usfda generic drug user fee act a complete review

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

INTRODUCTION

INTRODUCTION

ISSN:2249-5347IJSID

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 MalluPlace:Sri Krishnadevaraya UniversityAnantapur, AP, India.E-mail:[email protected]

ABSTRACT

USFDA has implemented several types user fee acts for human and animalmedicines, bio-Similar, colors, exports, tobacco and medical devices. After severaldiscussion and negotiations with Generic Pharmaceutical Association (GPhA), USFDA hasrecently implemented Generic Drug User Fee Act (GDUFA) for Generic Drugs. GDUFA keygoals are Safety, Efficacy and Access. From the GDUFA implementation, USFDA will get thefunds 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 inUSFDA team, speed up the facility inspections and approval process of all types ofapplications including the prioritization of the paragraph-IV.Keywords: USFDA, Generic Drug User Fee Act (GDUFA) amendments 2012, Drug MasterFile (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 bythe 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 inthe industry. The collected fees are used to provide the safety and effective medicines to the patients. FDA has user fees forhuman and animal drugs, medical and mammography devices, color additives, exports and tobacco products. The Division ofUser Fees (DUF) is responsible for the overall management of the program, Office of Financial Management (OFM). The OFMhas collecting the user fee from manufacturer.USFDA has implemented about thirteen user fee acts for protecting health and providing safety, efficacy medicines forhumans 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 Fees9. 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 FeesGENERIC DRUG USER FEE ACT (GDUFA)Pharmaceutical industry has grown rapidly by submitting the number of DMFs and ANDAs. FDA has the more backlogof Type-II DMF, ANDA applications and inspections (domestic and foreign). In the year 2010, FDA has initiated the discussionswith Generic Pharmaceutical Association (GPhA) and finally the USFDA has implemented the user fee for generic drugsthrough 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 fundingappropriated by Congress. User fee for generic drugs provides the funding to achieve the same surveillance inspectionfrequency for both domestic and foreign manufacturers to insure that all industry participants in the U.S. generic drug systemare held to consistent good manufacturing practice (GMP) standards. The three strong scopes of GDUFA are:

Figure-6: GDUFA Key GoalsSafety: Ensure that industry participants, foreign or domestic, who participate in the U.S. generic drug system are heldto consistent high quality standards and are inspected biennially, using a risk-based approach, with foreign and domesticparity.Access: Expedite the availability of low cost, high quality generic drugs by bringing greater predictability to the reviewtimes for ANDAs, amendments and supplements.



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Transparency: Enhance FDA’s ability to protect Americans in the complex global supply environment by requiring theidentification of facilities involved in the manufacture of generic drugs, active pharmaceutical ingredients, and improvingFDA’s 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 basemanagement, immediate response letters to the applicant and special focus on paragraph-IV submissions. The main goals ofGDUFA 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 OGD’s 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 30minute 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 Feeprogram is designed to keep individual fee amounts as low as possible to supplement appropriated funding to ensure thatconsumers continue to receive the significant benefits offered by generic drugs which provided more than $824 billion dollarsin savings to the nation’s 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 FDAagency for Type-II DMF and ANDA submission and facilities. The detailed fee applicability and fee structure has represented inthe table-1; Figure-7.



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Figure-7: GDUFA user fee

Figure-8: GDUFA user fee applicability and fee types



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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 programimplementation] 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 ofoverseas inspection.Source of Fees:Fees will be derived from both applications and facilities in a 30%-70% split. Fees will be split between finisheddosage 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 topay 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) filingfee

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 $ 299Backlog Fee ------ $ 50ANDA/PAS 24% $ 59.8DMF 6% $ 14.9API Facility 14% $ 34.9FDF Facility 56% $ 139.4Total Value 100% $ 299

Table-2: User fee details as per the GDUF ActBacklog Fee

Requirement Paymentfrequency

1st year statutorily directed revenue targetand method of calculating individual fee

Effective datePending 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-31st 2012Details: Any original ANDA that has not been withdrawn, tentatively approved, or approved by September 28, 2012, isconsidered 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 FeeRequirement Payment frequency 1st year statutorily directed

revenue target and methodof calculating individual fee

EffectivedateA type II API-DMF holder whose DMFis referenced by an initial letter ofauthorization in a generic drugsubmission on or after Oct-1st 2012

Once for each API-DMF, no laterthan when first letter ofauthorization is submitted. ~$15 million divided bycurrent estimates of annual No.of DMF application Oct-31st2012Details: Only type-II API DMFs need to pay the GDU fee and effective date is Oct-1st 2012 GDUFA does not make a distinction between DMFs submitted before or after October 1, 2012. Holders of DMFsreviewed 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 forDMF 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 FeesRequirement Payment

frequency1st year statutorily directed revenue target and

method of calculating individual feeEffective

dateANDA and PAS Fee: An applicantsubmitting an ANDA or PAS on orafter Oct-1st 2012 Once, at timeof submissionof ANDA orPAS~$60 million divided by a weighted average ofcurrent estimates of annual ANDA and PASapplications. Oct-31st2012Fee 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-31st2012

Details: Each applicant that submits, on or after October 1, 2012, an abbreviated new drug application (ANDA) or a priorapproval 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 tochange 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 perapplication. 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 eachAPI, the applicant must pay the API-related fee for each such facility.

Facility FeeRequirement Payment frequency 1st year statutorily

directed revenuetarget and method

of calculatingindividual fee

Effective date

ActivePharmaceuticalIngredient(API)The owner of a facility identified orintended to be identified, in atleast on generic drug submissionthat is pending or approved toproduce one or more generic drugfinished dosage form (FDF) and orAPIs

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 itsterritories and possessions will pay a higherfee reflecting the increased costs ofinspection.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 forexpectations 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 feepayment. 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 account2. Submit a Generic Drug User Fee Cover Sheet electronically3. Submit a payment for the Generic Drug User Fee Cover SheetAll generic drug organization can initiate the fee payment process from Oct-1 2012 and for user fee payment applicantneed to create the GDUFA cover sheet. This cover sheet will calculate the fee value for all type of user fees. User fee should bepaid 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 depositor Credit card payment (Pay.gov) or send payment by check, bank draft, U.S. postal money order, or wire transfer. Paymentmust be made in U.S currency drawn on a U.S. bank by electronic payments. Generally, USFDA will not invoice for fee’s andexpects that firms will self-identify and pay. However, in rare and unusual circumstances, USFDA may find it necessary to issuean invoice. Positron Emission Tomography (PET) drug manufacturers are the only human generic drug manufacturersexcluded from payment of GDUFA fees. They are, however, required to self-identify. PET manufacturers should complete ageneric 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 tobenefit significantly from reductions in the review time needed to commercialize their products and from the certaintyassociated 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.jspReview of Generic drug submissions post GDUFAUSFDA will expedite review of paragraph IV ANDA application that is submitted on the first day that any valid Paragraph IVapplication for the drug in question is submitted. This added to current expedite process like President’s Emergency Plan forAIDS Relief (PEPFAR), product for which a nationwide shortage has been identified, etc.GDUFA adds a new requirement to USFDA’s existing refuse to receive policy with respect to payment of fees and the time ofreceipt 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 providesnotification 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 providesnotification 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 feewithin 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 theirimplementation.USFDA continue to accept applications in paper format for the time being. Applications received in paper format after October1, 2012, however, will not be included as part of the new performance metrics established in GDUFA. Additionally, electronicsubmissions will be required 24 months after issuance of final electronic submission guidance.

Process for requesting a teleconference to clarify deficiencies and answer questions following FDA’s issuance of a

complete response Level: An applicant may request a 30-minute teleconference within ten business days after FDA issues afirst-cycle review complete response letter to discuss the deficiencies noted in the letter. The request for a teleconferencemust be submitted in writing to the ANDA file and appropriately identified on its cover page as a “Post Complete ResponseTeleconference Meeting Request.” The request should include a list of specific written questions for discussion. The scope of



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the questions should be limited to the content of FDA’s complete response letter. Priority for such teleconferences will begiven to expedited and first major amendment applications and other applicationsGDUFA Limitations:After October 1, 2012, any ANDA/PAS not considered to have been received for scientific reasons is refunded 75% ofthe 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 byOFM.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, FDA’s 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) 796-7200Email: [email protected]: 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: FDA1350 Piccard Drive, Suite 200A, Rockville, MD20850.



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Figure-11: GDUFA user fee Details and Time linesCONCLUSIONGUDFA implementation will provide additional funds to USFDA. These additional funds will help the USFDA toincrease the facility inspections, speed up the review process and increasing the data base management. In turn to GDUFAimplementation, USFDA like to provide the significant benefit to industries from reductions in the review time needed tocommercialize their products and from the certainty associated with performance review metrics and program efficiencies.Further, USFDA provided metric goal/measurement for Original ANDA review as60% 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 2014For Backlog metrics, the review and act on 90% of backlog applications pending on Oct 1, 2012 by end of FY 2017.

DISCLAIMERThe authors do not claim anything; the purpose of this review is solely educational. This article is built on theinformation provided by the public USFDA CDER domain website



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REFERENCES1. CDER’s 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.pdf8. http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM296451.pdf9. http://www.drugstorenews.com/article/generic-drug-user-fee-act-passes-senate10. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm316790.htm11. http://www.gpo.gov/fdsys/pkg/FR-2012-07-26/html/2012-18232.htm12. http://pharma.about.com/od/FDA/a/2012-Renewal-Of-The-Prescription-Drug-User-Fee-Act-Pdufa.htm13. http://www.rediff.com/money/report/us-to-charge-fee-on-generic-drug-sale-application/20120621.htm14. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm316790.htm15. https://userfees.fda.gov/OA_HTML/gdufaFAQ.html16. http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf17. http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061432.html

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

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64.htm

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

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

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usfda generic drug user fee act a complete review

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