating individual fee

Effective

date

A type II API-DMF holder whose DMFis referenced by an initial letter of

authorization in a generic drugsubmission on or after Oct-1st2012

Once for each API-DMF, no laterthan when first letter of

authorization is submitted.

~$15 million divided bycurrent estimates of annual No.

of DMF application

Oct-31st

2012

Details: Only type-II API DMFs need to pay the GDU fee and effective date is Oct-1 st2012 GDUFA does not make a distinction between DMFs submitted before or after October 1, 2012. Holders of DMFs

reviewed prior to GDUFA implementation must pay the one-time DMF fee if their DMF is referenced in a new genericdrug submission on or after October 1, 2012

A one-time application fee for a Type II Drug Master File (DMF) that is to be referenced on or after October 1, 2012 in ageneric drug submission (new ANDA, supplement or amendment).

A Type II DMF covers the manufacture of an active pharmaceutical ingredient (API) or drug substance. DMF fee can be paid by DMF holder before a letter of authorization requested by the ANDA holder. The advantage for

DMF holders are the Fee paid DMF will undergo an initial completeness assessment by USFDA using the factors(factors will be published in forthcoming USFDA guidance) and if DMF passes the completeness assessment it will beplaced on a publicly available list of DMF available for reference

FY13 Fee = 6% of $249 Million / number of estimated Type II DMFs referenced for the first time in FY13. (Example: IfType II DMFs = 350, then DMF fee is $42,686.)

DMF fee is incurred when a generic drug submission references the Type II DMF for the first time on or after October1, 2012.

The FY13 fee due date is dependent on the later of the following:


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Date of first generic drug submission that references Type II DMF 30 calendar days after fee amount is published in the Federal Register 30 calendar days after enactment of appropriations act

Generic Drug Submission Fees

Requirement Payment frequency

1styear statutorily directed revenue target andmethod of calculating individual fee

Effectivedate

ANDA and PAS Fee: An applicant

submitting an ANDA or PAS on orafter Oct-1st2012

Once, at time

of submissionof ANDA orPAS

~$60 million divided by a weighted average of

current estimates of annual ANDA and PASapplications.

Oct-31st

2012

Fee for API not referenced to as (a)(3) (F) fee ^

(a)(3) (F) ^Fee is expected to generate a smallportion of the total above.

Oct-31st

2012

Details: Each applicant that submits, on or after October 1, 2012, an abbreviated new drug application (ANDA) or a prior

approval supplement (PAS) shall be subject to a fee. User fees are required for all PASs (including labeling) that require prior approval under FDA regulations. Changes-Being-Effected (CBE-0 and CBE-30) supplements are not required to pay a user fee. FDA reserves the right to

change any CBE to a PAS. If changed, the applicant will be notified to resubmit its application as a PAS and to pay thePAS user fee.

For FY13, 24% of $249 million will be collected for ANDA/PAS fees. This amounts to $59.76 million. ANDA applications may cost about $56,000 per application. PAS applications will be half that amount at $28,000 per

application. The FY13 fee due date is dependent on the later of the following:

Date of ANDA / PAS submission 30 calendar days after fee amount is published in the Federal Register 30 calendar days after enactment of appropriations act

^ The information related (a)(3)(F) fee is as follows,If a generic (ANDA, amendment to an ANDA or a PAS to an ANDA) drug submission includes API information otherthan by reference to a DMF e.g., the applicant manufactures an API in its own facility or facilities is the applicantrequired to pay an additional fee?Yes. The applicant is required to pay an API-related fee for each API manufactured in its own facility or facilities forwhich it has not previously paid an API-related fee. As with a DMF fee, this fee is paid only once.The amount of the API-related fee is a function of the number of APIs referenced in the application and the number offacilities in which those APIs are manufactured. If the ANDA references more than one facility as manufacturing each

API, the applicant must pay the API-related fee for each such facility.Facility Fee

Requirement Payment frequency 1styear statutorilydirected revenue

target and methodof calculatingindividual fee

Effective date

ActivePharmaceutical

Ingredient(API)

The owner of a facility identified orintended to be identified, in at

least on generic drug submissionthat is pending or approved to

produce one or more generic drugfinished dosage form (FDF) and or

APIs

Annually ~$174 million totalAPI: ~$35 million dividedby number of API facilities.

FDF: ~$139 million divided by number ofFDF facilities.

Facilities located outside of the US and its

territories and possessions will pay a higherfee reflecting the increased costs of

inspection.

FinishedDosage Forms

(FDF)

Details: Facilities that manufacture or intend to manufacture generic drugs active pharmaceutical ingredients(API),

finished dose formulas(FDF), or both Sites and organizations that pack human generic drugs Sites where bioanalytical studies are conducted Sites where clinical research is conducted Sites where contract analytical testing is conducted


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Facilities that produce positron emission tomography(PET) drugs or API of such drugs For FY13, the target revenue will be divided by the number self-identified API and FDF facilities, adjusted for

expectations about how many of each will be located outside the US. The statute calls for a differential to be appliedto foreign facilities, and dictates that the difference be at least $15,000 and not more than $30,000 above theanalogous amount for a US facility.

The FY13 fee due date is dependent on the later of the following: 45 calendar days after fee amount is published in the Federal Register 30 calendar days after enactment of appropriations act

The facility will be placed on a publicly-available arrears list if the facility fee is not paid in full within 20 days of thedue date.

No new abbreviated new drug application (ANDA) referencing such facility will be received. All APIs and FDFs manufactured in such facilities will be deemed misbranded.

GDUFA FEE PAYMENT PROCESS:

FDA has released the user fee process details for generics and it includes the cover sheet and user registration for fee

payment. The high level process for submitting a Generic Drug User Fee Cover Sheet is:

1. Register in the User Fee System by creating a secure user account

2. Submit a Generic Drug User Fee Cover Sheet electronically

3. Submit a payment for the Generic Drug User Fee Cover Sheet

All generic drug organization can initiate the fee payment process from Oct-1 2012 and for user fee payment applicant

need to create the GDUFA cover sheet. This cover sheet will calculate the fee value for all type of user fees. User fee should be

paid after completing the generation of GDUFA cover sheet.

Figure-10: GDUFA user fee payment process steps


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GDUFA cover sheet creation:

GDFUA fees apply only to generic drug manufactured for human use.

Payment submission: Generic applicant can pay the user fee by using Automated Clearing House (ACH) direct deposit

or Credit card payment (Pay.gov) or send payment by check, bank draft, U.S. postal money order, or wire transfer. Payment

must be made in U.S currency drawn on a U.S. bank by electronic payments. Generally, USFDA will not invoice for fees and

expects that firms will self-identify and pay. However, in rare and unusual circumstances, USFDA may find it necessary to issue

an invoice. Positron Emission Tomography (PET) drug manufacturers are the only human generic drug manufacturers

excluded from payment of GDUFA fees. They are, however, required to self-identify. PET manufacturers should complete a

generic drug user fee cover sheet for $0.

No reduced fees available for small business or others. As USFDA determines that small generic companies are expected to

benefit significantly from reductions in the review time needed to commercialize their products and from the certainty

associated with performance review metrics and program efficiencies.

Please visit the for GDUFA user fee payment for all type of payments.

https://userfees.fda.gov/OA_HTML/gdufaCAcdLogin.jsp

Review of Generic drug submissions post GDUFA

USFDA will expedite review of paragraph IV ANDA application that is submitted on the first day that any valid Paragraph IV

application for the drug in question is submitted. This added to current expedite process like Presidents Emergency Plan for

AIDS Relief (PEPFAR), product for which a nationwide shortage has been identified, etc.

GDUFA adds a new requirement to USFDAs existing refuse to receive policy with respect to payment of fees and the time o

receipt of an ANDA.

Failure to pay an ANDA fee within 20 calendar days of the applicable due date will result in the ANDA not being received.

Failure to pay the fee for a DMF referenced in the ANDA within 20 calendar days of the date that FDA provides

notification of that failure will result in the ANDA not being received.

Failure to pay a facility fee for any facility referenced in the ANDA within 20 calendar days of the date that FDA provides

notification of that failure will result in the ANDA not being received.

If an application is substantially complete except for failure to pay the ANDA fee, or the failure to pay the facility fee

within 20 days of notification, the application will be deemed received as of the date the fee is paid.

FDA will publish further guidance on any other changes to its refuse to receive policy for public comment in advance of their

implementation.

USFDA continue to accept applications in paper format for the time being. Applications received in paper format after October

1, 2012, however, will not be included as part of the new performance metrics established in GDUFA. Additionally, electronic

submissions will be required 24 months after issuance of final electronic submission guidance.

Process for requesting a teleconference to clarify deficiencies and answer questions following FDAs issuance of a

complete response Level: An applicant may request a 30-minute teleconference within ten business days after FDA issues a

first-cycle review complete response letter to discuss the deficiencies noted in the letter. The request for a teleconference

must be submitted in writing to the ANDA file and appropriately identified on its cover page as a Post Complete Response

Teleconference Meeting Request. The request should include a list of specific written questions for discussion. The scope o


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the questions should be limited to the content of FDAs complete response letter. Priority for such teleconferences will be

given to expedited and first major amendment applications and other applications

GDUFA Limitations:

After October 1, 2012, any ANDA/PAS not considered to have been received for scientific reasons is refunded 75% of

the application fee. Refunds for overpayment and payments in error must be requested in writing within 180 days of payment.

The Office of Financial Management (OFM) processes the refunds. All inquiries regarding refunds should be addressed by

OFM.

Address for Payment (Note: USFDA will not be able to process the payment correctly without Firms GDUFA cover sheet PIN

(Payment Identification Number)).

Check payment by mail: Food and Drug Administration, P.O. Box 979108, St. Louis, MO 63197-9000.

Check payment by delivered by a courier service: U.S. Bank, Attn: Government Lockbox 979108, 1005 Covention Plaza, St.

Louis, MO 63101.

Wire Transfer Payment:

If needed for accounting purposes, FDAs tax identification number is 53-0196965.

Note: a) Wire Transfers to the Department Of The Treasury are distinct from online ACH payments via Pay.gov.

b) If wire transfer done by financial institutions than the fees should include the fees for handling wire transfers.

c) The total fee amount should be paid at least 1 day before the submission arrives at USFDA.

FDA records as the submission receipt date the later of the following :

1) The date the submission was received by USFDA (If fees paid earlier to this date).

2) The date USFDA is notified that payment has been received (If ANDA submitted earlier to this date).

User Fee Helpdesk:

Phone: (301) 796-7200

Email: [email protected]

Mail: Food and Drug Administration, User Fees Financial Support Team, 1350 Piccard Drive, Suite 200A, Rockville, MD20850.

New York Federal Reserve Bank, US Department of Treasury,TREAS NYC, 33 Liberty Street, New York, NY10045

FDA Deposit Account Number: 75060099

US Department of Treasury Routing/Transit number: 021030004

SWIFT Number: FRNYUS33

Beneficiary: FDA


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Figure-11: GDUFA user fee Details and Time lines

CONCLUSION

GUDFA implementation will provide additional funds to USFDA. These additional funds will help the USFDA to

increase the facility inspections, speed up the review process and increasing the data base management. In turn to GDUFA

implementation, USFDA like to provide the significant benefit to industries from reductions in the review time needed to

commercialize their products and from the certainty associated with performance review metrics and program efficiencies.

Further, USFDA provided metric goal/measurement for Original ANDA review as

60% of submission within 15 months for FY 2015

75% of submission within 15 months for FY 2016 90% of submission within 10 months for FY 2017 Expedite paragraph IV (Day 1 submissions) submission FY 2013 and FY 2014

For Backlog metrics, the review and act on 90% of backlog applications pending on Oct 1, 2012 by end of FY 2017.

DISCLAIMER

The authors do not claim anything; the purpose of this review is solely educational. This article is built on the

information provided by the public USFDA CDER domain website


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REFERENCES

1. CDERs MAPP 6050.1, Refusal to Accept Application for Filing From Applicants in Arrears .

2. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119184.htm.

3. Fees-Exceed-the-Costs Waivers Under the Prescription Drug User Fee Act, and its addendum at the guidance Web page.

4. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

5. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/default.htm.

6. FDA guidelines: Self-Identification of Generic Drug Facilities, Sites, and Organizations.

7. http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf


9. http://www.drugstorenews.com/article/generic-drug-user-fee-act-passes-senate

10. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm316790.htm

11. http://www.gpo.gov/fdsys/pkg/FR-2012-07-26/html/2012-18232.htm

12. http://pharma.about.com/od/FDA/a/2012-Renewal-Of-The-Prescription-Drug-User-Fee-Act-Pdufa.htm

13. http://www.rediff.com/money/report/us-to-charge-fee-on-generic-drug-sale-application/20120621.htm

14. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm316790.htm

15. https://userfees.fda.gov/OA_HTML/gdufaFAQ.html


17. http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061432.html

18. https://smallbusiness.dnb.com/establish-your-business/12334338-1.html

19. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/ucm0731

64.htm

20. http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061432.htm

21. https://smallbusiness.dnb.com/establish-your-business/12334338-1.html

22. http://www.fda.gov/edrls

23. http://www.fda.gov/RegulatoryInformation/FOI/PrivacyAct/

24. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM322676.pdf

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