Opportunities and Challenges brought by Generic Drug User Fee Act in 2013
Author: / Samrat Sisodia. MS, MBA, RACPrincipal Regulatory Affairs CMC Specialist
Affiliation: / Upsher-Smith Laboratories
6701 Evanstad Dr., Maple Grove, MN 55369
Home Address: / 6251 Alvarado Ln N, Maple Grove, MN 55311
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Telephone : / +1-631-935-2191
Introduction
When the President Obama signed the Generic Drug User Fee Act (GDUFA) in to law on July, 9, 2012, it marked the beginning of the long due overhaul of generic drug regulation process. With generic drug application review time well over 30 months in USA, this act brings the much needed change and relief in the system. The implementation GDUFA’s is expected to ensure fast access to the generic drugs and overall reduction in price burden of the generic drugs in the USA (GPO, 2012). The current act is largely inspired by Prescription Drugs User Fee Act (PDUFA) which has been in law of land for New Drug Application (NDA) review process for quite some time now. Like PDUFA one of the key objectives of GDUFA is to lay down clear expectations for higher quality future generic submission in front of the generic industry (FDA, 2013). GDUFA act as written, expects to meet its immediate and long term goals by setting minimum quality standards for the generic application. In return, GDUFA provides generic industry with standard review time, science based action letters, and clear open ended communication channels, which are largely unavailable to generic industry currently.
The Office of Generic Drugs (OGD) at the FDA has stated to increase the resources and review personals in order to meet the proposed GDUFA goals. In this effort OGD was recently elevated to “Supper Office Status” designation within the Food and Drug Administration (FDA). Super Office Status for OGD brings additional administrative power and oversight that was currently lacking. The United States Congress also allows the FDA to fund GDUFA program by the levying establishment and application fees.
Overall GDUFA will be the landmark act in the history of the Department of Health and Human Services, USA. GDUFA will push for the quality generics and speedy access of the generics to the patients. It is a win-win for both the customer and industry. As transition happens from current generic review system to the GDUFA process in the year 2013, there are quite a few opportunities and challenges that generic industry should be mindful about. The attempts to explore opportunities and challenges presented to the generic industry as GDUFA implementations goes in effect.
Background
The GDUFA program charter states the “Safety, Access, and Transparency” as the fundamental objective of the program (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012). The purpose of the GDUFA program is to ensure greater compliance of the generic industry to the highest quality standards and improving the timely access and availability of the quality generics. The Agency has already begun to enhance the review process and site identification requirements for the generic industry. The Food and Drug Administration (FDA) is committed to being more transparent in its communications and feedback to the industry. At the end of the GDUFA’s five year goal, 90% of the Abbreviated New Drug Applications (ANDAs) are expected to be reviewed in 10 months. (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012)
The GDUFA program aims for inflation adjusted $299 million revenue for each of the five years of the program (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012). Assuming 78% of the retail prescriptions in 2010 were generics, the cost of the total GDUFA program is less than 10 cents per prescription (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012). The Agency assumes that the GDUFA program will be funded through 750 ANDAs, 750 prior approval supplements (PAS), 350 newly reference Type II Drug Master Files (DMFs) and approximately 2000 facilities fees associated with ANDAs (FDA does not envision significant increase in the drug facilities at this time) (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012). In all, 70% of the fees will be raised via facility fees and rest 30% from the ANDA, PAS and DMF fees (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012). All of the GDUFA goals are for the electronic Common Technical Document (eCTD) submissions only, any paper or partial electronic submission would not be considered against any GDUFA performance goals (FDA, Generic Drug User Fee Act Program Performance Goals and Procedures Draft, 2012).
As the Agency and generic industry gears for the implementation of the GDUFA program, year 2013 would pose unique opportunities and challenges, especially, when both the industry and the Agency figure out the specifics and interpretations of the law. The FDA guidances like “Draft Guidance for Industry Generic Drug User Fee Amendments of 2012: Questions and Answers” and “Draft Guidance for Industry Self-Identification of Generic Drug Facilities, Sites, and Organizations” provides maiden insight to the FDA’s interpretation of the GDUFA requirements and expectations. These guidances certainly enhance generic industry’s interpretation, but as with all big initiatives, it is challenging to find out the correct and appropriate way of implementing the GDUFA requirements for their respective operations. This article lists some of the opportunities and challenges that the generic industry may face in 2013.
Opportunities ahead in 2013:
1. Industry can expect multidivisional complete response (CR) letters on the original ANDA, PAS and DMFs. Currently for the generic submissions, OGD typically issues the Chemistry, Manufacturing and Controls (CMC), Bioequivalence and Labeling deficiencies at various review intervals. Receiving consolidated CR would avoid multiple changes to the same documents (Specifications, test methods etc.) which are frequent occurrence in individual divisional comments.
2. FDA would allow the ANDA and DMF sponsors to seek teleconference with the FDA after the first cycle CR. This is move in the right direction and will certainly improve the deficiency response quality and reduces the time required to seek approval for the submission.
3. Paragraph IV (P-IV) submission would be automatically considered for the expedited review. The MAPP 5240.3 would allow FDA to consider applications for expedited review for all the application which are eligible for approval during the review period as a result of no blocking exclusivities, patent(s)/ or applicable stays.
4. Facility inspections and its details (e.g. last inspection date) would be made public on the FDA’s website in a timely manner. Industry can quickly make acceptability determination of any facility using the database and can save time during vendor selection and application drafting process.
5. FDA would undertake and develop the CMC databases for consistent and efficient review. The industry can expect more consistent review and deficiency questions on the applications. Having such a database is going to increase the OGD reviewer’s ability to see review across the various OGD teams for similar products or related issues. This database is will also allow industry and reviewers to reference old review to justify any scientific stance, in essence wheel won’t be invented again during the review process. The database will force normalcy to the review statistics.
6. Response to the disputes (procedural and scientific) can now occur within 30 calendar days upon the OGD’s receipt. Currently, management at OGD has less than expected visibility to the disputes that generic industry faces. Having formal procedure provides dispute lodging and remediation steps the desired visibility with in the OGD. A word caution, at this time no GDUFA goals are tied around dispute resolution in the program.
Challenges ahead in 2013:
1. The self site-identification requirements would make things challenging for the generic industry. The revised FDA form 356h now requires list and details of all the sites used in manufacturing, packaging, testing of the finished drug product and Active Pharmaceutical Ingredient (API) and the sites involved in testing of packaging component and excipients. This requirement will drive for extra control and oversight over the component’s vendors and testing sites for self-identification requirements. To give an example, an API manufacturing site, which also produce finished dosage form, needs to self-identify itself for the both operations. If they happen to self-identify only for API operation, an ANDA sponsor referring such a site in its application may find itself in a difficult position during an ANDA review due to the incomplete self-identification done by the API manufacturer.
2. Stricter Refuse to File (RTF) standards for the ANDAs. As indicated by the Agency on multiple occasions, in order to streamline and standardize the ANDA quality and data requirements, FDA is going to change the ANDA completeness check list and Question Based Review (QBR) questionnaire to force the generic industry to demonstrate elements of Quality by Design (QbD) along with sufficient data requirement to support quality applications. Industry might see some increases in RTF letter issued by the Agency this year.
3. With the newly implemented completeness assessment of the DMFs, all the newly referenced Type II DMFs will have to be submitted at least two- three months prior to the submission of the ANDAs. This will be a change from current practice where some ANDA applicants prefer DMF holders to submit DMFs on the date of the ANDA submission. This is typically done to keep the ANDA filing as discrete as possible.
4. As the Agency increases its resources for the site inspections, there will be more frequent follow-up audits for the high risk operations and manufacturing units. Especially for the drug product and drug substance manufacturers in India and China will see heightened scrutiny and eventually will drive the whole region for stricter cGMP and quality standards.
5. Industry can expect more sample requests for analysis by the FDA laboratories. Drugs with complex formulations, narrow therapeutic index, and severe adverse events etc. are going to have heightened scrutiny by the Agency and might result in sample analysis as part of the FDA’s risk mitigation strategy.
Conclusions
The numbers of ANDAs filed are rapidly growing, which were around 900 in the year 2011. The numbers of ANDAs pending for review were about 2600 in the year 2011. So, obviously FDA had tough job ahead of them. Hence, the fees earned will help the FDA to increase its resources and expedite the approval process of ANDAs.
The GDUFA may superficially seem to be burdensome for generic companies. However, for the generic companies which are serious to have their ANDA approval in the fact track and gain market share as soon as possible, the GDUFA is positive news.
References
FDA. (2012). Generic Drug User Fee Act Program Performance Goals and Procedures Draft.
FDA. (2013). Retrieved from http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm337385.htm
GPO. (2012). www.gpo.gov. Retrieved from http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf