10 A guide to PDUFA V Authors Virginia Beakes-Read JD RN, Executive Director, Global Regulatory Policy and Intelligence, Eisai, Inc; Florence Houn MD MPH FACP, Vice President, Regulatory Policy and Strategy, Celgene Corporation; Andrea Masciale JD, Vice President, Global Regulatory Policy and Intelligence, Janssen Pharmaceutical Companies of Johnson & Johnson; Kim Quaintance, Senior Director, Global Regulatory Policy and Intelligence, Eisai, Inc. Keywords Food and Drug Administration Safety and Innovation Act (FDASIA); Prescription Drug User Fee Act (PDUFA); PDUFA V Goals Letter; Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs ; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER); Regulatory Project Manager (RPM); Risk evaluation and mitigation strategy (REMS). Abstract This article highlights important new programmes in the reauthorised Prescription Drug User Fee Act (PDUFA) which came into force on 1 October 2012. To facilitate future reference, we have provided tools such as a timeline of key events and descriptions of the critical aspects of the new review programme. Also included is a question-and-answer section, addressing issues that regulatory affairs professionals are likely to face, and providing some solutions and recommendations. Finally, the article summarises the FDA s commitments, which include enhanced communication during drug development; advancing the science of meta-analysis methodologies; aiding the development of endpoint assessment tools; improving benefit risk assessment in regulatory decision-making; standardising risk evaluation and mitigation strategies (REMS); modernising pharmacovigilance processes and enhancing drug safety information systems and infrastructures. Background On 9 July 2012, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144). 1 Because the new law reauthorised the Prescription Drug User Fee Act (PDUFA) for the fifth time, the user fee programme is known as PDUFA V. PDUFA V will be in effect from 1 October 2012 until 30 September 2017 (ie, FDA fiscal years 2013 2017). As in previous authorisations, many important aspects of the user fee programme are set forth in a document separate from the statute, informally described as the Goals Letter. The 2012 letter, the PDUFA Reauthorization Performance Goals and Procedures; Fiscal Years 2013-2017 (the PDUFA V Goals Letter), contains the negotiated agreement between the FDA, industry, patient and consumer advocates, healthcare professionals and other public stakeholders. 2 The PDUFA V Goals Letter reauthorises many of the review performance goals for the FDA s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), and further enhances many existing programmes in CDER and CBER. It also describes an important new review programme for PDUFA V for new molecular entity (NME) new drug applications (NDAs) and original biologic license applications (BLAs), called the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs ( the Program ). This was developed to facilitate the resolution of review issues in a timely manner, allowing an efficient and effective review. By enhancing communication and transparency between CDER staff and industry sponsors, the Program will ideally result in more first-cycle approvals. Among the new review elements added to achieve that goal are mid-cycle communications, late-cycle s and a filing review period that adds 60 days to the overall time between FDA receipt and the PDUFA goal date. The Goals Letter also includes provisions to enhance regulatory science, benefit risk assessment, and the FDA drug safety system. The Program The PDUFA V Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs was designed to ultimately result in more first-cycle approvals. New elements in "the Program" are highlighted in Figure 1. Questions and uncertainty about the Program are expected. Regulatory professionals will need to help product teams and management understand the nuances of the new review programme. Our own experts have already answered some questions you can expect to receive, and these are detailed below. Questions and answers Q What is the Program under PDUFA V? A The Program refers to the new molecular entity NDA and original BLA review model under PDUFA V. It is characterised by: 1 Agreement between the FDA and the sponsor on what constitutes a complete application and what components may be received by the FDA within 30 days of receipt of the application 2 A mid-cycle communication with the FDA and the sponsor 3 A late-cycle between the FDA and the sponsor. In exchange for greater communication, the PDUFA goal dates change from being calculated from ten s (standard review) and six s (priority review) from receipt date of application submission to filing date of the application by the FDA. Filing occurs within 60 days of the FDA receiving an application and means that the FDA has made a threshold determination that the application is sufficiently complete to permit a substantive review. This period is also being referred to by some as the PDUFA V 60 day validation period. (For a graphical representation of the PDUFA V Program timeline, see Figure 1.) Q We submitted our NME NDA before 1 October 2012, but are awaiting a filing decision by the FDA. Will our application be under the Program per PDUFA V? A No. As your NME application was submitted and received by the FDA before 1 October 2012, and you are awaiting an agency filing
11 determination (a threshold determination under 21 CFR 314.101 for NDAs, or, for BLAs, under 21 CFR 601.2, that the application is sufficiently complete to permit a substantive review by the agency), your application will not be subject to the Program. Be aware that what counts is the receipt date and time by the FDA. For example, if a company s electronic submission was sent before 1 October 2012 (Monday), such as on Friday 28 September 2012, but because the time needed to complete the FDA Gateway Transfer was lengthy, and included a weekend, the FDA receipt date and time of your submission could have been on 1 October 2012. Q I am having trouble getting a response from the division s Regulatory Project Manager (RPM) about obtaining the FDA review team s comments on our Phase 3 protocol. We really need to hear back before we begin our global studies. Under PDUFA V there are new communications liaison staffs in both CDER and CBER. Is my problem something they would handle? A The liaison staff serves as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions. The staff also serves as a secondary point of communication within the CDER for sponsors who are encountering problems in communication with the review team for their investigational new drug (IND) (for example, in instances when they have not received a response from the review team to a simple or clarifying question or referral to the formal process within 30 days of the sponsor s initial request). In such cases the liaison staff will assist in evaluating the issues and working with the review team and the sponsor to facilitate resolution of the problem. So while you can contact the liaison staff for assistance in getting a response, it is always advisable to work things out with the RPM as the RPM knows both your project and the review team the best. Q I heard that the Program under PDUFA V only applies to NME NDAs and original BLAs. Am I correct in assuming nothing has changed for other NDAs, supplemental NDAs (sndas), sblas, and manufacturing supplements? A No. There are some policies in PDUFA V that apply to these other, non-program applications. The PDUFA V policies affecting sndas, sblas, non-nme NDAs and manufacturing supplements are: l Major amendments to an original application, efficacy supplement or resubmission of any of these applications submitted at any time during the review cycle may extend the goal date by three s. This differs from the current situation where major amendment to an original application, efficacy supplement, or resubmission of any of these applications, submitted within the last 90 days of a PDUFA goal date, may extend the goal date by three s. A major amendment may include a major new clinical safety/ efficacy study report; major re-analysis of previously submitted study(ies); submission of a risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) not included in the original application, or significant amendments to a previously submitted REMS with ETASU. These latter two reasons for extension are new under PDUFA V. l A major amendment to a manufacturing supplement submitted at any time during the review cycle may extend the PDUFA goal date by two s. This differs from the current situation where a major amendment to a manufacturing supplement submitted within the last two s of the PDUFA goal date extends the goal date by two s. l l l l Only one extension can be given per review cycle. Also, for all requests there are changes: Sponsors can request pre-ind (Type B) and Type C s that allow the FDA to provide written response only (WRO) to questions, or the FDA may at its own discretion determine that WRO is the most appropriate. If the latter is the case, the FDA will notify the sponsor of the date the agency intends to send the response, and the response to questions will be within the respective goals (eg, 60 days or 75 days) Type A packages (the briefing book) will be due with the request. Other goals remain same with respect to submitting the package for Type B and Type C s. Meetings regarding REMS or postmarketing requirements that occur outside the context of the review of a marketing application will be classified as Type B. Finally, post-action s requested within three s after a regulatory action that was not an approval (ie, issuance of a complete response letter) shall be classified as a Type A. Q I see a discrepancy in the PDUFA Goals Letter regarding agreement of submission of late items. In one place it states that a limited number of agreed upon items must be received not later than 30 calendar days after the submission of the original application (see II.A.I.c.) and in another place it states those items are expected to be received not later than 30 calendar days after receipt of the original application (see II.A.2.b). Does the 30 calendar days apply from sponsor submission date or FDA receipt date? A We ve clarified this with the FDA and the expectation is receipt of those agreed upon late items not later than 30 calendar days after receipt of the original application. Q Can you tell me more about the late-cycle under the Program? I can understand the occurring before an Advisory Committee and the agenda would be about the, correct? What about late-cycle s when there is no Advisory Committee planned? A The late-cycle is a great opportunity to understand the FDA s evaluation of your application and address agency concerns to enable a first-cycle approval. If your application is going before an Advisory Committee, issues that will be presented to the Advisory Committee should be discussed. However, with or without an Advisory Committee on your near horizon, the late-cycle allows you to discuss any and all concerns the FDA has about your application, including those that are not traditionally discussed at the Advisory Committee, such CMC, inspectional issues, labelling, REMS, paediatric, postmarketing requirements or commitments, etc. In other words, any matter that could preclude approval should be discussed to allow your company to understand the concerns and to exchange ideas with the FDA on how to address those concerns. Discussing all those approval issues will give you as much time as possible to respond. Q How much is the FDA going to tell us during the mid-cycle teleconference? Will we get this in writing? A The division s RPM will contact you after the division holds its internal mid-cycle to arrange a time for a telephone call regarding the outcome of the division s mid-cycle. The call will convey information on the status of the review. This update
12 Table 1: Enhanced communication during drug development Purpose: To implement FDA philosophy that timely interactive communication with sponsors during drug development is a core agency activity to help facilitate efficient and effective drug development programmes. September 2014 March 2015 18 s after close of Draft Guidance comment period Develop dedicated drug development communication and training staff, focused on enhancing communication between the FDA and sponsors during drug development. Training provided to all IND review staff in CDER, including best practices for communicating with sponsors and roles of liaison staff. Publication of Draft Guidance for review staff and industry describing best practices for communication during drug development. Public comments will be accepted. Publication of Final Guidance for review staff and industry describing best practices for communication during drug development. Table 2: Advancing the science of meta-analysis methodologies Purpose: To develop a dedicated review team with expertise to evaluate different scientific methods and explore the practical application of scientific approaches and best practices for the conduct of meta-analyses in the context of the FDA review process. September 2015 18 s after close of Draft Guidance comment period Public on current and emerging scientific approaches and methods for the conduct of metaanalysis, and to facilitate feedback and input on the use of meta-analyses in the FDA review process. Publication of Draft Guidance on the FDA s intended approach to using meta-analyses in the review process. Public comments will be accepted. Publication of Final Guidance on the FDA s intended approach to using meta-analyses in the review process. Table 3: Advancing the use of biomarkers and pharmacogenomics Purpose: To develop staff capacity to review submissions that contain complex issues involving pharmacogenomics and biomarkers. Public on current status of biomarkers and pharmacogenomics and potential strategies to facilitate scientific exchanges in regulatory and non-regulatory contexts. Training for CDER and CBER staff on approaches to conducting a pharmacogenomics review of a new product application. Table 4: Advancing development of patient-reported outcomes (PROs) and other endpoint assessment tools Purpose: To develop clinical and statistical staff capacity to efficiently and effectively respond to submissions that involve PROs and other outcomes assessment tools and undertake activities that will allow for greater understanding of challenges that arise during development of outcomes assessment tools, potential strategies to overcome the challenges, and greater consistency in the FDA s approach. September 2014 Public on the FDA s qualification standards for drug development tools, new measurement theory, and implications for multinational trials.
13 Table 5: Advancing development of drugs for rare diseases Purpose: To advance the development of drugs for rare diseases by expanding the rare disease programme within CDER and creating a liaison position within CBER. Ongoing March 2014 September 2015 September 2016 Completion of a staffing and implementation plan for CDER and CBER rare disease programmes. CDER staff will increase by five employees, and CBER will establish a liaison position. Dissemination of guidance and policy to CDER and CBER staff on advancing and facilitating development of drugs for rare diseases, including the enhancement of understanding among FDA reviewers of approaches and challenges to developing such drugs. Increased outreach to industry, patient representatives and patient organisations on development of drugs for rare diseases. Public on complex issues in clinical trials for drugs for rare diseases, including endpoint selection, reasonable safety exposures, dose selection, and development of PRO instruments. Training for CDER and CBER review staff on development, review and approval of drugs for rare diseases. Training will be part of reviewer training core curriculum. Evaluation tool to evaluate success of the rare disease programmes, including reviewer training. Table 6: Enhancing benefit risk assessment in regulatory decision-making Purpose: To develop and implement a structured benefit risk assessment in the new drug approval process. December 2012 Ongoing December 2014 September 2017, but after first two public s Publication of draft five-year plan for structured benefit risk assessment in the new drug approval process, including an evaluation of the effect of the framework in the review process. Public comments will be accepted. Begin execution of FDA plan to implement the benefit risk framework across review divisions in the pre- and post-market review process. Updates to FDA plan for the benefit risk framework included as needed and posted on FDA website. Public workshop on benefit risk frameworks and methods and their application to regulatory decision-making. More details to be included in the five-year plan. Public workshop on results and lessons learned in implementing frameworks at regulatory agencies in the preand post-market review process. More details to be included in the five-year plan. Revisions to CDER and CBER review templates and procedural documents to incorporate structured benefit risk assessment into the review process. Training on revisions to be provided. More details to be included in the fiveyear plan. Identification of disease areas that could benefit from a more systematic and expansive approach to obtaining patient perspective on disease severity or unmet medical need. Identification will take place through a public process. 20 public s four per year over the course of the five-year PDUFA V programme on disease areas identified as potentially benefiting from a systematic and expansive approach to obtaining patient perspective on disease severity and unmet medical need. Each to focus on a different disease area. Proposal for how the FDA will incorporate patient perspectives on disease severity and unmet medical need into the agency s decision-making. Increased use of patient representatives as Special Government Employee consultants to CDER and CBER to provide patients views early in the development process and ensure perspectives are considered in regulatory discussions.
14 Table 7: Measure the effectiveness of risk evaluation and mitigation strategies (REMS), standardise REMS, and better integrate REMS into the healthcare system Purpose: To enhance REMS by measuring their effectiveness and developing techniques to standardise REMS and integrate them into the existing and evolving healthcare system. December 2013 September 2014 Publication of FDA guidance on how to apply the statutory criteria for REMS to determine whether a REMS is necessary to ensure that the benefits of a drug outweigh the risks. Public comments will be accepted on a Draft Guidance. One or more public s on strategies to standardise REMS, with the goal of reducing the burden of implementing REMS in various healthcare settings. Publication of FDA report identifying at least one priority project the agency will undertake in each of the following areas: pharmacy systems; prescriber education; providing benefit risk information to patients; and practice settings. The report will include a plan for completion of each project. One or more public workshops on methodologies for assessing whether REMS are mitigating the risks they purport to mitigate and for assessing the effectiveness and impact of REMS. Publication of FDA guidance on methodologies for assessing REMS. Public comments will be accepted on a Draft Guidance. Table 8: Sentinel as a tool for evaluating drug safety issues Purpose: To determine the feasibility of using Sentinel to evaluate drug safety issues that may require regulatory action. Activities will be focused on issues that affect classes of drugs or multiple products. September 2017 September 2015 September 2017 Public s on current and emerging Sentinel projects, including projects that should be undertaken. Fund four to six activities to further evaluate safety signals that, in previous cases, have served as the basis for regulatory action(s) or to more broadly help determine the utility and validity of the Sentinel system. Interim assessment evaluating the strengths, limitations and appropriate use of Sentinel for informing regulatory actions to manage safety issues. Assessment evaluating the strengths, limitations and appropriate use of Sentinel for informing regulatory actions. Table 9: Activities designed to modernise the process of pharmacovigilance Purpose: To conduct and support efforts to maximise the usefulness of tools employed for adverse event signal detection and risk assessment. Training for FDA staff on use of data other than passive spontaneous reports, including populationbased epidemiological data and other types of observational data resources, to target post-marketing surveillance, evaluate class effects of drugs, and potentially conduct signal detection. Information technology infrastructure needed to support access and analysis of data from resources including population-based epidemiological data and observational data.
15 Table 10: Drug safety information systems and infrastructure Purpose: To continue development of standards-based information systems to support how the FDA obtains and analyses post-market drug safety data and manages emerging drug safety information. Enhanced adverse event reporting system and surveillance tools, information technology infrastructure to support access and analyses of externally-linked databases, and workflow tracking system. Table 11: Improving review through required electronic submissions and standardisation of electronic drug application data Purpose: To establish standards and format of electronic submissions to enhance the quality and efficiency of the FDA s review of NDAs, BLAs and IND applications. December 2012 12 s after close of Draft Guidance comment period 24 s after publication of Final Guidance 36 s after publication of Final Guidance June 2013 September 2017 Publication of Draft Guidance on standards and format of electronic submission of applications. Public comments will be accepted. Publication of Final Guidance on standards and format of electronic submission of applications. Require that all new original NDAs and BLAs, new NDA and BLA efficacy supplements, new NDA and BLA labelling supplements, new manufacturing supplements, amendments to all such submissions, and all other new NDA submissions be submitted in electronic format. Require that all original commercial INDs, except those for expanded access under section 561 of the Food, Drug and Cosmetic Act, be submitted in electronic format. Publication of proposed project plan for development of standardised clinical data terminology for distinct therapeutic indications. Public comments will be accepted. Plan to be updated annually. Standardised clinical data terminology and detailed implementation guides, developed through open standards development organisations (ie, the Clinical Data Interchange Standards Consortium (CDISC)). Public input requested on the use of relevant existing nonclinical data standards and involvement of existing standards development organisations to develop new standards or refine existing standards for nonclinical data. will include any significant issues identified by the review team to date, any information requests, information regarding major safety concerns and preliminary review team thinking regarding risk management, proposed date(s) for the late-cycle, updates regarding the Advisory Committee (if one is anticipated), and other projected milestone dates for the remainder of the review cycle. The PDUFA requirement is only for a telephone call; FDA minutes are not stipulated. It remains to be seen about provision of FDA documentation of the call. Q You said the Program applies to NME NDA and original BLAs but not non-nme original NDAs. What is a non-nme original NDA and what would a non-original BLA be? And are user fees different for the Program applications and non-program non-nme original NDAs? Also, does the Program s mid-cycle teleconference and late-cycle apply to resubmissions when the original NME NDA or BLA, which was under the Program, got a complete response (CR)? A Non-NME original NDAs are: NDAs for a new formulation, new dosage form, new salt, ester, or non-covalent derivative, new fixed dose combinations, new manufacturer, or for a marketed drug without an NDA. An example of a non-original BLA would be a change in formulation/ process requiring comparability data and other clinical data that requires the submission of a new BLA rather than an efficacy supplement. With regard to user fees, the same user fee applies to both Program applications and non-program applications. In terms of resubmissions, the Program is focusing on improving first-cycle approvals, so the mid-cycle teleconference and late-cycle s do not apply for the second cycle of an application that got a CR under the Program first cycle. Sorry! Q I understand the requirement for complete NME NDA and BLA applications under the Program may be backed up with more refuse-tofile actions at the FDA. At the pre-nda/bla, do you recommend sponsors provide the FDA with proposals on what constitutes a complete application? How detailed should the proposals be?
16 Figure 1: PDUFA V NME/Original BLA Enhanced Review Process ( The Program ) Filing review 1 Filing review 2 1 2 3 4 5 6 7 8 9 10 Actual time in s after submission 0 1 2 3 4 5 6 7 8 9 10 11 12 Receipt of application At least 2 s presubmission Presubmission Submission of agreed-upon components 30 days after receipt Mid-cycle 5 s after receipt for standard 3 s after receipt for priority Issue action letter PDUFA 10 for standard PDUFA 6 for priority Begin PDUFA review clock Communication priority decision or RTF 60 days after receipt COMMUNICATE FILING REVIEW ISSUES 74 days after receipt New information includes mid-cycle date and preliminary plans for AC Mid-cycle communication 2 weeks after midcycle CONDUCT REVIEW AND ISSUE DISCIPLINE REVIEW LETTERS Discipline review letters to be issued prior to late-cycle If a discipline review letter is not issued, substantive issues identified to date from that discipline will be communicated in the brief memorandum provided as part of the late-cycle background package Late-cycle package due (if no AC) 12 days prior to late-cycle Late-cycle (if no AC) 3 s prior to action for standard 2 s prior to action for priority Complete inspections 2 s prior to end of review cycle Diagram key This diagram presents major milestones, activities and events that occur during the review of applications subject to the PDUFA V Program for Enhanced Review Transparency and Communication for NME NDAs and original BLAs ( the Program ) The diagram depicts a standard review, with milestone dates for a priority review shown in red text. FDA communications Other milestone dates RTF = Refuse-to-file AC = Advisory Committee Original 21st Century Review Process Visual Design by Leadership Performance Solutions Late-cycle package due (if AC) 20 days prior to AC Late-cycle due (if AC) 12 days prior to AC Advisory Committee 3 s prior to action for standard 2 s prior to action for priority See opposite page for explanatory notes on procedures.
17 Figure 1: PDUFA V NME/Original BLA Enhanced Review Process ( The Program ) Explanatory notes Pre-submission Pre-submission s are strongly encouraged for applications subject to the Program. These s should be held sufficiently in advance to allow for meaningful response to FDA feedback, and not less than two s prior to the planned submission. The FDA and the applicant will reach agreement on the content of a complete application, including preliminary discussion of the need for risk evaluation and mitigation strategies (REMS) or other risk management actions. The FDA and the applicant may also reach agreement on late submission of a limited number of application components (eg, updated stability data or a final, audited, nonclinical study report). These components must be submitted no later than 30 days after receipt* of the original application. *The Goals Letter states that these components must be submitted no later than 30 days after submission. The FDA has confirmed, consistent with the language used for the original application submission, that this should be 30 days after receipt of the original application. Original application submission An application submitted without a pre-submission or agreements on content of the application is expected to be complete at the time of original submission. Applications are expected to include a comprehensive and readily located list of all clinical sites and manufacturing facilities included or referenced in the application. Incomplete applications including agreed upon, latesubmitted components that are not received within 30 days of receipt of the submission will be subject to a Refuse-to- File decision. Applications subject to a Refuse-to-File action and subsequently filed over protest by the applicant will not be subject to the Program. Unsolicited amendments are expected to be rare and not to contain major new information or analyses. Review of amendments will be handled based on the most efficient path toward completion of a comprehensive review in accordance with the guidance Good Review Management Principles and Practices for PDUFA Products (GRMPs). Mid-cycle communication The mid-cycle communication is a telephone call between the applicant and the FDA Regulatory Project Manager and other appropriate FDA review team members within two weeks of the mid-cycle review. It is unclear how this call will be documented by the FDA and shared with the applicant. The purpose of the telephone communication is to provide the applicant with an update on the status of the review, and will include any significant issues identified by the review team to date, information regarding major safety concerns and preliminary thinking regarding risk management, the proposed date for the late-cycle, updates regarding plans for the Advisory Committee (if planned), and other projected milestones for the remainder of the review cycle. Discipline review letters Discipline review letters will be issued following completion of primary and secondary discipline reviews according to existing guidance. The FDA intends to issue discipline review (DR) letters in advance of the planned late-cycle. If a DR letter is not issued in advance of the late-cycle, substantive issues identified to date from that discipline will be communicated in the brief memorandum provided as part of the late-cycle background package. Late-cycle The late-cycle is a between the applicant and the signatory authority for the application, appropriate review team members, and appropriate team leaders or supervisors. The purpose of the is to provide the applicant with an update on the status of the review late in the review cycle. Potential topics for discussion include major deficiencies identified to date; issues to be discussed at the Advisory Committee (if planned), a current assessment of the need for REMS or other risk management actions; information requests from the review team; and additional data or analyses the applicant may wish to submit, including whether such data or analyses will be reviewed in the current review cycle and if so, if the submission will be considered a major amendment that triggers an extension to the review clock. Applications discussed at an Advisory Committee The late-cycle will occur at least 12 days prior to the Advisory Committee. The FDA intends to convene Advisory Committee s at least three s prior to the PDUFA goal date for standard applications, and at least two s prior to the PDUFA goal date for priority applications. The background package for the late-cycle will be sent at least 20 days prior to the Advisory Committee, and will include the FDA s Advisory Committee background package, any DR letters issued, current assessment of the need for REMS or other risk management actions, and a brief memorandum from the review team outlining substantive application issues and potential questions and/or points for discussion for the Advisory Committee. Applications not discussed at an Advisory Committee The late-cycle will occur at least three s prior to the PDUFA goal date for standard applications, and at least two s prior to the PDUFA goal date for priority applications. The background package for the late-cycle will be sent at least 12 days prior to the, and will include any DR letters issued, a current assessment of the need for REMS or other risk management actions, and a brief memorandum from the review team outlining substantive application issues. See opposite page for explanatory notes on procedures shown in this Figure.
18 A Yes, it would be good to discuss your proposal for specific items of a limited number of application components that you would like to submit to and be received by the FDA late (ie, within 30 days of application receipt by the FDA). Agreement must be reached at the pre-nda/bla for these components and that agreement must be captured in the minutes. These components must be of a type that would not be expected to materially impact the ability of the review team to begin its review. Examples of application components that may be appropriate for delayed submission include updated stability data (eg, 15- data to update 12- data submitted with the original submission) or the final audited report of a preclinical study (eg, carcinogenicity) where the final draft report is submitted with the original application. Major components of the application (eg, the complete study report of a Phase 3 clinical trial or the full study report of required long-term safety data) are expected to be submitted with the original application and are not subject to agreement for late submission. If the applicant does not have a pre-nda/bla with the FDA, and no agreement exists between the FDA and the applicant on the contents of a complete application or delayed submission of certain components of the application, the applicant s submission is expected to be complete at the time of original submission. Incomplete applications, including applications with components that are not received within 30 calendar days after receipt of the original submission, will be subject to a refuse-to-file decision. Applications that are subject to a refuse-to-file action, and are subsequently filed over protest, will not be subject to the procedures of the Program, but will instead be subject to the six- and ten- review performance goals for priority and standard applications of non-program original NDAs. Since applications are expected to be complete at the time of submission, unsolicited amendments are expected to be rare and not to contain major new information or analyses. PDUFA V commitments by the FDA Under PDUFA V, the FDA has committed to certain activities ultimately aimed at enhancing the agency s review capabilities and efficiency. Tables 1 11 give an at-a-glance view of the FDA s commitments. It is clear from these tables that the FDA is committed to strengthening regulatory science initiatives, improving benefit risk assessment in regulatory decision making, enhancing and modernising the drug safety system, and improving the review process through required electronic submissions and standardisation of electronic data. References 1 FDASIA (http://www.gpo.gov/fdsys/pkg/bills-112s3187enr/pdf/bills- 112s3187enr.pdf) also reauthorises the Medical Device User Fee Act (MDUFA III) and authorises new fee programmes under the Generic Drug User Fee Act (GDUFA) and Biosimilar User Fee Act (BSUFA). Under FDASIA, the Best Pharmaceuticals for Children Act (BPCA) and Pharmaceutical Research Equity Act (PREA) were made permanent and no longer will be subject to reauthorisation every 5 years. FDASIA also enhances opportunities for accelerating drug development with new amendments to the accelerated approval provision, the creation of breakthrough therapy designation, a rare pediatric disease priority review voucher, and enhancing regulatory science activities with industry and academia. Other significant provisions of FDASIA include those relating to drug shortages, advisory committee conflict of interests, and risk evaluation and mitigation strategies (REMS). 2 FDA. http://www.fda.gov/downloads/forindustry/userfees/ prescriptiondruguserfee/ucm270412.pdf TOPRA The Organisation for Professionals in Regulatory Affairs Ref: BAS/ONL The first interactive online foundation course for very new recruits, PAs, administrators, support staff, Agency staff, Students in Regulatory Affairs and other related areas such as Pharmaceutical, Medical Device, Manufacturing, Marketing and other companies. Aim of this programme To make the course more accessible for new recruits to the industry outside of the UK Helping TOPRA meet its increasing demand for the course around the globe Providing a different mode of learning for the new regulatory professionals of today Designed to allow you to proceed at your own pace, in your own time and more importantly at your own home/office or workplace, without having to travel to attend the course of study personally. The modules are: What is Regulatory Affairs? Regulatory control of clinical trials Marketing Authorisation Applications European application procedures Post Authorisation activity For more information, please contact TOPRA via email: s@topra.org or tel: +44 (0) 20 7510 2560 or go to the website: /onlinebasics Online Basics 5* hours Lifelong Learning *For more information please visit / lifelonglearning