Imperial Journal of Interdisciplinary Research (IJIR) Vol-3, Issue-2, 2017 ISSN: 2454-1362, http://www.onlinejournal.in
GDUFA – A Backbone of Generic’s K.Santhosh Kumar & T.M.Pramod Kumar*, Pharmaceutical Regulatory Affairs Group, Dept. of Pharmaceutics., JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysuru, Karnataka, India. Abstract: The human generic pharmaceutical drug industry has saved the American health care system over $1.6 trillion over the 10-year period.FDA helps ensure that human generic drug products are thoroughly tested and shown to meet the statutory standards for approval, in most cases by proof that they contain the same active ingredients, are identical in strength and dosage-form, deliver the same amount of active ingredients to the site of action, and maintain the same strict standards of good manufacturing practice regulations as their brand name counterparts. GDUFA was based on PDUFA( For NDA) On July 9, 2012, the President signed the Food and Drug Administration Safety and Innovation Act (FDASIA) into law, which included the authorization of the Generic Drug User Fee Amendments (GDUFA) for 5 years (FY 2013 through FY 2017) and will need to be reauthorized to continue past FY 2017. GDUFA authorizes FDA to collect user fees for human generic drug activities and enables FDA to advance a safer, more efficient, and more affordable human generic drug review program. Furthermore, GDUFA enhances FDA’s ability to protect Americans in the complex global supply environment by requiring the self-identification of facilities involved in the manufacture of generic drugs and associated active pharmaceutical ingredients (API) and by ensuring that foreign and domestic industry participants in the U.S. generic drug system are held to consistent, high-quality standards and are inspected with comparable rigor and frequency, using a risk-based approach. Key words: GDUFA, Designed, Authorizes, Rigor, Pharmaceutical Introduction:Since 1984, the Food and Drug Administration (FDA) has approved over 8,000 generic drugs, which comprise approximately seventy-eight percent of currently filled prescriptions. The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) has governed the approval of generic drugs.The Act provides an expedited approval process for generic drugs that have an identical Reference Listed Drug (RLD).
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Provided a generic drug is the “same” as its listed drug counterpart, its manufacturer is permitted to forgo clinical testing, on the condition that the drug maintains the same label as the listed drug.The generic drug manufacturers have no authority to modify or update their own safety labels.The inability to independently update labels has led to issues concerning generic drug manufacturers’ liability for failure to warn of safety concerns, which have been recently addressed by the U.S. Supreme Court. Congress has begun to address these concerns with the enactment of the Generic Drug User Fee Amendments of 2012 (“GDUFA”). The GDUFA recognizes the growth of the generic drug industry by expediting the approval process for generics, saving time and money for the industry, and ensuring Americans have access to low cost, quality medicine. In exchange for faster approval times, the generic industry must pay user fees, as the branded pharmaceuticals do.The GDUFA is the beginning of major reform for the generic drug industry, placing some of the same obligations and benefits on the generic industry that the brand name manufacturers have.1 The growth of the generic industry and the issues presented in recent Supreme Court cases have prompted the FDA to reconsider current federal mandate and to suggest generic drug manufacturers be permitted to update their safety labels in response to safety issues that have been discovered.The proposed regulation would require generic-drug makers to update their labels in light of newly acquired safety information to avoid injury to consumers, which could result in legal liability.This Note argues that allowing genericdrug makers to update safety labels as soon as new information is received will increase patient safety and prevent injuries by providing timely updates to safety information.This would also allow generic drugs that no longer have a brand-name counterpart to update their labels.2 The Generic Drug User Fee Amendments of 2012 (GDUFA) is designed to speed access to safe and effective generic drugs to the public and reduce costs to industry. The law requires industry to pay user fees to supplement the costs of reviewing generic drug applications and inspecting facilities.
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Imperial Journal of Interdisciplinary Research (IJIR) Vol-3, Issue-2, 2017 ISSN: 2454-1362, http://www.onlinejournal.in Additional resources will enable the Agency to reduce a current backlog of pending applications, cut the average time required to review generic drug applications for safety, and increase riskbased inspections.7 GDUFA is designed to build on the success of the Prescription Drug User Fee Act (PDUFA). Over the past 20 years, PDUFA has ensured a more predictable, consistent, and streamlined premarket program for industry and helped speed access to new, safe and effective prescription drugs for patients. GDUFA will also enhance global supply chain safety by requiring that generic drug facilities and sites around the world self-identify. The passage of GDUFA brought high expectations for the timely review of human generic drug applications, creating parity between domestic and foreign firms, and reducing the backlog of human generic drug approval applications. Pursuant to GDUFA’s design, FDA has restructured the generic drug program. The GDUFA restructuring through FY 2015, was a deep, foundational transformation which has prepared FDA to meet goal dates, starting in FY 2015, agreed upon in the Generic Drug User Fee Act Program Performance Goals and Procedures (GDUFA Commitment Letter). The restructuring of the program included, among other things, the hiring and training of many new employees, reorganizing the Office of Generic Drugs (OGD) into a Center for Drug Evaluation and Research (CDER) “Super Office”, establishing a new Office of Pharmaceutical Quality, replacing fragmented information technology systems with a new integrated system (i.e., CDER Informatics Platform), and substantially enhancing review and business processes. Now that FDA has successfully accomplished this transformation, there are still goals and challenges ahead to continue the modernization of the generic drug program. For example, GDUFA goal dates for FY 2015 Abbreviated New Drug Applications (ANDAs) went into effect on October 1, 2014. As such, an ANDA received on October 1, 2014, received a 15month GDUFA goal date of December 31, 2015; therefore, it is too soon to report on FDA’s final performance on its FY 2015 ANDA review goals. The Agency’s efforts in restructuring the generic drug program in the first few years of GDUFA are already contributing to an increase in productivity (including taking actions on 82 percent of the backlog by the end of FY 2015) and FDA is confident it will meet its GDUFA goals. FY 2015 GDUFA Performance Report 3
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Discussion : To help FDA ensure that participants in the U.S. generic drug system comply with U.S. quality standards, and to increase the likelihood that American consumers get timely access to low cost, high quality generic drugs, FDA and industry have jointly agreed to a comprehensive user fee program, to be supplemental to traditional appropriated funding, that is focused on three key aims: 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 riskbased 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 abbreviated new drug applications, amendments and supplements, increasing predictability and timeliness in the review process. Transparency -Enhance FDA’s ability to protect Americans in the complex global supply environment by requiring the identification of facilities involved in the manufacture of generic drugs and associated active pharmaceutical ingredients, and improving FDA’s communications and feedback with industry in order to expedite product access.5 MAJOR GOALS OF GDUFA :Application metrics – For Abbreviated New Drug Applications (ANDAs) in the year 5 cohort, FDA will review and act on 90 percent of complete electronic ANDAs within 10 months after the date of submission. Certain amended applications may have differing metrics as discussed below. Backlog metrics – FDA will review and act on 90 percent of all ANDAs, ANDA amendments and ANDA prior approval supplements regardless of current review status (whether electronic, paper, or hybrid) pending on October 1, 2012 by the end of FY 2017. CGMP Inspection metrics – FDA will conduct risk-adjusted biennial CGMP surveillance inspections of generic API and generic finished dosage form (FDF) manufacturers, with the goal of achieving parity of inspection frequency between foreign and domestic firms in FY 2017.
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Imperial Journal of Interdisciplinary Research (IJIR) Vol-3, Issue-2, 2017 ISSN: 2454-1362, http://www.onlinejournal.in Efficiency Enhancements –
BACKLOG FEES A one-time application fee associated with a population of abbreviated new drug applications (ANDAs) that are submitted to FDA prior to October 1, 2012 which are pending* and have not received tentative approval. Under GDUFA, each person that owns an abbreviated new drug application that is pending on October 1, 2012, and that has not received a tentative approval prior to that date, shall be subject to a backlog fee for each such application (section 744B(a)(1)(A) of the FD&C Act). The backlog fee is due no later than 30 days after publication of this notice (section 744B(a)(1)(D) of the FD&C Act).
FDA will implement various efficiency enhancements discussed below on October 1, 2012 or upon enactment of the program, whichever is later. Regulatory Science – FDA will continue, and for some topics begin undertaking various regulatory science initiatives discussed below on October 1, 2012 or upon enactment of the program, whichever is later, focusing first on the initiatives discussed below and with additional initiatives to be identified with input from an industry working group.6
The backlog fee is assessed one time only, for FY 2013, and no backlog fee will be assessed in subsequent years. Once incurred, the backlog fee obligation can only be discharged by payment in full. Under section 744B(a)(1)(B) of the FD&C Act, FDA calculates the backlog fee by taking the exact number of pending abbreviated new drug applications in the backlog that have not received tentative approval as of October 1, 2012, and dividing $50,000,000 by that number. Since there are 2,868 applicable applications in the backlog, the backlog fee is calculated to be $17,434 ($50,000,000 divided by 2,868 rounded to the nearest dollar).
GDUFA FEES GDUFA calls for four types of fees. These can be categorized as application fees and facility fees. Application fees include:A) B) C) D)
Backlog Fees DMF Fees New ANDA’s & PAS filling fees Facility Fees ( API & FDF Facility )
S.no
Fiscal Year 2013
1
17,434
Fiscal Year 2014($)
Fiscal Year 2015($)
-----
-----
A one-time application fee for a Type II Drug Master File (DMF) that is to be referenced on or after October 1, 2012 in a generic drug submission (new ANDA, supplement or amendment). A Type II DMF covers the manufacture of an active Fiscal Year 2013
1
21,340
-----
Fiscal Year 2017($) -----
pharmaceutical ingredient (API) or drug substance. The DMF fee aligns to a completeness assessment that FDA performs to determine if the Type II DMF may be deemed available for reference and placed on a publicly-available DMF Reference List.
DMF FEES
S.no
Fiscal Year 2016($)
Fiscal Year 2014($)
Fiscal Year 2015($)
Fiscal Year 2016($)
31,460
26,720
42,170
ANDA’S & PAS FILLING FEES –
Under GDUFA, the FY 2017 ANDA and PAS fees are owed by each applicant that submits an ANDA or a PAS, on or after October 1, 2016. These fees are due on the receipt date of the ANDA or PAS.
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Fiscal Year 2017($) 51,140
Section 744B(b)(2)(B) specifies that the ANDA and PAS fees will make up 24 percent of the $323,011,000, which is $77,523,000 (rounded to the nearest thousand dollars), and further specifies that the PAS fee is equal to half the ANDA fee.
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Imperial Journal of Interdisciplinary Research (IJIR) Vol-3, Issue-2, 2017 ISSN: 2454-1362, http://www.onlinejournal.in ANDA’S Fees S.no
Fiscal Year 2013
1
51,520
Fiscal Year 2014($)
Fiscal Year 2015($)
Fiscal Year 2016($)
63,860
58,740
76,030
Fiscal Year 2017($) 70,480
PAS Fees S.no
Fiscal Year 2013
Fiscal Year 2014($)
Fiscal Year 2015($)
1
25,760
31,930
29,370
FACILITY FEES Any person that owns a facility that is identified or intended to be identified in at least one generic drug submission that is pending or approved to produce one or more generic drug FDFs and/or APIs is required to pay facility fees. For purposes of self-identification and payment of fees, GDUFA defines API and FDF manufacturers somewhat differently from the way these traditional categories of manufacturers have been defined historically. For example, generic drug manufacturers who mix an API when the substance is unstable or cannot be transported on its own are considered API manufacturers and not FDF manufacturers for self-identification and the payment of GDUFA user fees only. GDUFA defines an FDF as: (A) a drug product in the form in which it will be administered to a patient, such as a tablet, capsule, solution, or topical application; (B) a drug product in a form in which reconstitution is necessary prior to administration to a patient, such as oral suspensions or lyophilized powders; or (C) any combination of an active pharmaceutical ingredient (as defined in the statute) with another component of a drug product for purposes of S.no Facilities Fiscal Fiscal Year Year 2013 2014($) 1 Domestic API 26,458 34,515 2 Foreign API 41,458 49,415 3 Domestic FDF 175,389 220,152 4 Foreign FDF 190,389 235,152
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Fiscal Year 2016($) 38,015
Fiscal Year 2017($) 70,480
production of a drug product described in subparagraph (A) or (B). GDUFA defines an API as: (A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended— (i) to be used as a component of a drug; and (ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body; or (B) a substance intended for final crystallization, purification, or salt formation, or any combination of those activities, to become a substance or mixture described in subparagraph (A). GDUFA specifies that the amount of the fee for a facility located outside the United States and its territories and possessions shall not be less than $15,000 and not more than $30,000 higher than the amount of the fee for a domestic facility. The differential amount is designed to reflect the higher costs of inspections funded, in part, through GDUFA. Fiscal Year 2015($) 34,515 49,515 220,152 235,152
Fiscal Year 2016($) 40,867 55,867 243,905 258,905
Fiscal Year 2017($) 44,234 59,234 258,646 273,646
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Imperial Journal of Interdisciplinary Research (IJIR) Vol-3, Issue-2, 2017 ISSN: 2454-1362, http://www.onlinejournal.in RTR (REFUSE TO RECEIVE) Identifies certain deficiencies and certain common deficiencies that are the basis for owner to file an ANDA. Outcomes i. RTR action indicates that FDA determined an ANDA is not sufficiently complete to permit a substantive review. ii. Describes how FDA will evaluate deficiencies identified during filing review
iii. iv. v.
Type of Deficiency
Definition
Major
If an ANDA contains 10 or more minor deficiencies or 1 or more major deficiencies, the application is not sufficiently complete to permit substantive review,Cannot be easily remedied If an ANDA contains 9 or fewer minor deficiencies and no major deficiencies, the applicant will have 7 calendar days to satisfactorily amend the ANDA to correct the minor deficiencies ,Can be easily remedied
Minor
Conclusion:The Generic Drug User Fee Act is a law designed to speed access to safe and effective generic drugs to the public, and reduce costs to industry.Up until October 2012, the law only required user fees for firms submitting new drug applications (NDAs). As of October 1, 2012, under GDUFA, all firms that manufacture human generic drug products, and active ingredients for human generic drug products, that are distributed in U.S. commerce are subject to FDA user fees.GDUFA fees will increase the ability of the Agency to perform critical program functions and to reduce costs considering the reduced review timelines. The purpose of GDUFA is to help FDA ensure that participants of the U.S. generic drug system comply with U.S. quality standards, and to increase the likelihood that American consumers get timely access to low cost, high quality generic drugs. FDA and industry jointly agreed to a comprehensive generic drug user fee program supplemental to traditional appropriated funding focused on three key aims:
Safety and effectiveness Access Transparency
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to determine whether it should receive an ANDA Clarifies definitions of major and minor deficiencies noted during filing review Provides examples of typical major deficiencies Provides examples of typical major deficiencies
No. of Acceptable Deficiencies None
Time to Remedy
9 or fewer
7 calendar days
N/A
GDUFA is a 5-year program and will last from FY 2013 – FY 2017. Program highlights include:
A 10-month review cycle for 90 percent Target revenue of approximately $299 million Completing the review of at least 90 percent of ANDAs, ANDA amendments and ANDA PASs that were pending status on October 1, 2012 Developing and utilizing databases to support GDUFA Improving communication between FDA and industry FDA completion of ANDA reviews with only minor administrative amendments Risk-based frequency FDA review and action on all ANDAs submitted on the first day that any valid Paragraph IV application is submitted within 30 months of submission Streamlined FDA hiring authority for all GDUFA-related positions FDA response to appeals on decisions concerning procedural or scientific matter involving generic drug review within 30 calendar days of OGD receipt of the written appeal when possible
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