[Congressional Record (Bound Edition), Volume 158 (2012), Part 13]
[Senate]
[Pages 18060-18081]
[From the U.S. Government Publishing Office, www.gpo.gov]




                           THE S.S.``BADGER''

  Mr. DURBIN. Mr. President, Chicagoans were asked in a recent poll to 
identify the one asset in the city of Chicago that meant the most to 
them. The overwhelming vote was for Lake Michigan--not surprising.
  Lake Michigan is the primary source of drinking water for more than 
10 million people--not just in my State of Illinois but in Wisconsin, 
Indiana, and Michigan. It supports a multibillion-dollar fishing 
industry that is important to local economies. And it is beautiful. It 
is a recreational asset for swimming, kayaking, boating, or just taking 
a walk along the beach. It is a gorgeous lake.
  I always look forward to getting up to Chicago. We have a condo that 
overlooks Lake Michigan that I consider to be a great place to sit and 
just look at this beautiful lake and what happens on it, whether I am 
drinking a cup of coffee in the morning with my wife or a glass of wine 
in the evening.
  But, unfortunately, the health of our great Lake Michigan is 
threatened every summer when a coal-burning ferry boat dumps tons of 
coal ash into the lake every day, all summer long.
  Meet the S.S. Badger. Many people have fond memories of this boat, 
the S.S. Badger, steaming from its homeport of Ludington, MI, to 
Manitowac,

[[Page 18061]]

WI, every summer. But they need to be reminded of one thing: The S.S. 
Badger is the last coal-fired ferry in the United States, and there is 
a reason it is the last one.
  Every year, based on the estimates given to us by the company, this 
boat dumps 600-plus tons of coal ash into Lake Michigan--600-plus tons 
every year since 1953. That is their record. What does that do to Lake 
Michigan? In the 59 years the S.S. Badger has been in operation, it has 
discharged a conservative estimate of 35,400 tons of coal ash into Lake 
Michigan. That is enough to coat the entire floor of Lake Michigan with 
a layer of ash 2\1/2\ inches thick.
  A recent article in the Chicago Tribune did a comparison of the 
amount of coal ash discharged from the Badger to the dry cargo residue 
discharged by all other vessels operating on Lake Michigan. Here is 
what they found:
  Fifty U.S. ships and 70 Canadian ships on Lake Michigan are 
responsible for a combined total of 89 tons of solid waste dumped every 
year. That is 120 ships, 89 tons in a year. The Badger by itself is 
responsible for almost 6 times more waste than these 120 vessel 
combined, even when using the most conservative estimate of what the 
Badger dumps overboard during the course of a summer.
  Yesterday the EPA vessel general permit that has enabled the coal-
fired car ferry S.S. Badger to discharge coal ash into Lake Michigan 
expired. The owner of the Badger insists that the coal ash is basically 
just sand. We know better.
  Scientists are concerned about coal ash because it contains such 
things as arsenic, lead, and mercury. Once in the lake, these chemicals 
enter the food chain through the water we drink and the fish we eat, 
and then they accumulate in our bodies and are associated with cancer 
and reproductive and neurological damage. We know how dangerous mercury 
contamination in fish is to human health.
  Well, it is time for the S.S. Badger to stop adding to the problem 
and either clean up its operation or close it down. If the Badger's 
owners had only recently realized that dumping coal ash was a problem, 
it might be OK to cut them some slack. But the Badger's owners have a 
long history of avoiding the steps needed to clean up their act.
  Most other vessels of the Great Lakes converted from coal to diesel 
fuel before the Badger made its first voyage. In 2008, when conversion 
to a new fuel was way overdue, the Bush administration granted the 
ferry a waiver to continue dumping coal ash through 2012. That was 5 
years too many of toxic dumping by this boat, but to make matters 
worse, the Badger's owners still have not made any reasonable efforts 
to stop dumping coal ash in the lake.
  Now they are attempting to persuade the EPA to give them just 5 more 
years to take a look at this problem. After I came out in opposition to 
this 5-year extension, the Badger's owner asked to meet me in my 
office. I, of course, agreed. He said he was applying for an EPA permit 
to continue dumping coal ash while he looks for ways to convert the 
Badger to run on liquefied natural gas. He wanted to make the Badger, 
he said, the greenest vessel on the Great Lakes. What a great idea, I 
thought. But it turns out it isn't even close to being realistic.
  Today there are few suppliers of liquefied natural gas in the area. 
There are no shipyards in the United States that are qualified to 
convert passenger vessels to run on liquefied natural gas. And it would 
take close to $50 million just to develop the infrastructure on the 
land needed to transport fuel to the dock for the Badger.
  One day, all the boats on Great Lakes might be powered by natural 
gas, but that isn't a realistic plan right now or within the next few 
years. It is just another delaying tactic from the owners of the S.S. 
Badger. These owners were given a deadline to convert the ship's fuel 
or dispose of the ash in a responsible way 5 years ago. The Badger has 
blatantly avoided complying with these EPA regulations.
  There has been an effort in the House of Representatives to provide a 
special exemption for this filthy boat on Lake Michigan forever. They 
want them declared some sort of a national historic monument or 
something and say that it shouldn't be governed by environmental 
regulations.
  These are Congressmen whose districts are on Lake Michigan. I have to 
ask them, what do you think about the lake and its future, when this 
boat is responsible for six times the solid waste of all the other 
ships that use Lake Michigan in commerce on an annual basis? Six times. 
That to me is a horrible thing to continue.
  They have had plenty of time to clean up their act and they failed. 
Now we have to get serious. I am hoping the EPA decides very quickly 
that it is time to end the coal-fired ferry tradition of the S.S. 
Badger. This is a vessel that generates and dumps 5 tons of coal ash 
laced with mercury, lead, and arsenic into Lake Michigan every single 
day. This great lake cannot take any more toxic dumping, no matter how 
historic or quaint the source may be.
  Mr. HARKIN. Mr. President, I ask unanimous consent that, pursuant to 
Public Law 112-144, the Food and Drug Administration Safety and 
Innovation Act, the following letters from the Secretary of Health and 
Human Services to the Chairman of the Committee on Health, Education, 
Labor, and Pensions of the Senate and the Chairman of the Committee on 
Energy and Commerce of the House of Representatives be printed into the 
Record.
  There being no objection, the material was ordered to be printed in 
the Record, as follows:

                 MDUFA Performance Goals and Procedures

       The performance goals and procedures agreed to by the 
     Center for Devices and Radiological Health (CDRH) and the 
     Center for Biologics Evaluation and Research (CBER) of the 
     United States Food and Drug Administration (``FDA'' or ``the 
     Agency'') for the medical device user fee program in the 
     Medical Device User Fee Amendments of 2012, are summarized 
     below.
       FDA and the industry are committed to protecting and 
     promoting public health by providing timely access to safe 
     and effective medical devices. Nothing in this letter 
     precludes the Agency from protecting the public health by 
     exercising its authority to provide a reasonable assurance of 
     the safety and effectiveness of medical devices. Both FDA and 
     the industry are committed to the spirit and intent of the 
     goals described in this letter.


                        I. Process Improvements

     A. Pre-Submissions
       FDA will institute a structured process for managing Pre-
     Submissions. Pre-Submissions subject to this process are 
     defined in Section VIII, Definitions and Explanations of 
     Terms. The Agency will continue to improve the Pre-Submission 
     process as resources permit, but not to the detriment of 
     meeting the quantitative review timelines and statutory 
     obligations. FDA will issue a draft guidance document and 
     final guidance document on Pre-Submissions.
       Upon receipt of a Pre-Submission that requests feedback 
     through a meeting or teleconference, FDA intends to schedule 
     the meeting or teleconference to occur within a timely 
     manner. In the Pre-Submission, the applicant will provide at 
     least three suggested dates and times when the applicant is 
     available to meet.
       It is FDA's intent that within 14 calendar days of receipt 
     of a request for a meeting or teleconference, FDA will 
     determine if the request meets the definition of a Pre-
     Submission, and will inform the applicant if it does not meet 
     the definition. FDA will also determine if the request 
     necessitates more than one meeting or teleconference. A 
     determination that the request does not meet the definition 
     of a Pre-Submission will require the concurrence of the 
     branch chief and the reason for this determination will be 
     provided to the applicant. If the request meets the 
     definition of a Pre-Submission, FDA and the applicant will 
     set a mutually agreeable time and date for the meeting.
       At least 3 business days prior to the meeting, FDA will 
     provide initial feedback to the applicant by email, which 
     will include: written responses to the applicant's questions; 
     FDA's suggestions for additional topics for the meeting or 
     teleconference, if applicable; or, a combination of both. If 
     all of the applicant's questions are addressed through 
     written responses, to the applicant's satisfaction, FDA and 
     the applicant can agree that a meeting or teleconference is 
     no longer necessary and the written responses provided by 
     email will be considered the final written feedback to the 
     Pre-Submission.
       Meetings and teleconferences related to Pre-Submission will 
     generally be limited to 1 hour. A longer meeting or 
     teleconference time can be scheduled by mutual agreement by 
     the applicant and FDA.
       Applicants will be responsible for developing draft minutes 
     for a Pre-Submission

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     meeting or teleconference, and provide the draft minutes via 
     email to FDA within 15 calendar days of the meeting. The 
     minutes will summarize the meeting discussions and include 
     agreements and any action items. FDA will provide any edits 
     to the draft minutes to the applicant via email within a 
     timely manner. These minutes will become final 15 calendar 
     days after the applicant receives FDA's edits, unless the 
     applicant indicates that there is a disagreement with how a 
     significant issue or action item has been documented. In this 
     case, within a timely manner, the applicant and FDA will 
     conduct a teleconference to discuss that issue with FDA. At 
     the conclusion of that teleconference, within a timely manner 
     FDA will finalize the minutes either to reflect the 
     resolution of the issue or note that this issue remains a 
     point of disagreement.
       FDA intends that feedback the Agency provides in a Pre-
     Submission will not change, provided that the information 
     submitted in a future investigational device exemption (IDE) 
     or marketing application is consistent with that provided in 
     the Pre-Submission and that the data in the future submission 
     do not raise any important new issues materially affecting 
     safety or effectiveness. Modifications to FDA's feedback will 
     be limited to situations in which FDA concludes that the 
     feedback does not adequately address important new issues 
     materially relevant to a determination of safety or 
     effectiveness. Such a determination will be supported by the 
     appropriate management concurrence consistent with applicable 
     guidance and SOPs.
     B. Submission Acceptance Criteria
       To facilitate a more efficient and timely review process, 
     FDA will implement revised submission acceptance criteria. 
     The Agency will publish guidance outlining electronic copy of 
     submissions (e-Copy) and objective criteria for revised 
     ``refuse to accept/refuse to file'' checklists. FDA will 
     publish draft and final guidance prior to implementation.
     C. Interactive Review
       The Agency will continue to incorporate an interactive 
     review process to provide for, and encourage, informal 
     communication between FDA and applicants to facilitate timely 
     completion of the review process based on accurate and 
     complete information. Interactive review entails 
     responsibilities for both FDA and applicants. As described in 
     the guidance document, Interactive Review for Medical Device 
     Submissions: 510(k)s, Original [Premarket Approvals] PMAs, 
     PMA Supplements, Original BLAs, and BLA Supplements, both FDA 
     and industry believe that an interactive review process for 
     these types of premarket medical device submissions should 
     help facilitate timely completion of the review based on 
     accurate and complete information. Interactive review is 
     intended to facilitate the efficient and timely review and 
     evaluation by FDA of premarket submissions. The interactive 
     review process contemplates increased informal interaction 
     between FDA and applicants, including the exchange of 
     scientific and regulatory information.
     D. Guidance Document Development
       FDA will apply user fee revenues to supplement the 
     improvement of the process of developing, reviewing, 
     tracking, issuing, and updating guidance documents. The 
     Agency will continue to develop guidance documents and 
     improve the Guidance Development process as resources permit, 
     but not to the detriment of meeting the quantitative review 
     timelines and statutory obligations.
       FDA will update its website in a timely manner to reflect 
     the following:
       1. The Agency's review of previously published device 
     guidance documents, including the deletion of guidance 
     documents that no longer represent the Agency's 
     interpretation of, or policy on, a regulatory issue, and 
     notation of guidance documents that are under review by the 
     Agency;
       2. A list of prioritized device guidance documents (an ``A-
     list'') that the Agency intends to publish within 12 months 
     of the date this list is published each fiscal year; and
       3. A list of device guidance documents (a ``B-list'') that 
     the Agency intends to publish, as the Agency's guidance-
     development resources permit each fiscal year.
       The Agency will establish a process allowing stakeholders 
     an opportunity to:
       1. Provide meaningful comments and/or propose draft 
     language for proposed guidance topics in the ``A'' and ``B'' 
     lists.
       2. Provide suggestions for new or different guidance 
     documents; and
       3. Comment on the relative priority of topics for guidance.
     E. Third Party Review
       The Agency will continue to support the third party review 
     program and agrees to work with interested parties to 
     strengthen and improve the current program while also 
     establishing new procedures to improve transparency. The 
     Agency will continue to improve the third party review 
     program as resources permit, but not to the detriment of 
     meeting the quantitative review timelines and statutory 
     obligations.
     F. Patient Safety and Risk Tolerance
       FDA will fully implement final guidance on the factors to 
     consider when making benefit-risk determinations in medical 
     device premarket review. This guidance will focus on factors 
     to consider in the premarket review process, including 
     patient tolerance for risk, magnitude of the benefit, and the 
     availability of other treatments or diagnostic tests.
       Over the period of MDUFA III, FDA will meet with patient 
     groups to better understand and characterize the patient 
     perspective on disease severity or unmet medical need.
       In addition, FDA will increase its utilization of FDA's 
     Patient Representatives as Special Government Employee 
     consultants to CDRH to provide patients' views early in the 
     medical product development process and ensure those 
     perspectives are considered in regulatory discussions. 
     Applicable procedures governing conflicts of interest and 
     confidentiality of proprietary information will be utilized 
     for these consultations.
     G. Low Risk Medical Device Exemptions
       By the end of FY 2013, FDA will propose additional low risk 
     medical devices to exempt from premarket notification. Within 
     two years of such proposal, FDA intends to issue a final rule 
     exempting additional low risk medical devices from premarket 
     notification.
     H. Emerging Diagnostics
       FDA will work with industry to develop a transitional In 
     Vitro Diagnostics (IVD) approach for the regulation of 
     emerging diagnostics.


II. Review Performance Goals--Fiscal Years 2013 Through 2017 As Applied 
                           to Receipt Cohorts

       The overall objective of the review performance goals 
     stated herein is to assure more timely access to safe and 
     effective medical devices.
     A. Original Premarket Approval (PMA), Panel-Track 
         Supplements, and Premarket Report Applications
       The performance goals in this section apply to all Original 
     Premarket Approval, Panel-Track Supplements, and Premarket 
     Report Applications, including those that are accepted for 
     priority review (previously referred to as expedited).
       FDA will communicate with the applicant regarding whether 
     the application has been accepted for filing review within 15 
     calendar days of receipt of the application. This 
     communication consists of a fax, email, or other written 
     communication that (a) identifies the reviewer assigned to 
     the submission, and (b) acknowledges acceptance/rejection of 
     the submission based upon the review of the submission 
     against objective acceptance criteria outlined in a published 
     guidance document.
       If the application is not accepted for filing review, FDA 
     will notify the applicant of those items necessary for the 
     application to be considered accepted for filing review.
       For those applications that are accepted for filing review, 
     FDA will communicate the filing status within 45 calendar 
     days of receipt of the application.
       For those applications that are not filed, FDA will 
     communicate to the applicant the specific reasons for 
     rejection and the information necessary for filing.
       If the application is filed, FDA will communicate with the 
     applicant through a Substantive Interaction within 90 
     calendar days of the filing date of the application for: 65% 
     of submissions received in FY 2013; 75% of submissions 
     received in FY 2014; 85% of submissions received in FY 2015; 
     and 95% of submissions received in FY 2016 through FY 2017.
       When FDA issues a major deficiency letter, that letter will 
     be based upon a complete review of the application and will 
     include all deficiencies. Any subsequent deficiencies will be 
     limited to issues raised by the information provided by the 
     applicant in its response, unless FDA concludes that the 
     initial deficiencies identified do not adequately address 
     important new issues materially relevant to a determination 
     of safety or effectiveness. Such a determination will be 
     supported by the appropriate management concurrence 
     consistent with applicable guidance and SOPs. Issues related 
     to post-approval studies, if applicable, and revisions to 
     draft labeling will typically be addressed through 
     interactive review once major deficiencies have been 
     adequately addressed.
       For submissions that do not require Advisory Committee 
     input, FDA will issue a MDUFA decision within 180 FDA Days 
     for: 70% of submissions received in FY 2013; 80% of 
     submissions received in FY 2014 and FY 2015; and 90% of 
     submissions received in FY 2016 and FY 2017.
       For submissions that require Advisory Committee input, FDA 
     will issue a MDUFA decision within 320 FDA Days for: 50% of 
     submissions received in FY 2013; 70% of submissions received 
     in FY 2014; 80% of submissions received in FY 2015 and FY 
     2016; and 90% of submissions received in FY 2017.
       If in any one fiscal year, the number of submissions that 
     require Advisory Committee input is less than 10, then it is 
     acceptable to combine such submissions with the submissions 
     for the following year(s) in order to form a cohort of 10 or 
     more submissions, upon which the combined years' submissions 
     will be subject to the performance goal for the fiscal year 
     in question. If the number of submissions that require 
     Advisory Committee input is less than 10 for FY 2017, it is

[[Page 18063]]

     acceptable to combine such submissions with the submissions 
     in the prior year in order to form a cohort of 10 or more 
     submissions; in such cases, FDA will be held to the FY 2017 
     performance goal for the combined years' submissions.
       To facilitate an efficient review prior to the Substantive 
     Interaction, and to incentivize submission of a complete 
     application, submission of an unsolicited major amendment 
     prior to the Substantive Interaction extends the FDA Day 
     review clock by the number of FDA Days that have elapsed. 
     Submission of an unsolicited major amendment after the 
     Substantive Interaction extends the FDA Day goal by the 
     number of FDA Days equal to 75% of the difference between the 
     filing date and the date of receipt of the amendment.
       For all PMA submissions that do not reach a MDUFA decision 
     by 20 days after the applicable FDA Day goal, FDA will 
     provide written feedback to the applicant to be discussed in 
     a meeting or teleconference, including all outstanding issues 
     with the application preventing FDA from reaching a decision. 
     The information provided will reflect appropriate management 
     input and approval, and will include action items for FDA 
     and/or the applicant, as appropriate, with an estimated date 
     of completion for each party to complete their respective 
     tasks. Issues should be resolved through interactive review. 
     If all of the outstanding issues are adequately presented 
     through written correspondence, FDA and the applicant can 
     agree that a meeting or teleconference is not necessary.
       In addition, information about submissions that miss the 
     FDA Day goal will be provided as part of FDA's Performance 
     Reports, as described in Section VI.
     B. 180-Day PMA Supplements
       FDA will communicate with the applicant through a 
     Substantive Interaction within 90 calendar days of receipt of 
     the submission for: 65% of submissions received in FY 2013; 
     75% of submissions received in FY 2014; 85% of submissions 
     received in FY 2015; and 95% of submissions received in FY 
     2016 through FY 2017.
       FDA will issue a MDUFA decision within 180 FDA Days for: 
     85% of submissions received in FY 2013; 90% of submissions 
     received in FY 2014 and FY 2015; and 95% of submissions 
     received in FY 2016 through FY 2017.
     C. Real-Time PMA Supplements
       FDA will issue a MDUFA decision within 90 FDA Days for: 90% 
     of submissions received in FY 2013 and FY 2014; and 95% of 
     submissions received in FY 2015 through FY 2017.
     D. 510(k) Submissions
       FDA will communicate with the applicant regarding whether 
     the submission has been accepted for review within 15 
     calendar days of receipt of the submission. For those 
     submissions that are not accepted for review, FDA will notify 
     the applicant of those items necessary for the submission to 
     be considered accepted.
       This communication includes a fax, email, or other written 
     communication that a) identifies the reviewer assigned to the 
     submission, and b) acknowledges acceptance/rejection of the 
     submission based upon the review of the submission against 
     objective acceptance criteria outlined in a published 
     guidance document. This communication represents a 
     preliminary review of the submission and is not indicative of 
     deficiencies that may be identified later in the review 
     cycle.
       FDA will communicate with the applicant through a 
     Substantive Interaction within 60 calendar days of receipt of 
     the submission for: 65% of submissions received in FY 2013; 
     75% of submissions received in FY 2014; 85% of submissions 
     received in FY 2015; and 95% of submissions received in FY 
     2016 through FY 2017.
       Deficiencies identified in a Substantive Interaction, such 
     as a telephone/email hold or Additional Information Letter, 
     will be based upon a complete review of the submission and 
     will include all deficiencies. Any subsequent deficiencies 
     will be limited to issues raised by the information provided 
     by the applicant in its response, unless FDA concludes that 
     the initial deficiencies identified do not adequately address 
     important new issues materially relevant to a determination 
     of substantial equivalence. Such a determination will be 
     supported by the appropriate management concurrence 
     consistent with applicable guidance and SOPs.
       For submissions received in FY 2013, FDA will issue a MDUFA 
     decision for 91% of 510(k) submissions within 90 FDA Days.
       For submissions received in FY 2014, FDA will issue a MDUFA 
     decision for 93% of 510(k) submissions within 90 FDA Days.
       For submissions received in FY 2015 through FY 2017, FDA 
     will issue a MDUFA decision for 95% of 510(k) submissions 
     within 90 FDA Days.
       For all 510(k) submissions that do not reach a MDUFA 
     decision within 100 FDA Days, FDA will provide written 
     feedback to the applicant to be discussed in a meeting or 
     teleconference, including all outstanding issues with the 
     application preventing FDA from reaching a decision. The 
     information provided will reflect appropriate management 
     input and approval, and will include action items for FDA 
     and/or the applicant, as appropriate, with an estimated date 
     of completion for each party to complete their respective 
     tasks. Issues should be resolved through interactive review. 
     If all of the outstanding issues are adequately presented 
     through written correspondence, FDA and the applicant can 
     agree that a meeting or teleconference is not necessary.
       In addition, information about submissions that miss the 
     FDA Day goal will be provided as part of FDA's Performance 
     Reports, as described in Section VI.
     E. Clinical Laboratory Improvement Amendments (CLIA) Waiver 
         by Application
       FDA will engage in a Substantive Interaction with the 
     applicant within 90 days for 95% of the applications.
       During the pre-submission process, if the applicant informs 
     FDA that it plans to submit a dual submission (510(k) and 
     CLIA Waiver application), FDA will issue a decision for 90% 
     of such applications within 210 FDA days.
       For ``CLIA Waiver by application'' submissions FDA will 
     issue a MDUFA decision for 95% of the applications that do 
     not require Advisory Committee input within 180 FDA days.
       For ``CLIA Waiver by application'' submissions FDA will 
     issue a MDUFA decision for 95% of the applications that 
     require Advisory Committee input within 330 FDA days.
       To provide greater transparency, FDA will issue guidance 
     regarding review and management expectations throughout the 
     entire submission process.
     F. Original Biologics Licensing Applications (BLAs)
       FDA will review and act on standard original BLA 
     submissions within 10 months of receipt for 90% of 
     submissions.
       FDA will review and act on priority original BLA 
     submissions within 6 months of receipt for 90% of 
     submissions.
     G. BLA Efficacy Supplements
       FDA will review and act on standard BLA efficacy supplement 
     submissions within 10 months of receipt for 90% of 
     submissions.
       FDA will review and act on priority BLA efficacy supplement 
     submissions within 6 months of receipt for 90% of 
     submissions.
     H. Original BLA and BLA Efficacy Supplement Resubmissions
       FDA will review and act on Class 1 original BLA and BLA 
     efficacy supplement resubmissions within 2 months of receipt 
     for 90% of submissions.
       FDA will review and act on Class 2 original BLA and BLA 
     efficacy supplement resubmissions within 6 months of receipt 
     for 90% of submissions.
     I. BLA Manufacturing Supplements Requiring Prior Approval
       FDA will review and act on BLA manufacturing supplements 
     requiring prior approval within 4 months of receipt for 90% 
     of submissions.


                       III. Shared Outcome Goals

       The program and initiatives outlined in this document are 
     predicated on significant interaction between the Agency and 
     applicants. FDA and representatives of the medical device 
     industry agree that the process improvements outlined in this 
     letter, when implemented by all parties as intended, should 
     reduce the average Total Time to Decision for PMA 
     applications and 510(k) submissions, provided that the total 
     funding of the device review program adheres to the 
     assumptions underlying this agreement. FDA and applicants 
     share the responsibility for achieving this objective of 
     reducing the average Total Time to Decision, while 
     maintaining standards for safety and effectiveness. Success 
     of this program will require the cooperation and dedicated 
     efforts of FDA and applicants to reduce their respective 
     portions of the total time to decision.
       FDA will be reporting total time performance quarterly as 
     described in Section VI. FDA and industry will participate in 
     the independent assessment of progress toward this outcome, 
     as described in Section V above. As appropriate, key findings 
     and recommendations from this assessment will be implemented 
     by FDA.
     A. PMA
       Beginning in Fiscal Year 2013, FDA will report on an annual 
     basis the average Total Time to Decision as defined in 
     Section VIII.G for the three most recent closed receipt 
     cohorts. For submissions received beginning in Fiscal Year 
     2013, the average Total Time to Decision goal for FDA and 
     industry is 395 calendar days. For submissions received 
     beginning in Fiscal Year 2015, the average Total Time to 
     Decision goal for FDA and industry is 390 calendar days. For 
     submissions received beginning in Fiscal Year 2017, the 
     average Total Time to Decision goal for FDA and industry is 
     385 calendar days.
     B. 510(k)
       Beginning in Fiscal Year 2013, FDA will report on an annual 
     basis the average Total Time to Decision as defined in 
     Section VIII.G for the most recent closed receipt cohort. For 
     submissions received beginning in Fiscal Year 2013, the 
     average Total Time to Decision goal for FDA and industry is 
     135 calendar days. For submissions received beginning in FY 
     2015, the average Total Time to Decision goal for FDA and 
     industry is 130 calendar days. For submissions received 
     beginning in FY 2017, the average Total Time to Decision goal 
     for FDA and industry is 124 calendar days.

[[Page 18064]]




                           IV. Infrastructure

     A. Scientific and Regulatory Review Capacity
       The Agency will apply user fee revenues to reduce the ratio 
     of review staff to front line supervisors in the Pre-Market 
     review program and to enhance and supplement scientific 
     review capacity by hiring device application reviewers and 
     leveraging external experts needed to assist with the review 
     of device applications.
       The Agency will seek to obtain streamlined hiring authority 
     for all MDUFA-related positions prior to and during the MDUFA 
     III period.
       During MDUFA III, FDA will also work with industry to 
     benchmark best practices for retaining employees (both 
     financial and non-financial).
     B. Training
       Prior to the commencement of MDUFA III, CDRH will implement 
     its Reviewer Certification Program. FDA commits to holding a 
     minimum of two medical device Vendor Days each year.
       CDRH will apply user fee revenues to supplement the 
     following training programs:
       1) Management training for Branch Chiefs and Division 
     Directors.
       2) MDUFA III Training Program for all staff.
       3) Reviewer Certification Program for new CDRH reviewers. 
     FDA will publish the curriculum of this program and other 
     course offerings. FDA will consider comments from 
     stakeholders when making updates to courses and determining 
     course offerings.
       4) Specialized training to provide continuous learning for 
     all staff.
     C. Tracking System
       FDA will continue efforts to improve its IT systems with a 
     future expectation of facilitating availability of real-time 
     status information for submissions.


         V. Independent Assessment of Review Process Management

       FDA and the device industry will participate in a 
     comprehensive assessment of the process for the review of 
     device applications. The assessment will include consultation 
     with both FDA and industry. The assessment shall be conducted 
     in two phases under contract to FDA by a private, independent 
     consulting firm capable of performing the technical analysis, 
     management assessment, and program evaluation tasks required 
     to address the assessment scope described below. For Phase 1, 
     FDA will award the contract no later than the end of the 
     second quarter of FY13. Findings on high-priority 
     recommendations (i.e., those likely to have a significant 
     impact on review times) will be published within six months 
     of award; final comprehensive findings and recommendations 
     will be published within 1 year of contract award. FDA will 
     publish an implementation plan within 6 months of receipt of 
     each set of recommendations. For Phase 2 of the independent 
     assessment, the contractor will evaluate the implementation 
     of recommendations and publish a written assessment no later 
     than February 1, 2016.
       The assessment will address FDA's premarket review process 
     using an assessment framework that draws from appropriate 
     quality system standards, including, but not limited to, 
     management responsibility, document controls and records 
     management, and corrective and preventive action.
       The scope of the assessment will include, but not be 
     limited to, the following areas:
       1. Identification of process improvements and best 
     practices for conducting predictable, efficient, and 
     consistent premarket reviews that meet regulatory review 
     standards.
       2. Analysis of elements of the review process (including 
     the Pre-Submission process, IDE, 510(k) and PMA reviews) that 
     consume or save time to facilitate a more efficient process. 
     This includes analysis of root causes for inefficiencies that 
     may affect review performance and total time to decision. 
     This will also include recommended actions to correct any 
     failures to meet MDUFA goals. Analysis of the review process 
     will include the impact of combination products, companion 
     diagnostics products, and laboratory developed tests on the 
     review process.
       3. Assessment of FDA methods and controls for collecting 
     and reporting information on premarket review process 
     resource use and performance.
       4. Assessment of effectiveness of FDA's Reviewer Training 
     Program implementation.
       5. Recommendations for ongoing periodic assessments and any 
     additional, more detailed or focused assessments.
       FDA will incorporate findings and recommendations, as 
     appropriate, into its management of the premarket review 
     program. FDA will analyze the recommendations for improvement 
     opportunities identified in the assessment, develop and 
     implement a corrective action plan, and assure its 
     effectiveness. FDA also will incorporate the results of the 
     assessment into a Good Review Management Practices (GRMP) 
     guidance document. FDA's implementation of the GRMP guidance 
     will include initial and ongoing training of FDA staff, and 
     periodic audits of compliance with the guidance.


                        VI. Performance Reports

       The Agency will report its progress toward meeting the 
     goals described in this letter, as follows. If, throughout 
     the course of MDUFA III, the Agency and Industry agree that a 
     different format or different metrics would be more useful, 
     the reporting will be modified accordingly as per the 
     agreement of both FDA and Industry.
       1. Quarterly reporting at the CDRH Division level/CBER 
     Center level (in recognition of the significantly smaller 
     number of submissions reviewed at CBER):
       1.1. For 510(k) submissions, reporting will include:
       i. Average and quintiles of the number of calendar days to 
     Substantive Interaction
       ii. Average, and quintiles of the number of FDA Days, 
     Industry Days, and Total Days to a MDUFA decision
       iii. Average number of review cycles.
       iv. Rate of submissions not accepted for review
       1.2. For PMA submissions, reporting will include:
       i. Average and quintiles of the number of calendar days to 
     Substantive Interaction for Original PMA, Panel-Track PMA 
     Supplement, and Premarket Report Submissions
       ii. Average and quintiles of the of FDA Days, Industry 
     Days, and Total Days to a MDUFA decision
       iii. Rate of applications not accepted for filing review, 
     and rate of applications not filed
       1.3. For Pre-Submissions, reporting will include:
       i. Number of all qualified Pre-Submissions received
       ii. Average and quintiles of the number of calendar days 
     from submission to meeting or teleconference (if necessary)
       iii. Number of Pre-Submissions that require a meeting
       1.4. For IDE applications, reporting will include:
       i. Number of original IDEs received
       ii. Average number of amendments prior to approval or 
     conditional approval of the IDE (this information will be 
     provided beginning no later than the quarter that starts 10/
     1/2013)
       2. CDRH will report quarterly, and CBER will report 
     annually, the following data at the Center level:
       2.1. Rate of NSE decisions for 510(k) submissions
       2.2. Rate of withdrawals for 510(k) and PMA submissions
       2.3. Rate of Not Approvable decisions for PMA submissions
       2.4. Key product areas or other issues that FDA identifies 
     as noteworthy because of a potential effect on performance, 
     including significant rates of Additional Information 
     requests
       2.5. Specific topic or product area as it relates to 
     performance goals, agreed upon at the previous meeting
       2.6. Number of submissions that missed the goals and the 
     total number of elapsed calendar days broken down into FDA 
     days and industry days
       2.7. Newly released draft and final guidance documents, and 
     status of other priority guidance documents
       2.8. Agency level summary of fee collections
       2.9. Independent assessment implementation plan status
       2.10. Results of independent assessment and subsequent 
     periodic audits and progress toward implementation of the 
     recommendations and any corrective action
       2.11. Number of discretionary fee waivers or reductions 
     granted by type of submission
       3. In addition, the Agency will provide the following 
     information on an annual basis:
       3.1. Qualitative and quantitative update on how funding is 
     being used for the device review process, including the 
     percentage of review time devoted to direct review of 
     applications
       3.2. How funding is being used to enhance scientific review 
     capacity
       3.3. The number of Premarket Report Submissions received
       3.4. Summary information on training courses available to 
     CDRH and CBER employees, including new reviewers, regarding 
     device review and the percentage of applicable staff that 
     have successfully completed each such course. CDRH will 
     provide information concerning any revisions to the new 
     reviewer training program curriculum.
       3.5. Performance on the shared outcome goal for average 
     Total Time to decision
       3.6. For 510(k) submissions, reporting will include:
       i. Number of submissions reviewed by a Third Party
       ii. Number of Special Submissions
       iii. Number of Traditional Submissions
       iv. Average and number of days to Accept/Refuse to Accept
       v. Number of Abbreviated Submissions
       3.7. For PMA submissions, reporting will include the number 
     of the following types of PMA submissions received:
       i. Original PMAs
       ii. Priority PMAs
       iii. Premarket Reports
       iv. Panel-Track PMA Supplement
       v. PMA Modules
       vi. 180-Day PMA Supplements
       vii. Real-Time PMA Supplements
       3.8. For De Novo Classification Petitions, reporting will 
     include:
       i. Number of submissions received
       ii. Average number of calendar days to a MDUFA decision

[[Page 18065]]


       3.9. For CLIA waiver applications, reporting will include:
       i. Number of CLIA waiver applications received
       ii. Average and quintiles of the number of calendar days to 
     Substantive Interaction
       iii. Average and quintiles of the number of FDA Days, 
     Industry Days, and Total Days to a MDUFA decision and a 
     discussion of any trends in the data


                       VII. Discretionary Waiver

       The Agency will seek authority to grant discretionary fee 
     waivers or reductions in the interest of public health. 
     Notwithstanding any fee waivers or reductions granted by the 
     Agency under this discretionary authority, FDA remains 
     committed to meeting the goals described in this letter. Any 
     submission subject to a fee waiver or reduction under this 
     discretionary authority shall not be subject to the goals 
     specified in this letter and shall be reviewed by the Agency 
     as resources permit. This discretionary authority will expire 
     at the end of MDUFA III.


              VIII. Definitions and Explanations of Terms

     A. Applicant
       Applicant means a person who makes any of the following 
     submissions to FDA: an application for premarket approval 
     under section 515; a premarket notification under section 
     510(k); an application for investigational device exemption 
     under section 520(g); a Pre-Submission; a CLIA waiver 
     application.
     B. Electronic Copy (e-Copy)
       An electronic copy is an exact duplicate of a paper 
     submission, created and submitted on a CD, DVD, or in another 
     electronic media format that FDA has agreed to accept, 
     accompanied by a copy of the signed cover letter and the 
     complete original paper submission. An electronic copy is not 
     considered to be an electronic submission.
     C. FDA Days
       FDA Days are those calendar days when a submission is 
     considered to be under review at the Agency for submissions 
     that have been accepted (510(k)) or filed (PMA). FDA Days 
     begin on the date of receipt of the submission or of the 
     amendment to the submission that enables the submission to be 
     accepted (510(k)) or filed (PMA).
     D. MDUFA Decisions
       Original PMAs: Decisions for Original PMAs are Approval, 
     Approvable, Approvable Pending GMP Inspection, Not 
     Approvable, Withdrawal, and Denial.
       180-Day PMA Supplements: Decisions for 180-Day PMA 
     Supplements include Approval, Approvable, and Not Approvable.
       Real-Time PMA Supplements: Decisions for Real-Time PMA 
     supplements include Approval, Approvable, and not Approvable.
       510(k)s: Decisions for 510(k)s are substantially equivalent 
     (SE) or not substantially equivalent (NSE).
       Submissions placed on Application Integrity Program Hold 
     will be removed from the MDUFA cohort.
     E. Pre-Submission
       A Pre-Submission includes a formal written request from an 
     applicant for feedback from FDA which is provided in the form 
     of a formal written response or, if the manufacturer chooses, 
     a meeting or teleconference in which the feedback is 
     documented in meeting minutes. A Pre-Submission meeting is a 
     meeting or teleconference in which FDA provides its 
     substantive feedback on the Pre-Submission.
       A Pre-Submission provides the opportunity for an applicant 
     to obtain FDA feedback prior to intended submission of an 
     investigational device exemption or marketing application. 
     The request must include specific questions regarding review 
     issues relevant to a planned IDE or marketing application 
     (e.g., questions regarding pre-clinical and clinical testing 
     protocols or data requirements). A Pre-Submission is 
     appropriate when FDA's feedback on specific questions is 
     necessary to guide product development and/or application 
     preparation.
       The following forms of FDA feedback to applicants are not 
     considered Pre-Submissions. However, if the requested 
     feedback meets the criteria for a Pre-Submission, outlined 
     above, FDA will contact the sponsor, and with the concurrence 
     of the sponsor, may convert the request to a Pre-Submission.
       General information requests initiated through the Division 
     of Small Manufacturers, International and Consumer Assistance 
     (DSMICA)
       General questions regarding FDA policy or procedures
       Meetings or teleconferences that are intended to be 
     informational only, including, but not limited to, those 
     intended to educate the review team on new device(s) with 
     significant differences in technology from currently 
     available devices, or to update FDA about ongoing or future 
     product development, without a request for FDA feedback on 
     specific questions related to a planned submission
       Requests for clarification on technical guidance documents, 
     especially where contact is recommended by FDA in the 
     guidance document. However, the following requests will 
     generally need to be submitted as a Pre-Submission in order 
     to ensure appropriate input from multiple reviewers and 
     management: recommendations for device types not specifically 
     addressed in the guidance document; recommendations for 
     nonclinical or clinical studies not addressed in the guidance 
     document; requests to use an alternative means to address 
     recommendations specified in a guidance document.
       Phone calls or email messages to reviewers that can be 
     readily answered based on a reviewer's experience and 
     knowledge and do not require the involvement of a broader 
     number of FDA staff beyond the routine involvement of the 
     reviewer's supervisor and more experienced mentors.
       Interactions requested by either the applicant or FDA 
     during the review of a marketing application (i.e., following 
     submission of a marketing application, but prior to reaching 
     an FDA Decision).
     F. Substantive Interaction
       Substantive Interaction is an email, letter, 
     teleconference, video conference, fax, or other form of 
     communication such as a request for Additional Information or 
     Major Deficiency letters by FDA notifying the applicant of 
     substantive deficiencies identified in initial submission 
     review, or a communication stating that FDA has not 
     identified any deficiencies in the initial submission review 
     and any further minor deficiencies will be communicated 
     through interactive review. An approval or clearance letter 
     issued prior to the Substantive Interaction goal date will 
     qualify as a Substantive Interaction.
       If substantive issues warranting issuance of an Additional 
     Information or Major Deficiency letter are not identified, 
     interactive review should be used to resolve any minor issues 
     and facilitate an FDA decision. In addition, interactive 
     review will be used, where, in FDA's estimation, it leads to 
     a more efficient review process during the initial review 
     cycle (i.e., prior to a Substantive Interaction) to resolve 
     minor issues such as revisions to administrative items (e.g., 
     510(k) Summary/Statement, Indications for Use statement, 
     environmental impact assessment, financial disclosure 
     statements); a more detailed device description; omitted 
     engineering drawings; revisions to labeling; or clarification 
     regarding nonclinical or clinical study methods or data.
       Minor issues may still be included in an Additional 
     Information or Major Deficiency letter where related to the 
     resolution of the substantive issues (e.g., modification of 
     the proposed Indications for Use may lead to revisions in 
     labeling and administrative items), or if they were still 
     unresolved following interactive review attempts. Both 
     interactive review and Substantive Interactions will occur on 
     the review clock except upon the issuance of an Additional 
     Information or Major Deficiency Letter which stops the review 
     clock.
     G. Total Time to Decision
       Total Time to Decision is the number of calendar days from 
     the date of receipt of an accepted or filed submission to a 
     MDUFA decision.
       The average Total Time to Decision for 510(k) submissions 
     is calculated as the trimmed mean of Total Times to Decision 
     for 510(k) submissions within a closed cohort, excluding the 
     highest 2% and the lowest 2% of values. A cohort is closed 
     when 99% of the accepted submissions have reached a decision.
       The average Total Time to Decision for PMA applications is 
     calculated as the three-year rolling average of the annual 
     Total Times to Decision for applications (for example, for 
     FY2015, the average Total Time to Decision for PMA 
     applications would be the average of FY2013 through FY2015) 
     within a closed cohort, excluding the highest 5% and the 
     lowest 5% of values. A cohort is closed when 95% of the 
     applications have reached a decision.
     H. BLA-related Definitions
       Review and act on--the issuance of a complete action letter 
     after the complete review of a filed complete application. 
     The action letter, if it is not an approval, will set forth 
     in detail the specific deficiencies and, where appropriate, 
     the actions necessary to place the application in condition 
     for approval.
       Class 1 resubmitted applications--applications resubmitted 
     after a complete response letter that includes the following 
     items only (or combinations of these items):
       (a) Final printed labeling
       (b) Draft labeling
       (c) Safety updates submitted in the same format, including 
     tabulations, as the original safety submission with new data 
     and changes highlighted (except when large amounts of new 
     information including important new adverse experiences not 
     previously reported with the product are presented in the 
     resubmission)
       (d) Stability updates to support provisional or final 
     dating periods
       (e) Commitments to perform Phase 4 studies, including 
     proposals for such studies
       (f) Assay validation data
       (g) Final release testing on the last 1-2 lots used to 
     support approval
       (h) A minor reanalysis of data previously submitted to the 
     application (determined by the Agency as fitting the Class 1 
     category)
       (i) Other minor clarifying information (determined by the 
     Agency as fitting the Class 1 category)

[[Page 18066]]

       (j) Other specific items may be added later as the Agency 
     gains experience with the scheme and will be communicated via 
     guidance documents to industry
       Class 2 resubmitted applications--resubmissions that 
     include any other items, including any item that would 
     require presentation to an advisory committee

PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FOR FISCAL YEARS 
                           2013 THROUGH 2017

       The performance goals and procedures of the FDA Center for 
     Drug Evaluation and Research (CDER) and the Center for 
     Biologics Evaluation and Research (CBER), as agreed to under 
     the fifth authorization of the prescription drug user fee 
     program, are summarized below.
       Unless otherwise stated, goals apply to cohorts of each 
     fiscal year (FY).


                      I. REVIEW PERFORMANCE GOALS

     A. NDA/BLA Submissions and Resubmissions\1\
       Note: \1\Refer to Section II.A.4 for a description of the 
     review program for NME NDAs and original BLAs.
       1. Review and act on 90 percent of standard NME NDA and 
     original BLA submissions within 10 months of the 60 day 
     filing date.
       2. Review and act on 90 percent of priority NME NDA and 
     original BLA submissions within 6 months of the 60 day filing 
     date.
       3. Review and act on 90 percent of standard non-NME 
     original NDA submissions within 10 months of receipt.
       4. Review and act on 90 percent of priority non-NME 
     original NDA submissions within 6 months of receipt.
       5. Review and act on 90 percent of Class 1 resubmitted 
     original applications within 2 months of receipt.
       6. Review and act on 90 percent of Class 2 resubmitted 
     original applications within 6 months of receipt.
     B. Original Efficacy Supplements
       1. Review and act on 90 percent of standard efficacy 
     supplements within 10 months of receipt.
       2. Review and act on 90 percent of priority efficacy 
     supplement within 6 months of receipt.
     C. Resubmitted Efficacy Supplements
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements within 2 months of receipt.
       2. Review and act on 90 percent of Class 2 resubmitted 
     efficacy supplements within 6 months of receipt.
     D. Original Manufacturing Supplements
       1. Review and act on 90 percent of manufacturing 
     supplements requiring prior approval within 4 months of 
     receipt, and review and act on 90 percent of all other 
     manufacturing supplements within 6 months of receipt.
     E. These review goals are summarized in the following tables:

          ORIGINAL AND RESUBMITTED APPLICATIONS AND SUPPLEMENTS
------------------------------------------------------------------------
        Submission cohort              Standard            Priority
------------------------------------------------------------------------
NME NDAs and original BLAs......  90% in 10 months    90% in 6 months of
                                   of the 60 day       the 60 day filing
                                   filing date.        date
Non NME NDAs....................  90% in 10 months    90% in 6 months of
                                   of the receipt      the receipt date
                                   date.
Class 1 Resubmissions...........  90% in 2 months of  90% in 2 months of
                                   the receipt date.   the receipt date
Class 2 Resubmissions...........  90% in 6 months of  90% in 6 months of
                                   the receipt date.   the receipt date
Original Efficacy Supplements...  90% in 10 months    90% in 6 months of
                                   of the receipt      the receipt date
                                   date.
Class 1 Resubmitted Efficacy      90% in 2 months of  90% in 2 months of
 Supplements.                      the receipt date.   the receipt date
Class 2 Resubmitted Efficacy      90% in 6 months of  90% in 6 months of
 Supplements.                      the receipt date.   the receipt date
------------------------------------------------------------------------


------------------------------------------------------------------------
                                    Prior approval         All other
------------------------------------------------------------------------
Manufacturing Supplements.......  90% in 4 months of  90% in 6 months of
                                   the receipt date.   the receipt date
------------------------------------------------------------------------

    II. NEW MOLECULAR ENTITY NDA AND ORIGINAL BLA PERFORMANCE GOALS

     A. Program for Enhanced Review Transparency and Communication 
         for NME NDAs and Original BLAs
       To promote greater transparency and improve communication 
     between the FDA review team and the applicant, FDA will 
     establish a review model (hereafter referred to as ``the 
     Program'') that will apply to all New Molecular Entity New 
     Drug Applications (NME NDAs) and original Biologics License 
     Applications (BLAs), including applications that are 
     resubmitted following a Refuse-to-File action, received from 
     October 1, 2012, through September 30, 2017.\2\ The goal of 
     the Program is to improve the efficiency and effectiveness of 
     the first cycle review process and decrease the number of 
     review cycles necessary for approval, ensuring that patients 
     have timely access to safe, effective, and high quality new 
     drugs and biologics. The Program shall be evaluated by an 
     independent contractor with expertise in assessing the 
     quality and efficiency of biopharmaceutical development and 
     regulatory review programs. The parameters of the Program are 
     as follows:
       Note: \2\The decision as to whether the application is 
     included or excluded from the Program is distinct from FDA's 
     determination as to whether the drug product contains a ``new 
     chemical entity,'' as defined under 21 CFR 314.108(a). 
     Determinations regarding new chemical entity exclusivity are 
     made at the time of approval of an application.
       1. Pre-submission meeting: The applicant is strongly 
     encouraged to discuss the planned content of the application 
     with the appropriate FDA review division at a pre-NDA/BLA 
     meeting
       a) The pre-NDA/BLA meeting should be held sufficiently in 
     advance of the planned submission of the application to allow 
     for meaningful response to FDA feedback and should generally 
     occur not less than 2 months prior to the planned submission 
     of the application.
       b) At the pre-NDA/BLA meeting, the FDA and the applicant 
     will agree on the content of a complete application for the 
     proposed indication(s), including preliminary discussions on 
     the need for risk evaluation and mitigation strategies (REMS) 
     or other risk management actions. This meeting will be 
     attended by the FDA review team including appropriate senior 
     FDA staff. The agreement and discussions will be summarized 
     at the conclusion of the meeting and reflected in the FDA 
     meeting minutes.
       c) At the meeting, the FDA and the applicant may also reach 
     agreement on submission of a limited number of application 
     components not later than 30 calendar days after the 
     submission of the original application. These submissions 
     must be of a type that would not be expected to materially 
     impact the ability of the review team to begin its review. 
     Any such agreement that is reached on delayed submission of 
     application components will be summarized at the conclusion 
     of the meeting and reflected in the FDA meeting minutes.
       (1) Examples of application components that may be 
     appropriate for delayed submission include updated stability 
     data (e.g., 15-month data to update 12-month data submitted 
     with the original submission) or the final audited report of 
     a preclinical study (e.g., carcinogenicity) where the final 
     draft report is submitted with the original application.
       d) Major components of the application (e.g., 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.
       2. Original application submission: Applications are 
     expected to be complete, as agreed between the FDA review 
     team and the applicant at the pre-NDA/BLA meeting, at the 
     time of original submission of the application. If the 
     applicant does not have a pre-NDA/BLA meeting with FDA, and 
     no agreement exists between 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.
       a) All applications are expected to include a comprehensive 
     and readily located list of all clinical sites and 
     manufacturing facilities included or referenced in the 
     application.
       b) Any components of the application that FDA agreed at the 
     pre-submission meeting could be submitted after the original 
     application are expected to be received not later than 30 
     calendar days after receipt of the original application.
       c) 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.
       (1) 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 6 and 10 month review performance goals for 
     priority and standard applications, respectively, as 
     described in Section I.
       d) 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.
       (1) Review of unsolicited amendments, including those 
     submitted in response to an FDA communication of 
     deficiencies, will be handled in accordance with the guidance 
     ``Good Review Management Principles and

[[Page 18067]]

     Practices (GRMPs) for PDUFA Products.'' This guidance 
     includes the underlying principle that FDA will consider the 
     most efficient path toward completion of a comprehensive 
     review that addresses application deficiencies and leads 
     toward a first cycle approval when possible.
       3. Day 74 Letter: FDA will follow existing procedures and 
     performance goals (see Section III) regarding identification 
     and communication of filing review issues in the ``Day 74 
     letter.'' For applications subject to the Program, the 
     timeline for this communication will be within 74 calendar 
     days from the date of FDA receipt of the original submission. 
     The planned review timeline included in the Day 74 letter for 
     applications in the Program will include the planned date for 
     the internal mid-cycle review meeting. The letter will also 
     include preliminary plans on whether to hold an Advisory 
     Committee (AC) meeting to discuss the application.
       4. Review performance goals: For NME NDA and original BLA 
     submissions that are filed by FDA under the Program, the 
     PDUFA review clock will begin at the conclusion of the 60 
     calendar day filing review period that begins on the date of 
     FDA receipt of the original submission. The review 
     performance goals for these applications are as follows:
       a) Review and act on 90 percent of standard NME NDA and 
     original BLA submissions within 10 months of the 60 day 
     filing date.
       b) Review and act on 90 percent of priority NME NDA and 
     original BLA submissions within 6 months of the 60 day filing 
     date.
       5. Mid-Cycle communication: The FDA Regulatory Project 
     Manager (RPM), and other appropriate members of the FDA 
     review team (e.g., Cross Discipline Team Leader (CDTL)), will 
     call the applicant, generally within 2 weeks following the 
     Agency's internal mid-cycle review meeting, to provide the 
     applicant with an update on the status of the review of their 
     application. Scheduling of the internal mid-cycle review 
     meeting will be handled in accordance with the GRMP guidance. 
     The RPM will coordinate the specific date and time of the 
     telephone call with the applicant
       a) The update should 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 meeting, updates 
     regarding plans for the AC meeting (if an AC meeting is 
     anticipated), and other projected milestones dates for the 
     remainder of the review cycle.
       6. Discipline Review (DR) Letters: The FDA review team will 
     follow existing guidance on issuance of DR Letters.
       a) Since the application is expected to be complete at time 
     of submission, FDA intends to complete primary and secondary 
     discipline reviews of the application and issue DR letters in 
     advance of the planned late-cycle meeting. In cases where a 
     DR letter is not issued in advance of the planned late-cycle 
     meeting, substantive issues identified to date from that 
     discipline will be communicated in the brief memorandum 
     described in 7(b)(1).
       7. Late-Cycle meeting: For all applications included in the 
     review Program, a meeting will be held between the FDA review 
     team and the applicant to discuss the status of the review of 
     the application late in the review cycle.
       a) FDA representatives at the late-cycle meeting are 
     expected to include the signatory authority for the 
     application, review team members from appropriate 
     disciplines, and appropriate team leaders and/or supervisors 
     from disciplines for which substantive issues have been 
     identified in the review to date.
       b) For applications that will be discussed at an Advisory 
     Committee (AC) meeting, the late-cycle meeting will occur not 
     less than 12 calendar days before the date of the AC meeting. 
     FDA intends to convene AC meetings no later than 3 months 
     (standard review) or no later than 2 months (priority review) 
     prior to the PDUFA goal date.
       (1) The Agency briefing package for the late-cycle meeting 
     will consist of the Agency's background package for the AC 
     meeting, which will be sent to the applicant not less than 20 
     calendar days before the AC meeting, any discipline review 
     letters issued to date, current assessment of the need for 
     REMS or other risk management actions, and a brief memorandum 
     from the review team outlining substantive application issues 
     including potential questions and/or points for discussion 
     for the AC meeting. FDA intends to provide final questions 
     for the AC to the sponsor and the AC 2 calendar days in 
     advance of the AC meeting.
       c) For applications that will not be discussed at an AC 
     meeting, the late-cycle meeting will generally occur not 
     later than 3 months (standard review) or two months (priority 
     review) prior to the PDUFA goal date.
       (1) The Agency background package for the late-cycle 
     meeting, which will be sent to the applicant not less than 12 
     calendar days before the meeting, will consist of any 
     discipline review letters issued to date, current assessment 
     of the need for REMS or other risk management actions, and a 
     brief memorandum from the review team outlining substantive 
     application issues.
       d) Potential topics for discussion at the late-cycle 
     meeting include major deficiencies identified to date; issues 
     to be discussed at the AC meeting (if planned); current 
     assessment of the need for REMS or other risk management 
     actions; information requests from the review team to the 
     applicant; and additional data or analyses the applicant may 
     wish to submit.
       (1) With regard to submission of additional data or 
     analyses, the FDA review team and the applicant will discuss 
     whether such data will be reviewed by the Agency in the 
     current review cycle and, if so, whether the submission will 
     be considered a major amendment and trigger an extension of 
     the PDUFA goal date.
       8. Inspections: FDA's goal is to complete all GCP, GLP, and 
     GMP inspections for applications in the Program within 6 
     months of the date of original receipt for priority 
     applications and within 10 months of the date of original 
     receipt for standard applications. This will allow 2 months 
     at the end of the review cycle to attempt to address any 
     deficiencies identified by the inspections.
       9. Quality System: As part of a quality system approach to 
     managing review in the Program, FDA will implement a tracking 
     system that will document review team performance of the key 
     milestones for each of the applications reviewed under the 
     Program.
       a) These milestones include: conduct of pre-NDA/BLA meeting 
     and agreement on content of complete application; submission 
     of any components of the application within 30 calendar days 
     of original application submission (as per pre-NDA/BLA 
     meeting agreement); issuance of the 74-day letter; completion 
     of mid-cycle communication with sponsor; completion of 
     primary and secondary reviews; DR letters issued; exchange of 
     late cycle meeting package; and conduct of late-cycle 
     meeting.
       b) The process tracking information will support review 
     management, and inform the subsequent analysis to be 
     conducted by an independent third party (see below). The 
     performance information generated by the tracking system will 
     also be summarized and reported in the PDUFA annual 
     performance report.
     B. Assessment of the Program
       The Program described in Section IIA shall be evaluated by 
     an independent contractor with expertise in assessing the 
     quality and efficiency of biopharmaceutical development and 
     regulatory review programs. The statement of work for this 
     effort will be published for public comment prior to 
     beginning the assessment. The assessments will occur 
     continuously throughout the course of the Program. Metrics 
     for the assessments will include adherence by the applicant 
     and FDA to the current GRMP guidance, submission of a 
     complete application at the time of original submission, 
     number of unsolicited amendments submitted by the applicant, 
     timing and adequacy of Day 74 letters, mid-cycle 
     communications, provision of late-cycle meeting memorandum 
     outlining potential issues and questions for AC meeting 
     consideration and discipline review letters; specific 
     milestones of the Program as described in Section IIA; time 
     to approval; percentage of applications approved on the first 
     review cycle; and the percentage of application reviews 
     extended due to major amendments. Following issuance of an 
     FDA regulatory action at the completion of the first review 
     cycle, the independent contractor will assess the 
     completeness and thoroughness of the submitted application, 
     Day 74 letter, mid-cycle communication, discipline review 
     letters and late-cycle meeting. This assessment will include 
     interviews of the sponsor and members of the review team, as 
     appropriate.
       1. Interim Assessment: An interim assessment of the Program 
     will be published by March 31, 2015, for public comment. By 
     June 30, 2015, FDA will hold a public meeting during which 
     public stakeholders may present their views on the success of 
     the Program to date including: improving the efficiency and 
     effectiveness of the first cycle review process; decreasing 
     the number of review cycles ultimately necessary for new 
     drugs and biologics that are approved; and helping to ensure 
     that patients have timely access to safe, effective, and high 
     quality new drugs and biologics. During the public meeting, 
     FDA will discuss the findings of the interim assessment, 
     including anonymized aggregated feedback from sponsors and 
     FDA review teams resulting from independent contractor 
     interviews. FDA will also address any issues identified to 
     date including actions proposed to improve likelihood of 
     success for the program.
       2. Final Assessment: A final assessment of the Program will 
     be published by December 31, 2016, for public comment. FDA 
     will hold a public meeting by no later than March 30, 2017, 
     during which public stakeholders may present their views on 
     the success of the Program, including improving the 
     efficiency and effectiveness of the first cycle review 
     process and decreasing the number of review cycles ultimately 
     necessary for new drugs and biologics that are approved. 
     During the public meeting, FDA will discuss the findings of 
     the final assessment, including anonymized aggregated 
     feedback from sponsors and FDA review teams resulting from 
     independent

[[Page 18068]]

     contractor interviews and discuss any issues identified and 
     plans for addressing these issues.


                  III. FIRST CYCLE REVIEW PERFORMANCE

     A. Notification of Issues Identified during the Filing Review
       1. Performance Goal: For original NDA/BLA applications and 
     efficacy supplements, FDA will report substantive review 
     issues identified during the initial filing review to the 
     applicant by letter, teleconference, facsimile, secure e-
     mail, or other expedient means.
       2. The timeline for such communication will be within 74 
     calendar days from the date of FDA receipt of the original 
     submission.
       3. If no substantive review issues were identified during 
     the filing review, FDA will so notify the applicant.
       4. FDA's filing review represents a preliminary review of 
     the application and is not indicative of deficiencies that 
     may be identified later in the review cycle.
       5. FDA will notify the applicant of substantive review 
     issues prior to the goal date for 90% of applications.
     B. Notification of Planned Review Timelines
       1. Performance Goal: For original NDA/BLA applications and 
     efficacy supplements, FDA will inform the applicant of the 
     planned timeline for review of the application. The 
     information conveyed will include a target date for 
     communication of feedback from the review division to the 
     applicant regarding proposed labeling, postmarketing 
     requirements, and postmarketing commitments the Agency will 
     be requesting.
       2. The planned review timeline will be included with the 
     notification of issues identified during the filing review, 
     within 74 calendar days from the date of FDA receipt of the 
     original submission.
       3. The planned review timelines will be consistent with the 
     Guidance for Review Staff and Industry: Good Review 
     Management Principles and Practices for PDUFA Products 
     (GRMPs), taking into consideration the specific circumstances 
     surrounding the individual application.
       4. The planned review timeline will be based on the 
     application as submitted.
       5. FDA will inform the applicant of the planned review 
     timeline for 90% of all applications and efficacy 
     supplements.
       6. In the event FDA determines that significant 
     deficiencies in the application preclude discussion of 
     labeling, postmarketing requirements, or postmarketing 
     commitments by the target date identified in the planned 
     review timeline (e.g., failure to demonstrate efficacy, 
     significant safety concern(s), need for a new study(ies) or 
     extensive re-analyses of existing data before approval), FDA 
     will communicate this determination to the applicant in 
     accordance with GRMPs and no later than the target date. In 
     such cases the planned review timeline will be considered to 
     have been met. Communication of FDA's determination may occur 
     by letter, teleconference, facsimile, secure e-mail, or other 
     expedient means.
       7. To help expedite the development of drug and biologic 
     products, communication of the deficiencies identified in the 
     application will generally occur through issuance of a DR 
     letter(s) in advance of the planned target date for 
     initiation of discussions regarding labeling, postmarketing 
     requirements, and postmarketing commitments the Agency may 
     request.
       8. If the applicant submits a major amendment(s) (refer to 
     Section XVI.B for additional information on major amendments) 
     and the review division chooses to review such amendment(s) 
     during that review cycle, the planned review timeline 
     initially communicated will generally no longer be 
     applicable. Consistent with the underlying principles 
     articulated in the GRMP guidance, FDA's decision to extend 
     the review clock should, except in rare circumstances, be 
     limited to occasions where review of the new information 
     could address outstanding deficiencies in the application and 
     lead to approval in the current review cycle.
       If the review division determines that the major amendment 
     will result in an extension of the PDUFA review clock, the 
     review division will communicate to the applicant at the time 
     of the clock extension a new planned review timeline, 
     including a new review timeline for communication of feedback 
     on proposed labeling, postmarketing requirements, and any 
     postmarketing commitments the Agency may request.
       In the rare case where the review division determines that 
     the major amendment will not result in an extension of the 
     PDUFA review clock, the review division may choose to retain 
     the previously communicated planned review timeline or may 
     communicate a new planned review timeline to the applicant.
       The division will notify the applicant promptly of its 
     decision regarding review of the major amendment(s) and 
     whether the planned review timeline is still applicable.
       For original NME NDA and original BLA applications, the new 
     planned review timeline will include a new planned date for 
     the internal mid-cycle review meeting if appropriate 
     depending on when during the course of review the major 
     amendment(s) is accepted for review.
     C. Report on Review Timeline Performance
       1. FDA will report its performance in meeting the goals for 
     inclusion of a planned review timeline with the notification 
     of issues identified during the filing review in the annual 
     PDUFA performance report.
       2. FDA will report its performance in meeting the planned 
     review timeline for communication of labeling comments, 
     postmarketing requirements, and postmarketing commitment 
     requests in the annual PDUFA performance report. The report 
     will include the percentage of applications for which the 
     planned target dates for communication of labeling comments, 
     postmarketing requirements, and postmarketing commitment 
     requests were met. The report will also note how often the 
     planned review timeline was met based on communication of 
     labeling comments, postmarketing requirements, and 
     postmarketing commitment requests by the target date, and how 
     often such communication did not occur due to FDA's 
     determination that significant deficiencies in the 
     application precluded communication of labeling comments, 
     postmarketing requirements, and postmarketing commitment 
     requests at the time initially projected. Communication of 
     labeling comments, postmarketing requirements, and 
     postmarketing commitment requests, or communication of FDA's 
     determination that significant deficiencies preclude 
     initiation of such discussions that occurs within 7 calendar 
     days of the target date stated in the planned review timeline 
     will be considered to have met the target date. FDA will also 
     report the number of times that the review timelines were 
     inapplicable due to the Agency's decision to review an 
     unsolicited major amendment or a solicited major amendment 
     that did not result in an extension of the review clock 
     (unless the review division chose to retain the previously 
     communicated planned review timeline).


      IV. REVIEW OF PROPRIETARY NAMES TO REDUCE MEDICATION ERRORS

       To enhance patient safety, FDA will utilize user fees to 
     implement various measures to reduce medication errors 
     related to look-alike and sound-alike proprietary names and 
     such factors as unclear label abbreviations, acronyms, dose 
     designations, and error prone label and packaging design.
     A. Review Performance Goals--Drug/Biological Product 
         Proprietary Names
       1. Proprietary names submitted during IND phase (as early 
     as end-of-phase 2)
       a) Review 90% of proprietary name submissions filed within 
     180 days of receipt. Notify sponsor of tentative acceptance 
     or non-acceptance.
       b) If the proprietary name is found to be unacceptable, the 
     sponsor can request reconsideration by submitting a written 
     rebuttal with supporting data or request a meeting within 60 
     days to discuss the initial decision (meeting package 
     required).
       c) If the proprietary name is found to be unacceptable, the 
     above review performance goals also would apply to the 
     written request for reconsideration with supporting data or 
     the submission of a new proprietary name.
       d) A complete submission is required to begin the review 
     clock.
       2. Proprietary names submitted with NDA/BLA
       a) Review 90% of NDA/BLA proprietary name submissions filed 
     within 90 days of receipt. Notify sponsor of tentative 
     acceptance/non-acceptance.
       b) A supplemental review will be done meeting the above 
     review performance goals if the proprietary name has been 
     submitted previously (IND phase after end-of-phase 2) and has 
     received tentative acceptance.
       c) If the proprietary name is found to be unacceptable, the 
     sponsor can request reconsideration by submitting a written 
     rebuttal with supporting data or request a meeting within 60 
     days to discuss the initial decision (meeting package 
     required).
       d) If the proprietary name is found to be unacceptable, the 
     above review performance goals apply to the written request 
     for reconsideration with supporting data or the submission of 
     a new proprietary name.
       e) A complete submission is required to begin the review 
     clock.


                      V. MAJOR DISPUTE RESOLUTION

       A. Procedure: For procedural or scientific matters 
     involving the review of human drug applications and 
     supplements (as defined in PDUFA) that cannot be resolved at 
     the signatory authority level (including a request for 
     reconsideration by the signatory authority after reviewing 
     any materials that are planned to be forwarded with an appeal 
     to the next level), the response to appeals of decisions will 
     occur within 30 calendar days of the Center's receipt of the 
     written appeal.
       B. Performance goal: 90% of such answers are provided 
     within 30 calendar days of the Center's receipt of the 
     written appeal.
       C. Conditions:
       1. Sponsors should first try to resolve the procedural or 
     scientific issue at the signatory authority level. If it 
     cannot be resolved at that level, it should be appealed to 
     the next higher organizational level (with a copy to the 
     signatory authority) and then, if necessary, to the next 
     higher organizational level.
       2. Responses should be either verbal (followed by a written 
     confirmation within 14 calendar days of the verbal 
     notification) or

[[Page 18069]]

     written and should ordinarily be to either grant or deny the 
     appeal.
       3. If the decision is to deny the appeal, the response 
     should include reasons for the denial and any actions the 
     sponsor might take to persuade the Agency to reverse its 
     decision.
       4. In some cases, further data or further input from others 
     might be needed to reach a decision on the appeal. In these 
     cases, the ``response'' should be the plan for obtaining that 
     information (e.g., requesting further information from the 
     sponsor, scheduling a meeting with the sponsor, scheduling 
     the issue for discussion at the next scheduled available 
     advisory committee).
       5. In these cases, once the required information is 
     received by the Agency (including any advice from an advisory 
     committee), the person to whom the appeal was made, again has 
     30 calendar days from the receipt of the required information 
     in which to either deny or grant the appeal.
       6. Again, if the decision is to deny the appeal, the 
     response should include the reasons for the denial and any 
     actions the sponsor might take to persuade the Agency to 
     reverse its decision.
       7. N.B. If the Agency decides to present the issue to an 
     advisory committee and there are not 30 days before the next 
     scheduled advisory committee, the issue will be presented at 
     the following scheduled committee meeting to allow 
     conformance with advisory committee administrative 
     procedures.


                           VI. CLINICAL HOLDS

       A. Procedure: The Center should respond to a sponsor's 
     complete response to a clinical hold within 30 days of the 
     Agency's receipt of the submission of such sponsor response.
       B. Performance goal: 90% of such responses are provided 
     within 30 calendar days of the Agency's receipt of the 
     sponsor's response.


        VII. SPECIAL PROTOCOL QUESTION ASSESSMENT AND AGREEMENT

       A. Procedure: Upon specific request by a sponsor (including 
     specific questions that the sponsor desires to be answered), 
     the Agency will evaluate certain protocols and issues to 
     assess whether the design is adequate to meet scientific and 
     regulatory requirements identified by the sponsor.
       1. The sponsor should submit a limited number of specific 
     questions about the protocol design and scientific and 
     regulatory requirements for which the sponsor seeks agreement 
     (e.g., is the dose range in the carcinogenicity study 
     adequate, considering the intended clinical dosage; are the 
     clinical endpoints adequate to support a specific efficacy 
     claim).
       2. Within 45 days of Agency receipt of the protocol and 
     specific questions, the Agency will provide a written 
     response to the sponsor that includes a succinct assessment 
     of the protocol and answers to the questions posed by the 
     sponsor. If the Agency does not agree that the protocol 
     design, execution plans, and data analyses are adequate to 
     achieve the goals of the sponsor, the reasons for the 
     disagreement will be explained in the response.
       3. Protocols that qualify for this program include: 
     carcinogenicity protocols, stability protocols, and Phase 3 
     protocols for clinical trials that will form the primary 
     basis of an efficacy claim. For such Phase 3 protocols to 
     qualify for this comprehensive protocol assessment, the 
     sponsor must have had an end of Phase 2/pre-Phase 3 meeting 
     with the review division so that the division is aware of the 
     developmental context in which the protocol is being reviewed 
     and the questions being answered.
       4. N.B. For products that will be using Subpart E or 
     Subpart H development schemes, the Phase 3 protocols 
     mentioned in this paragraph should be construed to mean those 
     protocols for trials that will form the primary basis of an 
     efficacy claim no matter what phase of drug development in 
     which they happen to be conducted.
       5. If a protocol is reviewed under the process outlined 
     above and agreement with the Agency is reached on design, 
     execution, and analyses and if the results of the trial 
     conducted under the protocol substantiate the hypothesis of 
     the protocol, the Agency agrees that the data from the 
     protocol can be used as part of the primary basis for 
     approval of the product. The fundamental agreement here is 
     that having agreed to the design, execution, and analyses 
     proposed in protocols reviewed under this process, the Agency 
     will not later alter its perspective on the issues of design, 
     execution, or analyses unless public health concerns 
     unrecognized at the time of protocol assessment under this 
     process are evident.
       B. Performance goal: 90% of special protocols assessments 
     and agreement requests completed and returned to sponsor 
     within timeframes.
       C. Reporting: The Agency will track and report the number 
     of original special protocol assessments and resubmissions 
     per original special protocol assessment.


                     VIII. MEETING MANAGEMENT GOALS

     A. Responses to Meeting Requests
       1. Procedure: Within 14 calendar days of the Agency's 
     receipt of a request from industry for a formal Type A 
     meeting, or within 21 calendar days of the Agency's receipt 
     of a request from industry for a formal Type B or Type C 
     meeting (i.e., a scheduled face-to-face, teleconference, 
     videoconference, or written response), CBER and CDER should 
     notify the requester in writing (letter or fax) of the date, 
     time, and place for the meeting, as well as expected Center 
     participants. In the case of pre-IND and Type C meeting 
     requests, the sponsor may request a written response to its 
     questions rather than a face-to-face meeting, videoconference 
     or teleconference. In some cases, while the sponsor may 
     request a face-to-face pre-IND or Type C meeting, the Agency 
     may determine that a written response to the sponsor's 
     questions would be the most appropriate means for responding 
     to the meeting request. When it is determined that the 
     meeting request can be appropriately addressed through a 
     written response to questions, FDA shall notify the requester 
     of the date it intends to send the response.
       2. Performance Goal: FDA will provide this notification 
     within 14 days for 90% of Type A meeting requests and within 
     21 days for 90% of Type B and Type C meeting requests.
     B. Scheduling Meetings
       1. Procedure: The meeting date should reflect the next 
     available date on which all applicable Center personnel are 
     available to attend, consistent with the component's other 
     business; however, the meeting should be scheduled consistent 
     with the type of meeting requested. If the requested date for 
     any of these types of meetings is greater than 30, 60, or 75 
     calendar days (as appropriate) from the date the request is 
     received by the Agency, the meeting date should be within 14 
     calendar days of the requested date.
       a) Type A Meetings should occur within 30 calendar days of 
     the Agency receipt of the meeting request.
       b) Type B Meetings should occur within 60 calendar days of 
     the Agency receipt of the meeting request. In the case of a 
     written response for a pre-IND meeting, the response should 
     be transmitted by FDA within 60 calendar days of the Agency 
     receipt of the meeting request.
       c) Type C Meetings should occur within 75 calendar days of 
     the Agency receipt of the meeting request. In the case of a 
     written response, the response should be transmitted by FDA 
     within 75 calendar days of the Agency receipt of the meeting 
     request.
       2. Performance goal: 90% of meetings are held within the 
     timeframe, and 90% of written responses are sent within the 
     timeframe.
     C. Meeting Minutes
       1. Procedure: The Agency will prepare minutes which will be 
     available to the sponsor 30 calendar days after the meeting. 
     The minutes will clearly outline the important agreements, 
     disagreements, issues for further discussion, and action 
     items from the meeting in bulleted form and need not be in 
     great detail. Meeting minutes are not required if the Agency 
     transmits a written response for pre-IND or Type C meetings.
       2. Performance goal: 90% of minutes are issued within 30 
     calendar days of date of meeting.
     D. Conditions
       For a meeting to qualify for these performance goals:
       1. A written request (letter or fax) should be submitted to 
     the review division; and
       2. The letter should provide:
       a) A brief statement of the purpose of the meeting, and in 
     the case of pre-IND and Type C meetings, the sponsor's 
     proposal for either a face-to-face meeting or a written 
     response from the Agency;
       b) A listing of the specific objectives/outcomes the 
     requester expects from the meeting;
       c) A proposed agenda, including estimated times needed for 
     each agenda item;
       d) A listing of planned external attendees;
       e) A listing of requested participants/disciplines 
     representative(s) from the Center; and
       f) The approximate time that supporting documentation 
     (i.e., the ``backgrounder'') for the meeting will be sent to 
     the Center (i.e., ``x'' weeks prior to the meeting), but 
     should be received by the Center at the time of the meeting 
     request for Type A meetings and at least 1 month in advance 
     of the scheduled meeting for Type B and Type C meetings 
     (including those for which a written response will be 
     provided)
       3. The Agency concurs that the meeting will serve a useful 
     purpose (i.e., it is not premature or clearly unnecessary). 
     However, requests for a ``Type B'' meeting will be honored 
     except in the most unusual circumstances.
       4. In general, meetings regarding REMS or postmarketing 
     requirements that occur outside the context of the review of 
     a marketing application shall be classified as Type B 
     meetings.
       5. In general, a post-action meeting requested by the 
     sponsor within three months after an FDA regulatory action 
     other than an approval (i.e., issuance of a complete response 
     letter) shall be classified as a Type A meeting.
       6. FDA shall publish revised draft guidance on formal 
     meetings between FDA and sponsors no later than the end of FY 
     2013.
       Sponsors are encouraged to consult available FDA guidance 
     to obtain further information on recommended meeting 
     procedures.


    ix. enhancing regulatory science and expediting drug development

       To enhance communications between FDA and sponsors during 
     drug development and to

[[Page 18070]]

     meet the challenges of emerging science in the areas of 
     clinical trial endpoint assessment tools, biomarkers and 
     pharmacogenomics, meta-analysis, and development of drugs for 
     rare diseases, FDA will conduct the following activities:
     A. Promoting Innovation Through Enhanced Communication 
         Between FDA and Sponsors During Drug Development
       1. FDA's philosophy is that timely interactive 
     communication with sponsors during drug development is a core 
     Agency activity to help achieve the Agency's mission to 
     facilitate the conduct of efficient and effective drug 
     development programs, which can enhance public health by 
     making new safe and effective drugs available to the American 
     public in a timely manner.
       2. By the end of FY 2013, FDA will develop a dedicated drug 
     development communication and training staff within the 
     Office of New Drugs in CDER and augment the manufacturers 
     assistance staff in CBER, focused on enhancing communication 
     between FDA and sponsors during drug development.
       3. Within CDER, the drug development communication and 
     training staff will include (1) a dedicated liaison staff to 
     facilitate general and, in some cases, specific interactions 
     with sponsors and (2) a training staff for CDER staff 
     training and for communication of best practices to the 
     sponsor community.
       4. The liaison staff will be composed of individuals who 
     are experienced and knowledgeable about the drug review 
     process (and in some cases may be on detail from the review 
     divisions), interact regularly with the staff in review 
     divisions, and are skilled in facilitating communications 
     between applicants and FDA staff.
       5. The liaison staff will conduct a range of tasks 
     associated with enhancing communication between the review 
     team and sponsors including identification and dissemination 
     of best practices for enhanced communication, and development 
     of training programs for review staff. In addition, they will 
     work in collaboration with sponsor stakeholders to develop 
     training for sponsors and receive feedback on FDA's programs 
     regarding best practices for communication during drug 
     development (e.g., participation in workshops and other 
     meetings to communicate CDER's policy and practice to the 
     sponsor community and to receive feedback on recommended 
     improvements).
       6. The liaison staff will serve 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 will also serve as a 
     secondary point of communication within CDER for sponsors who 
     are encountering problems in communication with the review 
     team for their IND (e.g., in instances when they have not 
     received a response from the review team to a simple or 
     clarifying question or referral to the formal meeting 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.
       7. By the end of FY 2014, the OND drug development and 
     communication staff will provide training to all CDER staff 
     involved in review of INDs. The training will include:
       a) CDER's philosophy that timely interactive communication 
     with sponsors during drug development is a core activity to 
     help achieve our mission to facilitate the conduct of 
     efficient and effective drug development programs, which can 
     enhance public health by making new safe and effective drugs 
     available to the American public in a timely manner.
       b) Best practices for triage of sponsor requests for advice 
     from the review team and timely communication of responses to 
     simple and clarifying questions or referral of more complex 
     questions to the formal meeting process.
       c) Best practices for communication between the review team 
     and the sponsor including establishing clear expectations and 
     agreement on appropriate mechanisms (e.g., when 
     teleconferencing or secure email may be the most appropriate 
     means of communication) and frequency of such communications.
       d) The role of the OND liaison staff in facilitating 
     overall enhanced drug development communication between CDER 
     and the drug development sponsor community and the staff's 
     role in facilitating resolution of individual communication 
     requests that have not been handled successfully in a timely 
     manner by the review team, which is the primary interface 
     with the sponsor regarding the drug under development.
       8. By the end of the second quarter of FY 2015, FDA will 
     publish draft guidance for review staff and industry 
     describing best practices for communication between FDA and 
     IND sponsors during drug development. The guidance will 
     describe FDA's philosophy regarding timely interactive 
     communication with sponsors as a core activity, the scope of 
     appropriate interactions between the review team and the 
     sponsor, outline the types of advice that are appropriate for 
     sponsors to seek from FDA in pursuing their drug development 
     program, describe the general expectations for the timing of 
     FDA response to sponsor inquiries of simple and clarifying 
     questions or referral of more complex questions to the formal 
     meeting process, and describe best practices and 
     communication methods (including the value of person-to-
     person scientific dialogue) to facilitate interactions 
     between the FDA review team and the sponsor during drug 
     development. FDA will publish final guidance within 18 months 
     of the close of the comment period for the draft guidance.
     B. Advancing the Science of Meta-Analysis Methodologies
       1. Develop a dedicated review team with appropriate 
     expertise to evaluate different scientific methods and to 
     explore the practical application of scientific approaches 
     and best practices, including methodological limitations, for 
     the conduct of meta-analyses in the context of FDA's 
     regulatory review process.
       2. By the end of FY 2013, hold a public meeting engaging 
     stakeholders in discussing current and emerging scientific 
     approaches and methods for the conduct of meta-analyses, and 
     to facilitate stakeholder feedback and input regarding the 
     use of meta-analyses in the FDA's regulatory review process.
       3. Considering feedback and input received through the 
     public meeting, publish a draft guidance document for comment 
     describing FDA's intended approach to the use of meta-
     analyses in the FDA's regulatory review process by the end of 
     FY 2015. This guidance will promote a better understanding 
     and more consistency among Agency, industry, and other 
     stakeholders regarding meta-analyses and their role in 
     regulatory decisionmaking.
       4. Complete the final guidance describing FDA's intended 
     approach to the use of meta-analyses in the FDA's regulatory 
     review process (or revised draft guidance, if appropriate) 
     within 1.5 years of the close of the public comment period.
     C. Advancing the Use of Biomarkers and Pharmacogenomics
       1. Develop staff capacity to review submissions that 
     contain complex issues involving pharmacogenomics and 
     biomarkers. This additional staff capacity will be integrated 
     into the clinical review divisions and the clinical 
     pharmacology and statistical review disciplines to ensure 
     greater understanding of biomarker use in application review 
     and efficient incorporation of qualified biomarkers in the 
     review process.
       2. Provide training for FDA staff on approaches to 
     conducting a pharmacogenomics review of a new product 
     application. This training will focus on the following: 
     facilitation of a greater understanding of the challenges 
     that arise when using pharmacogenomic markers and other 
     biomarkers in a development program (including programs 
     involving companion diagnostics), development of approaches 
     to address these challenges, and promotion of consistency in 
     regulatory review through an understanding of best practices 
     in assessment of applications that use biomarkers in the drug 
     development program.
       3. By the end of FY 2013, hold a public meeting to discuss 
     the current status of biomarkers and pharmacogenomics and 
     potential strategies to facilitate scientific exchanges in 
     regulatory and non-regulatory contexts.
     D. Advancing Development of Patient-Reported Outcomes (PROs) 
         and Other Endpoint Assessment Tools
       1. Develop clinical and statistical staff capacity to more 
     efficiently and effectively respond to submissions that 
     involve PROs and other outcomes assessment tools. These staff 
     will advance the development of these tools by providing IND 
     and qualification consultations and through promoting best 
     practices for review and qualification of outcomes assessment 
     tools. The additional capacity includes staff who will focus 
     on review and qualification of endpoint assessment tools, 
     including IND consultations with sponsors, as well as staff 
     who will be integrated into the review divisions to 
     facilitate evaluation of these tools and improve familiarity 
     and understanding of assessment tools among review staff. 
     These activities will allow for greater understanding of 
     challenges that arise during development of outcomes 
     assessment tools, potential strategies to overcome these 
     challenges, and greater consistency in FDA's approach to 
     review, qualification, and usage of these tools as part of 
     the drug development process.
       2. By the end of FY 2014, hold a public meeting to discuss 
     FDA's qualification standards for drug development tools, new 
     measurement theory, and implications for multi-national 
     trials.
     E. Advancing Development of Drugs for Rare Diseases
       1. By the end of FY 2013, FDA will complete a staffing and 
     implementation plan for the CDER Rare Disease Program within 
     the Office of New Drugs and a CBER Rare Disease liaison 
     within the Office of Center Director.
       2. FDA will increase by five the staff of the CDER Rare 
     Disease Program and establish and fill the CBER Rare Disease 
     liaison position.
       3. On an ongoing basis, the staff in the Rare Disease 
     Programs of the two Centers will develop and disseminate 
     guidance and

[[Page 18071]]

     policy related to advancing and facilitating the development 
     of drugs and biologics for rare diseases, including improving 
     understanding among FDA reviewers of approaches to studying 
     such drugs; considering non-traditional clinical development 
     programs, study design, endpoints, and statistical analysis; 
     recognizing particular challenges with post-market studies; 
     and encouraging flexibility and scientific judgment, as 
     appropriate, on the part of reviewers when evaluating 
     investigational studies and marketing applications for drugs 
     for rare diseases. Rare Disease Program staff will also 
     engage in increased outreach to industry regarding 
     development of such drugs and to patient representatives and 
     organizations.
       4. By mid-FY 2014, FDA, through the Rare Disease Program, 
     will conduct a public meeting to discuss complex issues in 
     clinical trials for studying drugs for rare diseases, 
     including such questions as endpoint selection, use of 
     surrogate endpoints/Accelerated Approval, and clinical 
     significance of primary endpoints; reasonable safety 
     exposures; assessment of dose selection; and development of 
     patient-reported outcome instruments. Participants in the 
     discussion will include FDA staff, academic and clinical 
     experts, and industry experts. A summary from the meeting 
     will be made available publicly through the FDA website.
       5. By the end of FY 2015, FDA will develop and implement 
     staff training related to development, review, and approval 
     of drugs for rare diseases. The training will be provided to 
     all CDER and CBER review staff, and will be part of the 
     reviewer training core curriculum. Among the key purposes of 
     this training are to familiarize review staff with the 
     challenges associated with rare disease applications and 
     strategies to address these challenges; to promote best 
     practices for review and regulation of rare disease 
     applications; and to encourage flexibility and scientific 
     judgment among reviewers in the review and regulation of rare 
     disease applications. The training will also emphasize the 
     role of the Rare Disease Program staff as members of the 
     review team to help ensure consistency of scientific and 
     regulatory approaches across applications and review teams.
       6. By the end of FY 2016, FDA, through the Rare Disease 
     Program, will develop an evaluation tool to evaluate the 
     success of the activities of the Rare Disease Program, 
     including the reviewer training. Among potential measures of 
     success are the development of a system to track rare disease 
     applications from IND submission through the post-marketing 
     period, increased number of reviewers receiving rare disease-
     specific training, increased number of activities 
     contributing to regulatory and biomedical science for rare 
     disease drug development, and meeting of PDUFA goals for rare 
     disease applications.


   X. ENHANCING BENEFIT-RISK ASSESSMENT IN REGULATORY DECISIONMAKING

       A. FDA will develop a five-year plan to further develop and 
     implement a structured benefit/risk assessment in the new 
     drug approval process. FDA will publish its draft plan for 
     public comment by the end of the first quarter of FY 2013. 
     FDA will begin execution of the plan to implement the 
     benefit-risk framework across review divisions in the pre-and 
     post-market human drug review process by the end of the 
     fourth quarter of FY 2013, and the Agency will update the 
     plan as needed and post all updates on the FDA website.
       The plan will include:
       1. A description of FDA's intended approach to build on the 
     Agency's current efforts to integrate a structured benefit/
     risk framework throughout the lifecycle of human drug 
     development.
       2. A plan to conduct two public workshops on benefit-risk 
     considerations from the regulator's perspective that will 
     begin by the first quarter of FY 2014. The first workshop 
     will be primarily informational by focusing discussion on the 
     various frameworks and methods available and their 
     application to regulatory decision-making. The second 
     workshop will focus on the results and lessons learned in 
     implementing frameworks at regulatory agencies in the pre- 
     and post-market drug review process.
       3. An evaluation plan to ascertain the impact of the 
     benefit-risk framework in the human drug review process. The 
     evaluation will consider the utility of the framework in 
     facilitating decision-making and review team discussions 
     across disciplines, risk management plan decision-making, 
     training of new review staff, and communicating regulatory 
     decisions. In particular, the evaluation will consider the 
     degree to which the framework supports or facilitates 
     balanced consideration of benefits and risks, a more 
     consistent and systematic approach to discussion and 
     decision-making, and communication of benefits and risks.
       B. As appropriate, FDA will revise the CDER Clinical Review 
     Template, Office and Division Director Summary Memo 
     Templates, and corresponding Manuals of Policies and 
     Procedures (MaPP) [and equivalent documents in CBER] to 
     incorporate a structured benefit/risk assessment into the 
     human drug review process on a timeframe outlined in the 
     five-year plan described in (A).
       C. Over the period of PDUFA V, FDA will initiate a public 
     process to nominate a set of disease areas that could benefit 
     from a more systematic and expansive approach to obtaining 
     the patient perspective on disease severity or unmet medical 
     need. FDA will convene 4 meetings per year (CDER will host 17 
     meetings and CBER will host 3 meetings throughout PDUFA V) 
     with each meeting focused on a different disease area. These 
     meetings will include participation of FDA review divisions, 
     the relevant patient advocacy community, and other interested 
     stakeholders. After each meeting, FDA will publish the 
     meeting proceedings and a summary analysis of the input 
     received by FDA that is relevant to FDA's consideration of 
     disease severity and unmet medical need. This knowledge will 
     be used to more fully develop an understanding of the disease 
     severity and an assessment of the current state of the 
     treatment armamentarium which are both critical components of 
     FDA's current benefit-risk framework in regulatory decision-
     making and communication. After the first two meetings, FDA 
     will develop a proposal for how FDA will incorporate these 
     perspectives into the Agency's decision-making.
       In addition, FDA will increase its utilization of FDA's 
     Patient Representatives as Special Government Employee 
     consultants to CDER and CBER to provide patients' views early 
     in the medical product development process and ensure those 
     perspectives are considered in regulatory discussions.
       D. FDA will train review and management staff on the 
     revised templates and MaPPs described in (B) and fully 
     integrate structured benefit/risk assessment into the 
     regulatory review process by a date specified in the five-
     year plan.


    XI. ENHANCEMENT AND MODERNIZATION OF THE FDA DRUG SAFETY SYSTEM

       FDA will continue to use user fees to enhance and modernize 
     the current U.S. drug safety system, including adoption of 
     new scientific approaches, improving the utility of existing 
     tools for the detection, evaluation, prevention, and 
     mitigation of adverse events, and enhancing communication and 
     coordination between post-market and pre-market review staff. 
     Enhancements to the drug safety system will improve public 
     health by increasing patient protection while continuing to 
     enable access to needed medical products. User fees will 
     provide support for 1) enhancing risk evaluation and 
     mitigation strategies (REMS) by measuring their effectiveness 
     and evaluating with stakeholder input appropriate ways to 
     better integrate them into the existing and evolving 
     healthcare system, and 2) continued development and 
     implementation of the Sentinel System.
     A. Measure the Effectiveness of REMS and Standardize and 
         Better Integrate REMS into the Healthcare System
       FDA will use user fee funds to continue to develop 
     techniques to standardize REMS and with stakeholder input 
     seek to integrate them into the existing and evolving (e.g., 
     increasingly electronic) healthcare system.
       1. By the end of FY 2013, FDA will develop and issue 
     guidance on how to apply the statutory criteria to determine 
     whether a REMS is necessary to ensure that the benefits of a 
     drug outweigh the risks.
       2. By the end of FY 2013, FDA will hold one or more public 
     meetings to include the pharmaceutical industry, other 
     government healthcare providers, patient groups, and partners 
     from other sectors of the healthcare delivery system to 
     explore strategies to standardize REMS, where appropriate, 
     with the goal of reducing the burden of implementing REMS on 
     practitioners, patients, and others in various healthcare 
     settings. To move towards increased integration of REMS into 
     the healthcare delivery system, FDA will issue a report of 
     its findings by the first quarter of FY 2014 that will 
     identify at least one priority project in each of the 
     following areas including a workplan for project completion: 
     pharmacy systems, prescriber education, providing benefit/
     risk information to patients, and practice settings.
       3. By the end of FY 2013, FDA will initiate 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, including 
     methods for assessing the effect on patient access, 
     individual practitioners, and the overall burden on the 
     healthcare delivery system. FDA will issue guidance by the 
     end of FY 2014 on methodologies for assessing REMS. This 
     guidance should specifically address methodologies for 
     determining whether a specific REMS with elements to assure 
     safe use (ETASU) is: (i) commensurate with the specific 
     serious risk listed in the labeling of the drug and (ii) 
     considering the observed risk, not unduly burdensome on 
     patient access to the drug.
     B. Sentinel as a Tool for Evaluating Drug Safety Issues That 
         May Require Regulatory Action
       FDA will use user fee funds to conduct a series of 
     activities to determine the feasibility of using Sentinel to 
     evaluate drug safety issues that may require regulatory 
     action, e.g., labeling changes, PMRs, or PMCs. The activities 
     will be selected and designed to focus on issues that affect 
     classes of drugs or multiple products.
       1. By the end of FY 2013, FDA will hold or support public 
     meetings engaging stakeholders to discuss current and 
     emerging Sentinel projects and facilitate stakeholder

[[Page 18072]]

     feedback and input regarding Sentinel projects that would be 
     appropriate to meet the goals stated above.
       2. Informed by the feedback and input received through the 
     public meeting, in FY 2013 through FY 2017, FDA will fund 4-6 
     activities, which will include multiple product or class-
     specific studies or methodology development. These activities 
     will be specifically designed to further evaluate safety 
     signals that, in previous cases, have served as the basis for 
     regulatory action(s) or designed more broadly to help 
     determine the utility and validity of the Sentinel System to 
     evaluate other types of signals in population-based 
     databases. The following are examples of potential 
     activities:
       a) Expanding the active surveillance mechanisms begun for 
     the H1N1 pandemic to substitute for the information gathered 
     in large ad hoc, manufacturer-conducted studies
       b) Evaluating risk for class-wide adverse events (e.g., 
     cardiovascular events, suicidality)
       3. By the end of FY 2015, FDA will conduct (or fund by 
     contract) an interim assessment to evaluate the strengths, 
     limitations and the appropriate use of Sentinel for informing 
     regulatory actions (e.g., labeling changes, PMRs and PMCs) to 
     manage safety issues.
       4. By the end of FY 2017, FDA will conduct (or fund by 
     contract) an assessment to evaluate the strengths, 
     limitations, and the appropriate use of Sentinel for 
     informing regulatory actions (e.g., labeling changes, PMRs 
     and PMCs) to manage safety issues.
     C. Conduct and support activities designed to modernize the 
         process of pharmacovigilance
       1. Continued use of expanded database resources: A critical 
     part of the transformation of the drug safety program is 
     maximizing the usefulness of tools used for adverse event 
     signal detection and risk assessment. Use of data other than 
     passive spontaneous reports, including population-based 
     epidemiological data and other types of observational data 
     resources will continue to enhance FDA's capability to 
     conduct targeted post-marketing surveillance, evaluate class 
     effects of drugs, and potentially conduct signal detection 
     using data resources other than reports from the Adverse 
     Event Reporting System (AERS). FDA will continue training and 
     development of existing staff on the use of these resources, 
     and develop the information technology infrastructure needed 
     to support access and analysis of data from these resources.
     D. Information Systems and Infrastructure
       FDA will continue the Agency's efforts on the following 
     standards-based information systems to support how FDA 
     obtains and analyzes post-market drug safety data and manages 
     emerging drug safety information:
       1. Enhanced adverse event reporting system and surveillance 
     tools;
       2. IT infrastructure to support access and analyses of 
     externally-linked databases; and
       3. Workflow tracking system.


  XII. IMPROVING THE EFFICIENCY OF HUMAN DRUG REVIEW THROUGH REQUIRED 
     ELECTRONIC SUBMISSIONS AND STANDARDIZATION OF ELECTRONIC DRUG 
                            APPLICATION DATA

       A. To enhance the quality and efficiency of FDA's review of 
     NDAs, BLAs, and INDs, FDA shall consult with stakeholders, 
     including pharmaceutical manufacturers and other research 
     sponsors, to issue draft guidance on the standards and format 
     of electronic submission of applications by December 31, 
     2012.
       B. FDA will issue final guidance no later than 12 months 
     from the close of the public comment period on the draft 
     guidance. Such final guidance and any subsequent revisions to 
     the final guidance shall be binding on sponsors, applicants, 
     and manufacturers no earlier than twenty-four months after 
     issuance of the final guidance.
       C. Requirements for electronic submission shall be phased 
     in according to the following schedule:
       1. Twenty-four (24) months after publication of the final 
     guidance: All new original NDA and BLA submissions, all new 
     NDA and BLA efficacy supplements and amendments, all new NDA 
     and BLA labeling supplements and amendments, all new 
     manufacturing supplements and amendments, and all other new 
     NDA submissions.
       2. Thirty-six (36) months after publication of the final 
     guidance: All original commercial INDs and amendments, except 
     for submissions described in section 561 of the Federal Food, 
     Drug, and Cosmetic Act.
       D. Because of the significant investments required to 
     change regulatory submission and review software, initial FDA 
     guidance shall specify the format of electronic submission of 
     applications using eCTD version 3.2.2 unless, after notice 
     and an opportunity for stakeholder comment, FDA determines 
     that another version will provide for more efficient and 
     effective applicant submission or FDA review. In general, 
     when FDA revises final guidance requiring submission using a 
     new version of electronic standards or formats, FDA shall 
     also accept submissions using the previous version for no 
     less than twenty-four (24) months.
       E. Clinical Terminology Standards: Using a public process 
     that allows for stakeholder input, FDA shall develop 
     standardized clinical data terminology through open standards 
     development organizations (i.e., the Clinical Data 
     Interchange Standards Consortium (CDISC)) with the goal of 
     completing clinical data terminology and detailed 
     implementation guides by FY 2017.
       1. FDA shall develop a project plan for distinct 
     therapeutic indications, prioritizing clinical terminology 
     standards development within and across review divisions. FDA 
     shall publish a proposed project plan for stakeholder review 
     and comment by June 30, 2013. FDA shall update and publish 
     its project plan annually.
       F. Development of terminology standards for data other than 
     clinical data: To address FDA-identified nonclinical data 
     standards needs, FDA will request public input on the use of 
     relevant already-existing data standards and the involvement 
     of existing standards development organizations to develop 
     new standards or refine existing standards. FDA will obtain 
     this input via publication of a Federal Register notice that 
     specifies a 60-day comment period.
       G. FDA shall periodically publish final guidance specifying 
     the completed data standards, formats, and terminologies that 
     sponsors must use to submit data in applications. In the case 
     of standards for study data, new data standards and 
     terminology shall be applicable prospectively and only 
     required for studies that begin 12 months after issuance of 
     FDA's final guidance on the applicable data standards and 
     terminology.


     XIII. PROGRESS REPORTING FOR PDUFA V AND CONTINUING PDUFA IV 
                              INITIATIVES

       On an annual basis, FDA will report on its website the 
     progress in each of the PDUFA V initiatives described in 
     Sections IX, X, XI, and XII. The annual reports will include: 
     (a) descriptions of the hiring and placement of new staff and 
     use of PDUFA resources to support the new initiatives in 
     Sections IX, X, XI.A, XI.B, and XII, and (b) progress reports 
     on achieving metrics described in each of the sections. Each 
     report will be posted on the FDA website no later than 120 
     days after the end of the fiscal year. The staff resources 
     will support the new initiatives described in Sections IX, X, 
     XIA, XIB and XII and the related work associated with these 
     initiatives to ensure their success.


                   XIV. INFORMATION TECHNOLOGY GOALS

     A. Objective
       FDA is committed to achieve the long-term goal of improving 
     the exchange, review, and management of human drug and 
     biologic applications throughout the product life cycle 
     through strategic investments in automated, standards-based 
     information technology (IT).
     B. Communications and Technical Interactions
       1. FDA will periodically update and publish to the FDA 
     website a five-year plan for business process improvement 
     enabled by IT investments.
       a) The plan will frame the strategy for prioritizing IT-
     enabled business process change, enumerate the business 
     process improvements expected from each IT investment, and 
     convey a consistent series of milestones for each initiative 
     to track pace and progress.
       b) FDA will conduct an annual assessment of progress 
     against the plan and publish on the FDA website a summary of 
     the assessment within 3 months after the close of each fiscal 
     year.
       c) FDA will publish updates to the plan as FDA deems 
     appropriate. FDA will publish on the FDA web site draft 
     revisions to the plan; solicit comments from the public on 
     those draft revisions; and consider the public comments 
     before completing and publishing updates to the plan.
       2. The FDA and industry stakeholders will meet on a 
     quarterly basis to discuss prospective implementation of the 
     plan, progress toward the long term goal, potential impacts 
     that future activities may have on FDA or stakeholders, and 
     potential revisions to the plan.
     C. Metrics and Measures
       On an annual basis, FDA will measure and report progress 
     toward achievement of the objectives defined in Section 
     XIV.A. Measures will include but are not limited to:
       1. The number and percentage of IND, NDA, and BLA 
     submissions received in valid electronic format in compliance 
     with FDA standards, categorized by types of submissions. 
     Increasing the number and percentage of IND, NDA, and BLA 
     submissions received in valid electronic format is a goal 
     that is supported by the FDA and industry stakeholders. 
     Achievement of this goal requires the cooperation of 
     regulated industry. To support the assessment of this goal, 
     the following information will be tracked and reported:
       a) Total number of submissions categorized by type of 
     submission
       b) Total number of submissions in valid electronic format 
     in compliance with FDA standards
       c) Total number of submissions received through the secure 
     electronic single point of entry versus other methods
       d) Total number of submissions received substantially on 
     paper or non-standardized electronic format
       e) Total number of standards-based electronic submissions 
     that fail to comply with FDA electronic submission standards, 
     along with a distribution of these submission failures across 
     categories of failure or problem type

[[Page 18073]]


       2. Number and significance of IT technical specifications 
     or e-submission guidance implemented requiring industry to 
     change submission content that are not forecasted accurately 
     in the five year plan or those whose content has not been 
     available to industry at least twelve months prior to 
     required implementation.
       3. Spending on Center IT systems and IT systems that are 
     common across the organizational divisions participating in 
     the process for the review of human drug applications. This 
     includes systems development versus maintenance spending; 
     infrastructure support; a report of total PDUFA fee-funded 
     spending versus appropriations-funded spending; FDA 
     enterprise versus PDUFA-program specific support.


                XV. IMPROVING FDA PERFORMANCE MANAGEMENT

     A. The studies conducted under this initiative are intended 
         to foster:
       1. Development of programs to improve access to internal 
     and external expertise
       2. Reviewer development programs, particularly as they 
     relate to drug review processes
       3. Advancing science and use of information management 
     tools
       4. Improving both inter- and intra-Center consistency, 
     efficiency, and effectiveness
       5. Improved reporting of management objectives
       6. Increased accountability for use of user fee revenues
       7. Focused investments on improvements in the process of 
     drug review
       8. Improved communication between the FDA and industry
     B. Studies will include:
       1. Assessment by an independent contractor of the Program 
     for NME NDAs and original BLAs as described in Section IIB.
       2. Assessment of the impact of the benefit-risk framework 
     in the human drug review process as described in Section 
     X.A.3.
       3. Development of a tool to evaluate the success of the 
     activities of the Rare Disease Program as described in 
     Section IX.D.6.
       4. Assessment of the impact of electronic submissions and 
     data standards on the efficiency and other performance 
     attributes of the human drug review process beginning in FY 
     2015.
       5. Assessments by an independent accounting firm of the 
     review activity adjustment methodology, as described in 
     section 736(c)(2), by the end of the second quarter of FY 
     2013 and by the end of the fourth quarter of FY 2015 with 
     recommendations for changes, if warranted.


               XVI. DEFINITIONS AND EXPLANATION OF TERMS

       A. The term ``review and act on'' means the issuance of a 
     complete action letter after the complete review of a filed 
     complete application. The action letter, if it is not an 
     approval, will set forth in detail the specific deficiencies 
     and, where appropriate, the actions necessary to place the 
     application in condition for approval.
       B. Goal Date Extensions for Major Amendments
       1. A major amendment 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 months.
       2. A major amendment may include, for example, a major new 
     clinical safety/efficacy study report; major re-analysis of 
     previously submitted study(ies); submission of a REMS with 
     ETASU not included in the original application; or 
     significant amendment to a previously submitted REMS with 
     ETASU. Generally, changes to REMS that do not include ETASU 
     and minor changes to REMS with ETASU will not be considered 
     major amendments.
       3. A major amendment to a manufacturing supplement 
     submitted at any time during the review cycle may extend the 
     goal date by two months.
       4. Only one extension can be given per review cycle.
       5. Consistent with the underlying principles articulated in 
     the GRMP guidance, FDA's decision to extend the review clock 
     should, except in rare circumstances, be limited to occasions 
     where review of the new information could address outstanding 
     deficiencies in the application and lead to approval in the 
     current review cycle.
       C. A resubmitted original application is a complete 
     response to an action letter addressing all identified 
     deficiencies.
       D. Class 1 resubmitted applications are applications 
     resubmitted after a complete response letter (or a not 
     approvable or approvable letter) that include the following 
     items only (or combinations of these items):
       1. Final printed labeling
       2. Draft labeling
       3. Safety updates submitted in the same format, including 
     tabulations, as the original safety submission with new data 
     and changes highlighted (except when large amounts of new 
     information including important new adverse experiences not 
     previously reported with the product are presented in the 
     resubmission)
       4. Stability updates to support provisional or final dating 
     periods
       5. Commitments to perform Phase 4 studies, including 
     proposals for such studies
       6. Assay validation data
       7. Final release testing on the last 1-2 lots used to 
     support approval
       8. A minor reanalysis of data previously submitted to the 
     application
       9. Other minor clarifying information (determined by the 
     Agency as fitting the Class 1 category)
       10. Other specific items may be added later as the Agency 
     gains experience with the scheme and will be communicated via 
     guidance documents to industry
       E. Class 2 resubmissions are resubmissions that include any 
     other items, including any items that would require 
     presentation to an advisory committee.
       F. A Type A meeting is a meeting which is necessary for an 
     otherwise stalled drug development program to proceed (a 
     ``critical path'' meeting) or to address an important safety 
     issue.
       G. A Type B Meeting is a 1) pre-IND, 2) end of Phase 1 (for 
     Subpart E or Subpart H or similar products) or end of Phase 
     2/pre-Phase 3, or 3) a pre-NDA/BLA meeting. Each requestor 
     should usually only request 1 each of these Type B meetings 
     for each potential application (NDA/BLA) (or combination of 
     closely related products, i.e., same active ingredient but 
     different dosage forms being developed concurrently).
       H. A Type C meeting is any other type of meeting.
       I. The performance goals and procedures also apply to 
     original applications and supplements for human drugs 
     initially marketed on an over-the-counter (OTC) basis through 
     an NDA or switched from prescription to OTC status through an 
     NDA or supplement.
       J. IT-specific definitions (refer also to Section XIV)
       1. ``Program'' refers to the organizational resources, 
     procedures, and activities assigned to conduct ``the process 
     for the review of human drug applications,'' as defined in 
     the Prescription Drug User Fee Act.
       2. ``Standards-based'' means compliant with published 
     specifications that address terminology or information 
     exchange between the FDA and regulated parties or external 
     stakeholders, as adopted by the FDA or other agencies of the 
     federal government, and often based on the publications of 
     national or international Standards Development 
     Organizations.
       3. ``FDA Standards'' means technical specifications that 
     have been adopted and published by the FDA through the 
     appropriate governance process. FDA standards may apply to 
     terminology, information exchange, engineering or technology 
     specifications, or other technical matters related to 
     information systems. FDA standards often are based on the 
     publications of other federal agencies, or the publications 
     of national or international Standards Development 
     Organizations.
       4. ``Product life cycle'' means the sequential stages of 
     human drug development, regulatory review and approval, post-
     market surveillance and risk management, and where 
     applicable, withdrawal of an approved drug from the market. 
     In the context of the process for the review of human drug 
     applications, the product life cycle begins with the earliest 
     regulatory submissions in the Investigational New Drug (IND) 
     phase, continues through the New Drug Application (NDA) or 
     Biological Licensing Application (BLA) review phase, and 
     includes post-market surveillance and risk management 
     activities as covered under the process for the review of 
     human drug applications.

   Generic Drug User Fee Act Program Performance Goals and Procedures

       The performance efficiencies, metric goals and procedures 
     to which FDA will agree upon commencement of a generic drug 
     user fee act (GDUFA) program (``the program''), as jointly 
     proposed by FDA and industry, are summarized below.


          Overall Purpose of the Generic Drug User Fee Program

       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 risk-based approach, with foreign and 
     domestic parity.
       Access--Expedite the availability of low cost, high quality 
     generic drugs by bringing greater predictability to the 
     review times for 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.
       Recognizing the critical role generic drugs play in 
     providing more affordable, therapeutically equivalent 
     medicine, the Generic

[[Page 18074]]

     Drug User Fee program is designed to keep individual fee 
     amounts as low as possible to supplement appropriated funding 
     to ensure that consumers continue to receive the significant 
     benefits offered by generic drugs which provided more than 
     $824 billion in savings to the nation's health care system in 
     the last decade alone. The additional resources called for 
     under the agreement, an inflation adjusted $299 million 
     annually for each of the five years of the program, will 
     provide FDA with the ability to perform critical program 
     functions that could not otherwise occur. This program is not 
     expected to add significantly to the cost of generic drugs: 
     given that a reported 3.99 billion retail prescriptions per 
     year were dispensed in the United States in 2010, and 
     assuming that 78% of these prescriptions were filled by 
     generic drugs, it equates to less than a dime per 
     prescription for the average cost of a prescription filled by 
     a generic drug in the United States. Moreover, with the 
     adoption of user fees and the associated savings in 
     development time, the overall expense of bringing a product 
     to market may decline and result in reduced costs.
       In addition to the public health benefits outlined above, 
     the program described in this letter is expected to provide 
     significant value to small companies and first time entrants 
     in the generic market who will benefit significantly from the 
     certainty associated with performance review metrics that 
     offer the potential to dramatically reduce the time needed to 
     commercialize a generic drug when compared to pre-GDUFA 
     review times.
       In addition, the variety of funding sources for the program 
     will assure that participants in the generic drug industry, 
     whether finished dosage form (FDF) manufacturers or Active 
     Pharmaceutical Ingredient (API) manufacturers appropriately 
     share the financial expense and benefits of the program. 
     Given that the total amount of annual user fee funding is 
     expected to be derived from a broad funding source, including 
     an estimated 2000 FDF and API facilities supporting 
     Abbreviated New Drug Applications (ANDAs), as well as 
     approximately 750 ANDAs, 750 prior approval supplements 
     (PASs) and 350 Type II Active Pharmaceutical Drug Master 
     Files (DMFs) annually, user fees are expected to provide a 
     measurable return on investment related to predictability of 
     inspection, and review timelines. The program's goals of 
     ensuring FDA has necessary resources to conduct needed 
     inspections as part of the complete review framework and 
     achieve parity of Good Manufacturing Practice (GMP) 
     inspections for foreign and domestic facilities by the 5th 
     year of the user fee program will also provide significant 
     value to industry participants given that outstanding 
     inspections can result in delays of ANDA approvals.
       Taken collectively, the user fee program and associated 
     performance metrics and fees are expected to provide 
     measurable public health benefits and are not expected to 
     competitively disadvantage any company or business sector 
     regardless of size or location.


                               END NOTES

     1. Source: IMS Health Report--GPHA. Savings achieved through 
     the use of generic pharmaceuticals: 2000-2009, July 2010.
     2. Source: ``The Use of Medicines in the United States: 
     Review of 2010'', Report by the IMS Institute for Healthcare 
     Informatics, slide 8, available at http://www.imshealth.com/
deployedfiles/imshealth/
Global/Content/IMS%20Institute/Static%20File/
IHII_UseOfMe_d_report.pdf.
     3. Ibid., slide 22.

                              1. OVERVIEW


          Overall Program Scope, Assumptions, and Aspirations

       The goals to which FDA is committing for generic drugs are 
     premised on the following assumptions:
       I. Funding for the program from user fees will be at 
     agreed-upon levels of approximately $299 million annually 
     adjusted for inflation and will supplement appropriated 
     funding from Congress as described further below.
       II. It is estimated that FDA will receive the funding 
     through approximately 750 abbreviated new drug applications 
     (ANDAs) per year submitted electronically, approximately 750 
     prior approval supplements (PASs) approximately 350 newly 
     referenced drug master files (DMFs) per year and through 
     approximately 2000 facilities associated with ANDAs. While 
     the total revenue collected can be defined in advance and is 
     constant as the resourcing level must be constant, the 
     individual fee will be determined each year based on the 
     variability of the fee source.
       III. Over the five year course of the program, there will 
     be no significant changes in the generic drug facility 
     inventory, either in terms of general number of facilities, 
     or the foreign and domestic facility split.
       IV. FDA will have streamlined hiring authority for all 
     GDUFA-related positions prior to or concurrent with the 
     implementation date of the program.
       V. FDA expects the program will be implemented starting on 
     the first day of Fiscal Year 2013, October 1, 2012 and 
     continue for five years, with the joint expectation that the 
     program will be continued at the end of five years under 
     terms to be negotiated before the end of FY 2017.
       VI. Industry and FDA will populate and maintain databases 
     as necessary for facilities, fee assessments, efficiency and 
     other enhancements as described further below and as needed 
     to support the Generic Drug User Fee Act. Because certain 
     databases to implement this program will need to be built, 
     and existing systems need to be expanded or modified, 
     industry will submit necessary information in electronic 
     format to FDA using appropriate standards to be specified by 
     the agency or as specified in statute.
       VII. FDA will aspire to the extent possible to maintain 
     levels of productivity at least similar to pre-GDUFA levels, 
     while hiring and training incremental staff necessary to 
     achieve the program performance goals, building necessary 
     systems and implementing outlined program changes in years 1 
     and 2 of the program (see goals for years 3-5 metrics).
       VIII. FDA will utilize a complete review standard (as 
     defined below), will aspire to hold first cycle deficiency 
     teleconferences with industry to discuss complete response 
     questions at a level at least similar to pre-GDUFA levels in 
     years 1 and 2 of the program (see goals for years 3-5 
     metrics) and will utilize an approach similar to the NDA 
     review process whereby FDA uses telephone information 
     requests to address easily correctable deficiencies during 
     the review process before and after issuance of complete 
     response letters.
       IX. FDA will aspire to complete reviews for applications 
     with only minor administrative amendments pending prior to 
     the expiration date of the controlling patent or applicable 
     exclusivity date regardless of the amendment(s) goal date.
       X. FDA will work towards achieving performance goals to 
     reach parity of GMP inspections of foreign and domestic 
     establishments, will prioritize inspections using a risk-
     based approach, and will prioritize inspections of 
     establishments associated with ANDAs that are otherwise 
     approvable or eligible for tentative approval except for an 
     outstanding inspection, as well as establishments associated 
     with ANDAs that have not been inspected previously. In 
     appropriate circumstances FDA can rely on a routine 
     surveillance inspection in lieu of an application-specific 
     inspection. Generally, among other considerations, FDA relies 
     on a previous inspection of a finished product site occurring 
     within 2 years of the current good manufacturing practice 
     (CGMP) evaluation for a pending application, 3 years for an 
     active pharmaceutical ingredient (API) site or a control 
     testing laboratory, and 4 years for a packaging-only site. 
     There are exceptions to this general practice, which are 
     usually related to the nature of the drug being processed or 
     the complexity of the associated processing operations. FDA 
     intends to continue the practice of using a risk-based 
     assessment in determining the length of time since the last 
     inspection, guided by a 2-year cycle for finished dosage 
     product sites and a 3-year cycle for API sites and 
     consideration of the type of finished product or API in the 
     application. Practically, this means that in making decisions 
     about pending applications for which FDA does not have 
     current inspection information within the time period 
     indicated, FDA may use previous FDA inspection information 
     and/or use inspection information from another regulatory 
     authority as appropriate.
       XI. FDA will strive to review and act on all ANDAs that are 
     submitted on the first day that any valid Paragraph IV 
     application for the drug in question is submitted within 30 
     months of submission to avoid causing first applicants to 
     inadvertently forfeit 180-day exclusivity eligibility under 
     21 U.S.C. Sec. 355(j)(5)(D)(i)(IV).
       XII. Because the agreed generic drug user fee program is 
     intended to be additive to budget appropriations, agreed upon 
     legislative language will require that annual program 
     appropriations from Congress must be equal to or exceed the 
     FDA appropriation for FY 2009.
       XIII. In order to generate the agreed upon levels of user 
     fee funding to achieve the enclosed performance goals, 
     metrics and efficiencies, legislative language will require 
     that approximately 70% of GDUFA fees shall be derived from 
     facility fees (for facilities producing or pending review to 
     produce active pharmaceutical ingredients or finished dosage 
     forms for a generic drug application), approximately 30% of 
     GDUFA fees shall be derived from application fees (DMF Fees 
     and ANDA and PAS (Prior Approval Supplement) Fees). As 
     discussed and agreed by the various industry business 
     segments, overall fees will be divided 80 percent to 20 
     percent between the finished dosage form (FDF) and API and 
     manufacturers, respectively in industry. In the first year of 
     the program, $50 million of the total GDUFA user fee funding 
     shall be generated by a one time backlog fee for ANDAs 
     pending (except for ANDAs that are pending but have received 
     tentative approval) on October 1, 2012.
       XIV. For appeals of decisions concerning procedural or 
     scientific matter involving review of pending ANDAs, ANDA 
     amendments and ANDA supplements FDA will aspire that the 
     response to appeals of decisions will occur within 30 
     calendar days of OGD receipt of the written appeal when 
     possible, though no reportable performance goals are 
     required.

[[Page 18075]]

       Note: If these assumptions differ significantly from 
     actuality, FDA may not be able to achieve the goals and 
     efficiency enhancements outlined in this goals letter, 
     despite the supplemental funding provided by the program.


        Summary of Major Program Goals including Five Year Goals

       Major Program (including 5 year) goals can be summarized as 
     follows:
       Note that FDA agrees to additional 5 year goals, as set 
     forth later in this goals letter, such as goals on 
     amendments, controlled correspondence, and prior approval 
     supplements, as well as goals for years prior to year 5 of 
     the program. The goals summarized in this section are a 
     subset of the complete year 5 goals, and are intended simply 
     to illustrate the scope of the program.
       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.
       Efficiency Enhancements--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.
       Details follow.

2. EFFICIENCY ENHANCEMENTS TO BE UNDERTAKEN ON OCTOBER 1, 2012, OR UPON 
              ENACTMENT OF THE PROGRAM, WHICHEVER IS LATER


                 A. ANDA Review Efficiency Enhancements

       Starting on October 1, 2012 or upon enactment of the 
     program, whichever is later, FDA will issue complete response 
     letters, rather than discipline specific letters, for all 
     ANDAs, including those pending on October 1, 2012.
       Complete response letters will reflect full division-level 
     review of deficiencies from all relevant review disciplines, 
     including inspections, and address other matters relating to 
     the ANDA and associated DMFs as well as consults with other 
     agency components (these will be subsumed into the 
     application metrics).
       FDA reviewers will make every reasonable effort to 
     communicate promptly to applicants easily correctable 
     deficiencies found in the ANDA and will utilize an approach 
     similar to the NDA review process whereby FDA uses telephone 
     information requests to address easily correctable 
     deficiencies during the review process before and after 
     issuance of complete response letters.
       When requested by the ANDA sponsor within 10 business days 
     of FDA issuing a first cycle complete response letter, as 
     provided by the sponsor in a written request that outlines 
     specific written questions the applicant would like to 
     discuss (limited to the content of the letter), FDA will 
     schedule a 30 minute teleconference to clarify issues and 
     answer questions. Priority for such teleconferences will be 
     given to expedited and first major amendment applications. 
     Although FDA will begin to develop procedures and tracking 
     systems for such teleconferences coincident with the start of 
     the program, there will be no teleconference goals for the 
     first two years of the program although FDA will aspire to 
     conduct such teleconferences as requested when reportable 
     performance goals are not otherwise required. In the first 
     two years, FY 2013 and FY 2014, FDA would aspire to hold 
     teleconferences with industry to address complete response 
     questions at a level similar to pre-GDUFA levels. 
     Subsequently, the goals for number of reportable 
     teleconferences (although FDA may conduct more such 
     teleconferences) will be:
       Closing out the teleconference request for 200 meetings in 
     FY 2015;
       Closing out the teleconference request for 250 meetings in 
     FY 2016;
       Closing out the teleconference request for 300 meetings in 
     FY 2017.
       FDA will develop enhanced refusal to receive standards for 
     ANDAs and other related submissions by the end of year 1 of 
     the program and will publish such standards in advance of 
     implementation.
       For ANDAs in the year 1 and 2 cohorts, FDA will expedite 
     review of Paragraph IV applications that are submitted on the 
     first day that any valid Paragraph IV application for the 
     drug in question is submitted. Expedited review will be 
     implemented consistent with existing procedure for expediting 
     applications as set forth in CDER's MAPP 5240.3, and will 
     also include those applications that become eligible for 
     approval during the review period as a result of no blocking 
     exclusivities, patent(s) and/or applicable stays based on 
     appropriate documentation submitted.
       Review metric goals (described below) only apply to 
     submissions made electronically, following the eCTD format in 
     effect at the date of submission.
       Backlog review metric goals (described below) apply to all 
     ANDA applications, amendments, and supplements regardless of 
     current review status in the queue as of October 1, 2012, 
     regardless of whether they were submitted in paper, 
     electronic, or hybrid format.


        B. Drug Master File (DMF) Review Efficiency Enhancements

       After the program's implementation date, upon payment of 
     the DMF fee by DMF holders anticipating reference by a 
     generic drug manufacturer, FDA will conduct a completeness 
     assessment of Type II API DMFs. Following a satisfactory 
     completeness assessment, FDA will deem the DMF available for 
     reference, placing the DMF number in a publicly available 
     list of Type II API DMFs available for reference.
       Review metric goals (described below) will only apply to 
     Type II API DMFs submitted after the program's implementation 
     date, if they are submitted electronically. Electronic DMFs 
     will follow the eCTD format in effect at date of submission.
       FDA will issue a letter detailing all identified 
     deficiencies, rather than discipline specific letters, for 
     all DMFs including those under review at the time of 
     enactment of the implementing legislation.
       The DMF deficiency letters will reflect full division-level 
     deficiency review of deficiencies from all relevant review 
     disciplines, including inspections, and address other matters 
     relating to the DMF review such as consults with other agency 
     components (these will be subsumed into the DMF metrics).
       FDA reviewers will make every reasonable effort to 
     communicate promptly to applicants easily correctable 
     deficiencies found in the DMF and will continue to utilize an 
     approach similar to the NDA review process whereby FDA uses 
     telephone information requests to address easily correctable 
     deficiencies during the review process before and after 
     issuance of complete response letters.
       When requested by a DMF holder within 10 business days of 
     FDA issuing a first cycle DMF deficiency letter, as provided 
     by the DMF holder in a written request that outlines specific 
     written questions the DMF holder would like to discuss 
     (limited to the content of the letter), FDA will schedule a 
     30 minute teleconference with a limit of one teleconference 
     per DMF holder per month, with the total number of 
     teleconferences not to exceed the number of teleconferences 
     for ANDAs, a teleconference to clarify issues and answer 
     questions. Priority for such teleconferences will be given to 
     DMFs referenced in expedited and first major deficiency 
     applications. Although FDA will begin to develop procedures 
     and tracking systems for such teleconferences coincident with 
     the start of the program, there will be no teleconference 
     goals for the first two years of the program although FDA 
     will aspire to conduct such teleconferences as requested when 
     reportable performance goals are not otherwise required. In 
     the first two years, FY 2013 and FY 2014, FDA would aspire to 
     hold teleconferences with industry to address DMF deficiency 
     questions at a level similar to pre-GDUFA levels (although 
     FDA may conduct more such teleconferences).
       Once a DMF has undergone a complete review and the ANDA 
     referencing same is either approved or tentatively approved--
     at such time there being no further outstanding deficiencies 
     to the DMF--FDA will issue the DMF holder a letter to 
     indicate that the DMF does not have any further open matters 
     as part of the review associated with the referencing ANDA.


                 C. Inspection Efficiency Enhancements

       To maximize the number of applications that can be reviewed 
     within the metric goals and to assist in securing the 
     pharmaceutical supply chain, FDA will employ a risk-adjusted 
     biennial CGMP surveillance inspection model for inspection of 
     generic API and FDF manufacturers, with the goal of achieving 
     parity of inspection frequency between foreign and domestic 
     establishments in FY 2017 and will prioritize inspections of 
     establishments associated with ANDAs that are otherwise 
     approvable or eligible for tentative approval except for an 
     outstanding inspection, as well as establishments that have 
     not been inspected previously.
       FDA will make inspection classification results and date of 
     the last facility inspection available to the public and 
     industry on FDA's website on timely basis.
       During the five years of the program, FDA will undertake a 
     study of foreign government regulator inspections (CGMP and 
     bioequivalence), report findings publicly, and develop a 
     program to utilize foreign inspection classifications when 
     and where appropriate.


                    D. Other Efficiency Enhancements

       FDA will develop new and/or enhance existing facility 
     databases (API and FDF manufacturing and clinical/ 
     bioequivalence site)

[[Page 18076]]

     to be populated by industry. These databases will, at a 
     minimum, contain information for generics-related firms, 
     including addresses and Data Universal Numbering System 
     (DUNS) numbers, and will link facilities to DMFs and ANDAs 
     and will contain other information as necessary.
       FDA will develop a current chemistry manufacturing and 
     controls (CMC) records database to aid in the efficiency of 
     review and inspection.
       FDA will develop and issue electronic data submission 
     standards.
       Because certain databases to implement this program will 
     need to be built, and existing systems need to be expanded or 
     modified, industry will submit necessary information in 
     electronic format to FDA using appropriate standards to be 
     specified by the agency or as specified in statute.

                   3. REGULATORY SCIENCE INITIATIVES


                            A. Working Group

       FDA will convene a working group and consider suggestions 
     from industry and other stakeholders to develop an annual 
     list of regulatory science initiatives for review by CDER 
     Director.


                            B. FY 2013 Plan

       The FY 2013 plan is appended.

                      4. METRIC GOALS/MEASUREMENTS


                       A. Human Resources Metrics

       FDA will hire and train at least 25 percent of incremental 
     staff in FY 2013, 50 percent in FY 2014 and will strive to 
     complete GDUFA-funded human resources hiring goals in FY 2015 
     as necessary to achieve the program's performance metrics and 
     goals.


  B. ANDA, ANDA Amendment, and ANDA Prior Approval Supplement Review 
              Metrics and DMF Reviews as Subsumed in Each

       ANDAs will be categorized according to cohort year.
       Once an ANDA is in a given year's cohort, dates of 
     submission of a subsequent amendment will not change the 
     cohort year. Regardless of the year in which an amendment is 
     submitted, any additional time periods to be added to the 
     base review period will be calculated using the time periods 
     corresponding to the original cohort year.
       Original (complete) ANDA Review (Certain amended 
     applications may have differing metrics as discussed below.)
       FDA will review and act on 60 percent of original ANDA 
     submissions within 15 months from the date of submission for 
     the year 3 cohort.
       FDA will review and act on 75 percent of original ANDA 
     submissions within 15 months from the date of submission for 
     the year 4 cohort.
       FDA will review and act on 90 percent of original ANDA 
     submissions within 10 months from the date of submission for 
     the year 5 cohort.
       For ANDAs in the year 1 and 2 cohorts, FDA will expedite 
     review of Paragraph IV applications that are submitted on the 
     first day that any valid Paragraph IV application for the 
     drug in question is submitted.
       Amendment Review
       All amendment metric goals are incremental, and the time 
     periods specified are calculated from the date of submission. 
     They will be added to the original review goal, but in no 
     case shall they shorten the original goal date. (In other 
     words, an amendment with a 6 month metric which was submitted 
     4 months prior to original goal date would add 2 months to 
     the review clock).
       An amendment pre Complete Response Letter adjusts the goal 
     date for the original application.
       Subsequent amendments pre Complete Response Letter also 
     adjust the goal date for the application and are additive.
       An amendment post Complete Response Letter sets a new goal 
     date for the application.
       Subsequent amendments post Complete Response Letter also 
     adjust the goal date for the application and are additive.
       Delaying amendments or amendments containing information 
     that FDA would otherwise ask for as a result of post ANDA 
     submission reference listed drug changes do not add to the 
     count of amendments.
       If any amendment contains multiple elements, the longest 
     goal date shall apply.
       Amendments shall be grouped as Tier 1, Tier 2 or Tier 3. 
     FDA agrees that unsolicited amendments that are submitted to 
     a pending ANDA that are neither Tier 1, Tier 2 or Tier 3 
     amendments, but rather are routine or administrative in 
     nature and do not require scientific review (e.g., requests 
     for final ANDA approval, patent amendments, general 
     correspondence, and USP monograph updates), will not lengthen 
     or impact the original review goal date.
       Tier 1 amendments include:
       All solicited first major and the first five minor 
     amendments.
       All unsolicited amendments indicated by sponsor and agreed 
     by FDA to be a result of either delaying actions as 
     determined by FDA's Office of Generic Drugs taking into 
     account the facts and information supplied by the ANDA 
     applicant or that otherwise would eventually be solicited.
       Tier 2 amendments include:
       All unsolicited amendments not arising from delaying 
     actions as determined by FDA's Office of Generic Drugs taking 
     into account the facts and information supplied by the ANDA 
     applicant excepting those amendments which only remove 
     information for review.
       Tier 3 amendments include:
       Any solicited major amendment subsequent to the first major 
     amendment.
       Any solicited minor amendment subsequent to the fifth minor 
     amendment.
       Tier 1 amendment goals:
       First major amendment
       FDA will review and act on 60 percent of first major 
     amendment submissions within 10 months from the date of 
     submission for the year 3 cohort.
       FDA will review and act on 75 percent of first major 
     amendment submissions within 10 months from the date of 
     submission for the year 4 cohort.
       FDA will review and act on 90 percent of first major 
     amendment submissions within 10 months from the date of 
     submission for the year 5 cohort.
       Minor amendments (first--third)
       FDA will review and act on 60 percent of first through 
     third minor amendment submissions within 3 months from the 
     date of submission for the year 3 cohort.
       FDA will review and act on 75 percent of first through 
     third minor amendment submissions within 3 months from the 
     date of submission for year 4 cohort.
       FDA will review and act on 90 percent of first through 
     third minor amendment submissions within 3 months from the 
     date of submission for the year 5 cohort.
       Minor amendments (fourth--fifth)
       FDA will review and act on 60 percent of fourth through 
     fifth minor amendment submissions within 6 months from the 
     date of submission for the year 3 cohort.
       FDA will review and act on 75 percent of fourth through 
     fifth minor amendment submissions within 6 months from the 
     date of submission for year 4 cohort.
       FDA will review and act on 90 percent of fourth through 
     fifth minor amendment submissions within 6 months from the 
     date of submission for the year 5 cohort.
       Except that if any Tier 1 amendment requires an inspection, 
     the goal shall be 10 months.
       Tier 2 amendment goals:
       FDA will review and act on 60 percent of amendment 
     submissions within 12 months from the date of submission for 
     the year 3 cohort.
       FDA will review and act on 75 percent of amendment 
     submissions within 12 months from the date of submission for 
     year 4 cohort.
       FDA will review and act on 90 percent of amendment 
     submissions within 12 months from the date of submission for 
     the year 5 cohort.
       Tier 3 amendment goals:
       There will be no GDUFA metrics for tier 3 amendments.
       Review of Complete Prior Approval Supplements (PASs) 
     (Certain amended PASs may have differing metrics as discussed 
     above in the Amendment Review section).
       FDA will review and act on 60 percent of PASs not requiring 
     inspection within 6 months from the date of submission for 
     receipts in FY 2015; FDA will review and act on 60 percent of 
     PASs requiring inspection within 10 months from the date of 
     submission for receipts in FY 2015.
       FDA will review and act on 75 percent of PASs not requiring 
     inspection within 6 months from the date of submission for 
     receipts in FY 2016; FDA will review and act on 75 percent of 
     PASs requiring inspection within 10 months from the date of 
     submission for receipts in FY 2016.
       FDA will review and act on 90 percent of PASs not requiring 
     inspection within 6 months from the date of submission for 
     receipts in FY 2017; FDA will review and act on 90 percent of 
     PASs requiring inspection within 10 months from the date of 
     submission for receipts in FY 2017.


                  C. Controlled Correspondence Metrics

       Controlled Correspondence
       FDA will respond to 70 percent of controlled correspondence 
     in 4 months from date of submission in FY 2015.
       FDA will respond to 70 percent of controlled correspondence 
     in 2 months from date of submission in FY 2016.
       FDA will respond 90 percent of controlled correspondence in 
     2 months from date of submission in FY 2017.
       If the controlled correspondence requires input from the 
     clinical division, one additional month will be added to the 
     goals outlined above.
       In the case of controlled correspondence which raises an 
     issue or question that is the same as or related to the issue 
     or question that is the subject of one or more pending 
     citizen petitions, or petitions for stay or reconsideration, 
     the above goals will apply from the date FDA issues responses 
     to the pending petitions.


                       D. 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.


                           E. Backlog metrics

       FDA will review and act on 90 percent of all ANDAs, ANDA 
     amendments, and ANDA

[[Page 18077]]

     prior approval supplements regardless of current review 
     status (whether electronic, paper, or hybrid) pending on 
     October 1, 2012 by the end of FY 2017.


                              Definitions

       For the purposes of this goals letter:
       Act on an application--means FDA will either issue a 
     complete response letter, an approval letter, a tentative 
     approval letter for an ANDA, or a refuse to receive action.
       Active pharmaceutical ingredient--means (A) a substance, or 
     a mixture when the substance is unstable or cannot be 
     transported on its own, intended to be used as a component of 
     a drug and intended 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 the final active pharmaceutical ingredient as defined 
     in paragraph (A).
       Backlog--refers to the queue of pending ANDAs, ANDA 
     amendments and ANDA supplements pending as of October 1, 
     2012.
       Delaying amendments--refers to amendments to an ANDA from 
     the ANDA sponsor to address actions by a third party that 
     would cause delay or impede application review or approval 
     timing and that were not or may not have been initially 
     recognized by FDA as necessary when the application was first 
     submitted. FDA's Office of Generic Drugs shall have broad 
     discretion to determine what constitutes a delaying event 
     caused by actions generally outside of the applicants control 
     taking into account facts and information supplied by the 
     ANDA sponsor.
       Closing out a request for a first cycle review 
     teleconference--means: 1) holding the teleconference; or 2) 
     responding to questions in the sponsor's teleconference 
     request in writing in lieu of holding the teleconference.
       Cohort--The program is structured based on 5 cohorts of 
     submission dates (original ANDAs, PASs and DMFs), 
     corresponding to the five fiscal years to be covered by the 
     program. The year 1 cohort refers to the dates of submissions 
     made electronically in FY 2013 (October 1, 2012 to September 
     30, 2013). The year 2 cohort refers to the dates of 
     submissions made electronically in FY 2014 (October 1, 2013 
     to September 30, 2014). The year 3 cohort refers to the dates 
     of submissions made electronically in FY 2015 (October 1, 
     2014 to September 30, 2015). The year 4 cohort refers to 
     submissions made electronically in FY 2016 (October 1, 2015 
     to September 30, 2016). The year 5 cohort refers to 
     submissions made electronically in FY 2017 (October 1, 2016 
     to September 30, 2017).
       Complete response letter--refers to a written communication 
     to an applicant or DMF holder from FDA usually describing all 
     of the deficiencies that the agency has identified in an 
     abbreviated application (including pending amendments) or a 
     DMF that must be satisfactorily addressed before the ANDA can 
     be approved. Complete response letters will reflect a 
     complete review and will require a complete response from 
     industry to restart the clock. Refer to 21 CFR 314.110 and 
     http://www.fda.gov/Drugs/GuidanceCompliance 
     RegulatoryInformation/LawsActsandRules/ucm084138.htm for 
     additional details. When a citizen petition may impact the 
     approvability of the ANDA, FDA will strive to address, where 
     possible, valid issues raised in a relevant citizen petition 
     in the complete response letter. If a citizen petition raises 
     an issue that would delay only part of a complete response, a 
     response that addresses all other issues will be considered a 
     complete response.
       Complete review--refers to a full division-level review 
     from all relevant review disciplines, including inspections, 
     and includes other matters relating to the ANDA and 
     associated DMFs as well as consults with other agency 
     components.
       Controlled correspondence--FDA'S Office of Generic Drugs 
     provides assistance to pharmaceutical firms and related 
     industry regarding a variety of questions posed as 
     ``controlled documents.'' See http://www.fda.gov/AboutFDA/
 CentersOffices/CDER/ucm 120610.htm. Controlled correspondence 
     does not include citizen petitions, petitions for 
     reconsideration or requests for stay.
       DMF or Type II Active Pharmaceutical Ingredient Drug Master 
     File--means a submission of information to the Secretary by a 
     person that intends to authorize the Food and Drug 
     Administration to reference the information to support 
     approval of a generic drug submission without the submitter 
     having to disclose the information to the generic drug 
     submission applicant.
       Electronic--refers to submissions in an all electronic eCTD 
     format in effect at the date of submission.
       Expedited review of application--While generally, review of 
     original ANDAs, ANDA amendments and ANDA supplements are 
     reviewed in the order received, (first-in, first-reviewed), 
     certain applications may be identified at the date of 
     submission for expedited review, as described in CDER's MAPP 
     5240.3. (See http://www.fda.gov/downloads/AboutFDA/
CentersOffices/CDER/ManualofPoliciesProcedures/ucm079787.pdf) 
     which includes expedited review of the original submission 
     and amendment(s) associated with the expedited review 
     qualifying application. Products to respond to current and 
     anticipated public health emergencies, products under special 
     review programs, such as the President's Emergency Plan for 
     AIDS Relief (PEPFAR), products for which a nationwide 
     shortage has been identified, and first generic products for 
     which there are no blocking patents or exclusivities on the 
     reference listed drug currently may qualify for expedited 
     review. For ANDAs in the year 1 and 2 cohorts, FDA will 
     expedite review of Paragraph IV applications that are 
     submitted on the first day that any valid Paragraph IV 
     application for the drug in question is submitted.
       Facility--means business or other entity under one 
     management either direct or indirect and at one geographic 
     location or address engaged in manufacturing or processing an 
     active pharmaceutical ingredient or a finished dosage form, 
     but does not include a business or other entity whose only 
     manufacturing or processing activities are one or more of the 
     following: repackaging, relabeling, or testing. For purposes 
     of this definition, separate buildings within close proximity 
     are considered to be at one geographic location or address if 
     the activities in them are closely related to the same 
     business enterprise, under the supervision of the same local 
     management, and are capable of being inspected by the Food 
     and Drug Administration during a single inspection.
       Finished Dosage Form--means (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 paragraph (m)(2), 
     with another component of a drug product for purposes of 
     production of such a drug product.
       First major deficiency application--means an ANDA which has 
     been issued its first complete response letter classified as 
     having major deficiency(ies).
       Generic Drug Program--refers to all agency activities 
     related to the determination of approvability of an ANDA.
       Major and minor amendments--All references to ``major'' and 
     ``minor'' amendments in this goals letter are intended to 
     refer to the distinctions that FDA described in its Guidance 
     for Industry: Major, Minor, Telephone Amendments to 
     Abbreviated New Drug Applications. See http://www.fda.gov/
 downloads/Drugs/GuidanceCompliance RegulatoryInformation/
     Guidances/ucm072888.pdf
       Parity--in reference to inspections, as between foreign and 
     domestic facilities, means inspection at an equal frequency 
     plus or minus 20 percent with comparable depth and rigor of 
     inspection.
       Refuse to receive--means refusal to file an application. 
     See 21 CFR 314.101 and http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/
UCM080561.pdf1993
       Solicited amendment--an amendment submitted in response to 
     a Complete Response letter.
       Submission date--is the date an ANDA, ANDA amendment, ANDA 
     supplement, or Type II active pharmaceutical drug master file 
     arrives in the appropriate electronic portal of the FDA.
       Prior Approval Supplements--A prior approval supplement is 
     a submission to allow a company to make a change in a product 
     that already has an approved ANDA. CDER must approve all 
     important ANDA changes (in packaging or ingredients, for 
     instance) to ensure the conditions originally set for the 
     product are still met. (Source: http://www.fda.gov/Drugs/
InformationOnDrugs/ucm079436.htm#S)
       Unsolicited amendment--an amendment with information not 
     requested by the FDA except for those unsolicited amendments 
     considered routine or administrative in nature and that do 
     not require scientific review (e.g., requests for final ANDA 
     approval, patent amendments, general correspondence, and USP 
     monograph updates).


                    FY 2013 Regulatory Science Plan

       Topic 1: Bioequivalence of local acting orally inhaled drug 
     products
       Impact: Continue to develop new and improved PD endpoints 
     and study designs or establishment of alternative approaches 
     to ensure equivalent local delivery of orally inhaled drug 
     product to the lung would lead to more efficient development 
     of generic products in a sector that lacks any generic 
     competition
       Topic 2: Bioequivalence of local acting topical 
     dermatological drug products
       Impact: Continue developing new bioequivalence methods in 
     order to reduce the need for relatively insensitive clinical 
     endpoint bioequivalence studies. Development of in vitro 
     release tests or other product characterization to ensure 
     consistent drug release or product performance
       Topic 3: Bioequivalence of local acting gastro-intestinal 
     drug products
       Impact: Developing new bioequivalence methods for direct 
     measurement of drug concentrations in the GI tract and 
     establishing better correlations between pharmacokinetic 
     measurements and GI concentration would

[[Page 18078]]

     allow more efficient demonstration of bioequivalence than by 
     clinical endpoint studies.
       Topic 4: Quality by design of generic drug products
       Impact: Continue developing science-based recommendations 
     for product development, raw material, APIs and process 
     controls, and life-cycle management of complex dosage forms 
     (e.g. orally inhaled drug products and modified-release 
     dosage forms)
       Topic 5: Modeling and simulation
       Impact: Modeling and simulation (including in-vitro and in-
     vivo correlations) is essential to efficient implementation 
     of quality by design and can help to identify and eliminate 
     unneeded in-vitro and/or in-vivo studies. Models (PK/PD, 
     exposure-response, clinical use simulation) support generic 
     drug evaluation policies especially for NTI drugs and complex 
     products.
       Topic 6: Pharmacokinetic studies and evaluation of anti-
     epileptic drugs
       Impact: Improving public confidence in bioequivalent 
     generic epilepsy drugs.
       Topic 7: Excipient effects on permeability and absorption 
     of BCS Class 3 Drugs
       Impact: Extension of biowaivers to BCS Class 3 Drugs and 
     eliminating the need for unnecessary in vivo bioequivalence 
     studies
       Topic 8: Product- and patient-related factors affecting 
     switchability of drug-device combination products (e.g., 
     orally inhaled and nasal drug products and injection drug 
     products)
       Impact: Establishing a systematic, science- and risk-based 
     approach to ensure device switchability, and improving the 
     patient's compliance and acceptability of generic devices
       Topic 9: Postmarketing surveillance of generic drug usage 
     patterns and adverse events.
       Impact: Improved data collection about usage patterns 
     (which strengths are used in which populations, extent of 
     switchability, back switches to RLD products, medication 
     errors) will be fed back into regulatory policy development 
     including those for excipients and impurities. Baseline data 
     collection on adverse event reports on switching to an 
     authorized generic would improve the ability to investigate 
     reports.
       Topic 10: Evaluation of drug product physical attributes on 
     patient acceptability
       Impact: Laboratory and human studies on physical attributes 
     such as tablet size, shape, coating, odor perception 
     (residual solvents), score configuration, taste masking or 
     color on the ability of patient to use (for example swallow) 
     or perceive quality (for example smell) will allow OGD to 
     provide better guidance to applicants on how these physical 
     attributes should be controlled and compared to the RLD.
       Topic 11: Postmarking assessment of generic drugs and their 
     brand-name counterparts
       Impact: Stronger public confidence in generic drugs because 
     of pro-active responses to product concerns. An integrated 
     response to product concerns involving laboratory 
     investigations and post-marketing data collection.
       Topic 12: Physicochemical characterization of complex drug 
     substances
       Impact: Developing analytical methods for demonstrating 
     pharmaceutical equivalence for complex drug substances (non-
     small molecules) characterized by natural source origin, 
     polydisperse mixture, and/or supramolecular structure, and 
     therefore expanding the boundary of the generic drug program 
     for these complex drug products
       Topic 13: Develop a risk-based understanding of potential 
     adverse impacts to drug product quality resulting from 
     changes in API manufacturing and controls.
       Impact: The ability to predict the potential impacts of 
     manufacturing changes on product quality will allow 
     manufacturers to target assessments and controls on high-risk 
     areas for regulators to focus their reviews on these areas 
     too.

    FY 2014 Regulatory Science Preliminary Topics for Consideration

       In addition to those topics to be identified by the Working 
     Group described in section 3.A of this letter, topics will 
     include recommendations for draft guidances to clarify FDA 
     recommendations with regard to complex product development 
     and to help limit deficiencies in applications.

   BIOSIMILAR BIOLOGICAL PRODUCT AUTHORIZATION PERFORMANCE GOALS AND 
             PROCEDURES FOR FISCAL YEARS 2013 THROUGH 2017

       FDA proposes the following goals contingent on the 
     allocation of resources for each of the fiscal years 2013-
     2017 of at least the inflation-adjusted value of $20 million 
     in non-user fee funds, plus collections of biosimilar user 
     fees, to support the process for the review of biosimilar 
     biological applications.


                      I. REVIEW PERFORMANCE GOALS

     A. Biosimilar Biological Product Application Submissions and 
         Resubmissions
       FY 2013
       1. Review and act on 70 percent of original biosimilar 
     biological product application submissions within 10 months 
     of receipt.
       2. Review and act on 70 percent of resubmitted original 
     biosimilar biological product applications within 6 months of 
     receipt.
       FY 2014
       1. Review and act on 70 percent of original biosimilar 
     biological product application submissions within 10 months 
     of receipt.
       2. Review and act on 70 percent of resubmitted original 
     biosimilar biological product applications within 6 months of 
     receipt.
       FY 2015
       1. Review and act on 80 percent of original biosimilar 
     biological product application submissions within 10 months 
     of receipt.
       2. Review and act on 80 percent of resubmitted original 
     biosimilar biological product applications within 6 months of 
     receipt.
       FY 2016
       1. Review and act on 85 percent of original biosimilar 
     biological product application submissions within 10 months 
     of receipt.
       2. Review and act on 85 percent of resubmitted original 
     biosimilar biological product applications within 6 months of 
     receipt.
       FY 2017
       1. Review and act on 90 percent of original biosimilar 
     biological product application submissions within 10 months 
     of receipt.
       2. Review and act on 90 percent of resubmitted original 
     biosimilar biological product applications within 6 months of 
     receipt.
     B. Supplements with Clinical Data
       1. Review and act on 90 percent of original supplements 
     with clinical data within 10 months of receipt.
       2. Review and act on 90 percent of resubmitted supplements 
     with clinical data within 6 months of receipt.
     C. Original Manufacturing Supplements
       1. Review and act on 90 percent of manufacturing 
     supplements within 6 months of receipt.
     D. Goals Summary Tables

                                                  ORIGINAL AND RESUBMITTED APPLICATIONS AND SUPPLEMENTS
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                       Performance goal
         Submission cohort          --------------------------------------------------------------------------------------------------------------------
                                              2013                    2014                    2015                   2016                   2017
--------------------------------------------------------------------------------------------------------------------------------------------------------
Original Biosimilar Biological       70% in 10 months of     70% in 10 months of     80% in 10 months of    85% in 10 months of    90% in 10 months of
 Product Application Submissions.     the receipt date.       the receipt date.       the receipt date.      the receipt date.      the receipt date
Resubmitted Original Biosimilar      70% in 6 months of the  70% in 6 months of the  80% in 6 months of     85% in 6 months of     90% in 6 months of
 Biological Product Applications.     receipt date.           receipt date.           the receipt date.      the receipt date.      the receipt date
--------------------------------------------------------------------------------------------------------------------------------------------------------


------------------------------------------------------------------------
 
------------------------------------------------------------------------
Original Supplements with Clinical Data...  90% in 10 months of the
                                             receipt date
Resubmitted Supplements with Clinical Data  90% in 6 months of the
                                             receipt date
Manufacturing Supplements.................  90% in 6 months of the
                                             receipt date
------------------------------------------------------------------------

                   II. FIRST CYCLE REVIEW PERFORMANCE

     A. Notification of Issues Identified during the Filing Review
       1. Performance Goal: For original biosimilar biological 
     product applications and supplements with clinical data, FDA 
     will report substantive review issues identified during the 
     initial filing review to the applicant by letter, 
     teleconference, facsimile, secure e-mail, or other expedient 
     means.
       2. The timeline for such communication will be within 74 
     calendar days from the date of FDA receipt of the original 
     submission.
       3. If no substantive review issues were identified during 
     the filing review, FDA will so notify the applicant.
       4. FDA's filing review represents a preliminary review of 
     the application and is not indicative of deficiencies that 
     may be identified later in the review cycle.
       5. FDA will notify the applicant of substantive review 
     issues prior to the goal date for 90% of applications.
     B. Notification of Planned Review Timelines
       1. Performance Goal: For original biosimilar biological 
     product applications and supplements with clinical data, FDA 
     will inform the applicant of the planned timeline for review 
     of the application. The information conveyed will include a 
     target date for communication of feedback from the review 
     division to the applicant regarding proposed labeling, 
     postmarketing requirements, and postmarketing commitments the 
     Agency will be requesting.
       2. The planned review timeline will be included with the 
     notification of issues identified during the filing review, 
     within 74 calendar days from the date of FDA receipt of the 
     original submission.
       3. The planned review timelines will be consistent with the 
     Guidance for Review Staff and Industry: Good Review 
     Management Principles and Practices for PDUFA Products 
     (GRMPs), taking into consideration the specific circumstances 
     surrounding

[[Page 18079]]

     the individual biosimilar biological product application.
       4. The planned review timeline will be based on the 
     application as submitted.
       5. FDA will inform the applicant of the planned review 
     timeline for 90% of all applications and supplements with 
     clinical data.
       6. In the event FDA determines that significant 
     deficiencies in the application preclude discussion of 
     labeling, postmarketing requirements, or postmarketing 
     commitments by the target date identified in the planned 
     review timeline (e.g., failure to demonstrate a biosimilar 
     biological product is highly similar to the reference 
     product, significant safety concern(s), need for a new 
     study(ies) or extensive re-analyses of existing data before 
     approval), FDA will communicate this determination to the 
     applicant in accordance with GRMPs and no later than the 
     target date. In such cases the planned review timeline will 
     be considered to have been met. Communication of FDA's 
     determination may occur by letter, teleconference, facsimile, 
     secure e-mail, or other expedient means.
       7. To help expedite the development of biosimilar 
     biological products, communication of the deficiencies 
     identified in the application will generally occur through 
     issuance of a discipline review (DR) letter(s) in advance of 
     the planned target date for initiation of discussions 
     regarding labeling, postmarketing requirements, and 
     postmarketing commitments the Agency may request.
       8. If the applicant submits a major amendment(s) (refer to 
     Section VIII.B for additional information on major 
     amendments) and the review division chooses to review such 
     amendment(s) during that review cycle, the planned review 
     timeline initially communicated (under Section II.B.1 and 2) 
     will generally no longer be applicable. Consistent with the 
     underlying principles articulated in the GRMP guidance, FDA's 
     decision to extend the review clock should, except in rare 
     circumstances, be limited to occasions where review of the 
     new information could address outstanding deficiencies in the 
     application and lead to approval in the current review cycle.
       If the review division determines that the major amendment 
     will result in an extension of the biosimilar biological 
     product review clock, the review division will communicate to 
     the applicant at the time of the clock extension a new 
     planned review timeline, including a new review timeline for 
     communication of feedback on proposed labeling, postmarketing 
     requirements, and any postmarketing commitments the Agency 
     may request.
       In the rare case where the review division determines that 
     the major amendment will not result in an extension of the 
     biosimilar biological product review clock, the review 
     division may choose to retain the previously communicated 
     planned review timeline or may communicate a new planned 
     review timeline to the applicant.
       The division will notify the applicant promptly of its 
     decision regarding review of the major amendment(s) and 
     whether the planned review timeline is still applicable.


      III. REVIEW OF PROPRIETARY NAMES TO REDUCE MEDICATION ERRORS

       To enhance patient safety, FDA will utilize user fees to 
     implement various measures to reduce medication errors 
     related to look-alike and sound-alike proprietary names and 
     such factors as unclear label abbreviations, acronyms, dose 
     designations, and error prone label and packaging design.
     A. Review Performance Goals--Biosimilar Biological Product 
         Proprietary Names
       1. Proprietary names submitted during the biosimilar 
     biological product development (BPD) phase
       a) Review 90% of proprietary name submissions filed within 
     180 days of receipt. Notify sponsor of tentative acceptance 
     or non-acceptance.
       b) If the proprietary name is found to be unacceptable, the 
     sponsor can request reconsideration by submitting a written 
     rebuttal with supporting data or request a meeting within 60 
     days to discuss the initial decision (meeting package 
     required).
       c) If the proprietary name is found to be unacceptable, the 
     above review performance goals also would apply to the 
     written request for reconsideration with supporting data or 
     the submission of a new proprietary name.
       d) A complete submission is required to begin the review 
     clock.
       2. Proprietary names submitted with biosimilar biological 
     product application
       a) Review 90% of biosimilar biological product application 
     proprietary name submissions filed within 90 days of receipt. 
     Notify sponsor of tentative acceptance/non-acceptance.
       b) A supplemental review will be done meeting the above 
     review performance goals if the proprietary name has been 
     submitted previously (during the BPD phase) and has received 
     tentative acceptance.
       c) If the proprietary name is found to be unacceptable, the 
     sponsor can request reconsideration by submitting a written 
     rebuttal with supporting data or request a meeting within 60 
     days to discuss the initial decision (meeting package 
     required).
       d) If the proprietary name is found to be unacceptable, the 
     above review performance goals apply to the written request 
     for reconsideration with supporting data or the submission of 
     a new proprietary name.
       e) A complete submission is required to begin the review 
     clock.


                      iv. major dispute resolution

       A. Procedure: For procedural or scientific matters 
     involving the review of biosimilar biological product 
     applications and supplements (as defined in BsUFA) that 
     cannot be resolved at the signatory authority level 
     (including a request for reconsideration by the signatory 
     authority after reviewing any materials that are planned to 
     be forwarded with an appeal to the next level), the response 
     to appeals of decisions will occur within 30 calendar days of 
     the Center's receipt of the written appeal.
       B. Performance goal: 90% of such answers are provided 
     within 30 calendar days of the Center's receipt of the 
     written appeal.
       C. Conditions:
       1. Sponsors should first try to resolve the procedural or 
     scientific issue at the signatory authority level. If it 
     cannot be resolved at that level, it should be appealed to 
     the next higher organizational level (with a copy to the 
     signatory authority) and then, if necessary, to the next 
     higher organizational level.
       2. Responses should be either verbal (followed by a written 
     confirmation within 14 calendar days of the verbal 
     notification) or written and should ordinarily be to either 
     grant or deny the appeal.
       3. If the decision is to deny the appeal, the response 
     should include reasons for the denial and any actions the 
     sponsor might take to persuade the Agency to reverse its 
     decision.
       4. In some cases, further data or further input from others 
     might be needed to reach a decision on the appeal. In these 
     cases, the ``response'' should be the plan for obtaining that 
     information (e.g., requesting further information from the 
     sponsor, scheduling a meeting with the sponsor, scheduling 
     the issue for discussion at the next scheduled available 
     advisory committee).
       5. In these cases, once the required information is 
     received by the Agency (including any advice from an advisory 
     committee), the person to whom the appeal was made, again has 
     30 calendar days from the receipt of the required information 
     in which to either deny or grant the appeal.
       6. Again, if the decision is to deny the appeal, the 
     response should include the reasons for the denial and any 
     actions the sponsor might take to persuade the Agency to 
     reverse its decision.
       7. Note: If the Agency decides to present the issue to an 
     advisory committee and there are not 30 days before the next 
     scheduled advisory committee, the issue will be presented at 
     the following scheduled committee meeting to allow 
     conformance with advisory committee administrative 
     procedures.


                           v. clinical holds

       A. Procedure: The Center should respond to a sponsor's 
     complete response to a clinical hold within 30 days of the 
     Agency's receipt of the submission of such sponsor response.
       B. Performance goal: 90% of such responses are provided 
     within 30 calendar days of the Agency's receipt of the 
     sponsor's response.


         VI. SPECIAL PROTOCOL QUESTION ASSESSMENT AND AGREEMENT

       A. Procedure: Upon specific request by a sponsor (including 
     specific questions that the sponsor desires to be answered), 
     the Agency will evaluate certain protocols and related issues 
     to assess whether the design is adequate to meet scientific 
     and regulatory requirements identified by the sponsor.
       1. The sponsor should submit a limited number of specific 
     questions about the protocol design and scientific and 
     regulatory requirements for which the sponsor seeks agreement 
     (e.g., are the clinical endpoints adequate to assess whether 
     there are clinically meaningful differences between the 
     proposed biosimilar biological product and the reference 
     product).
       2. Within 45 days of Agency receipt of the protocol and 
     specific questions, the Agency will provide a written 
     response to the sponsor that includes a succinct assessment 
     of the protocol and answers to the questions posed by the 
     sponsor. If the Agency does not agree that the protocol 
     design, execution plans, and data analyses are adequate to 
     achieve the goals of the sponsor, the reasons for the 
     disagreement will be explained in the response.
       3. Protocols that qualify for this program include any 
     necessary clinical study or studies to prove biosimilarity 
     and/or interchangeability (e.g., protocols for comparative 
     clinical trials that will form the primary basis for 
     demonstrating that there are no clinically meaningful 
     differences between the proposed biosimilar biological 
     product and the reference product, and protocols for clinical 
     trials intended to support a demonstration of 
     interchangeability). For such protocols to qualify for this 
     comprehensive protocol assessment, the sponsor must have had 
     a BPD Type 2 or 3 Meeting, as defined in section VIII (F and 
     G), below, with the review division so that the division is 
     aware of the developmental context in which the protocol is 
     being reviewed and the questions being answered.
       4. If a protocol is reviewed under the process outlined 
     above, and agreement with the

[[Page 18080]]

     Agency is reached on design, execution, and analyses, and if 
     the results of the trial conducted under the protocol 
     substantiate the hypothesis of the protocol, the Agency 
     agrees that the data from the protocol can be used as part of 
     the primary basis for approval of the product. The 
     fundamental agreement here is that having agreed to the 
     design, execution, and analyses proposed in protocols 
     reviewed under this process, the Agency will not later alter 
     its perspective on the issues of design, execution, or 
     analyses unless public health concerns unrecognized at the 
     time of protocol assessment under this process are evident.
       B. Performance goal:
       For FY 2013, 70% of special protocols assessments and 
     agreement requests completed and returned to sponsor within 
     timeframes.
       For FY 2014, 70% of special protocols assessments and 
     agreement requests completed and returned to sponsor within 
     timeframes.
       For FY 2015, 80% of special protocols assessments and 
     agreement requests completed and returned to sponsor within 
     timeframes.
       For FY 2016, 85% of special protocols assessments and 
     agreement requests completed and returned to sponsor within 
     timeframes.
       For FY 2017, 90% of special protocols assessments and 
     agreement requests completed and returned to sponsor within 
     timeframes.
       C. Reporting: The Agency will track and report the number 
     of original special protocol assessments and resubmissions 
     per original special protocol assessment.


                     VII. MEETING MANAGEMENT GOALS

     A. Responses to Meeting Requests
       1. Procedure: Within 14 calendar days of the Agency's 
     receipt of a request and meeting package from industry for a 
     BPD Type 1 Meeting, or within 21 calendar days of the 
     Agency's receipt of a request and meeting package from 
     industry for a Biosimilar Initial Advisory Meeting or a BPD 
     Type 2, 3, or 4 Meeting, as defined in section VIII(D-H), 
     below, CBER and CDER should notify the requester in writing 
     of the date, time, place, and format (i.e., a scheduled face-
     to-face, teleconference, or videoconference) for the meeting, 
     as well as expected Center participants.
       2. Performance Goal: FDA will provide this notification 
     within 14 days for 90 percent of BPD Type 1 Meeting requests 
     and within 21 days for 90 percent of Biosimilar Initial 
     Advisory Meeting and BPD Type 2, 3 and 4 Meeting requests.
     B. Scheduling Meetings
       1. Procedure: The meeting date should reflect the next 
     available date on which all applicable Center personnel are 
     available to attend, consistent with the component's other 
     business; however, the meeting should be scheduled consistent 
     with the type of meeting requested.
       a) Biosimilar Initial Advisory Meeting should occur within 
     90 calendar days of the Agency receipt of the sponsor-
     submitted meeting request and meeting package.
       b) BPD Type 1 Meetings should occur within 30 calendar days 
     of the Agency receipt of the sponsor-submitted meeting 
     request and meeting package.
       c) BPD Type 2 Meetings should occur within 75 calendar days 
     of the Agency receipt of the sponsor-submitted meeting 
     request and meeting package.
       d) BPD Type 3 Meetings should occur within 120 calendar 
     days of the Agency receipt of the sponsor-submitted meeting 
     request and meeting package.
       e) BPD Type 4 Meetings should occur within 60 calendar days 
     of the Agency receipt of the sponsor-submitted meeting 
     request and meeting package.
       2. Performance goal:
       For FY 2013, 70% of Biosimilar Initial Advisory Meetings 
     and BPD Type 1-4 Meetings are held within the timeframe.
       For FY 2014, 70% of Biosimilar Initial Advisory Meetings 
     and BPD Type 1-4 Meetings are held within the timeframe.
       For FY 2015, 80% of Biosimilar Initial Advisory Meetings 
     and BPD Type 1-4 Meetings are held within the timeframe.
       For FY 2016, 85% of Biosimilar Initial Advisory Meetings 
     and BPD Type 1-4 Meetings are held within the timeframe.
       For FY 2017, 90% of Biosimilar Initial Advisory Meetings 
     and BPD Type 1-4 Meetings are held within the timeframe.
     C. Meeting Minutes
       1. Procedure: The Agency will prepare minutes which will be 
     available to the sponsor 30 calendar days after the meeting. 
     The minutes will clearly outline the important agreements, 
     disagreements, issues for further discussion, and action 
     items from the meeting in bulleted form and need not be in 
     great detail.
       2. Performance Goal: FDA will provide meeting minutes 
     within 30 days of the date of the meeting for 90 percent of 
     Biosimilar Initial Advisory Meetings and BPD Type 1-4 
     Meetings.
     D. Conditions
       For a meeting to qualify for these performance goals:
       1. A written request (letter or fax) and supporting 
     documentation (i.e., the meeting package) should be submitted 
     to the appropriate review division or office. The request 
     should provide:
       a) A brief statement of the purpose of the meeting, the 
     sponsor's proposal for the type of meeting, and the sponsor's 
     proposal for a face-to-face meeting or a teleconference;
       b) A listing of the specific objectives/outcomes the 
     requester expects from the meeting;
       c) A proposed agenda, including estimated times needed for 
     each agenda item;
       d) A list of questions, grouped by discipline. For each 
     question there should be a brief explanation of the context 
     and purpose of the question.
       e) A listing of planned external attendees; and
       f) A listing of requested participants/disciplines 
     representative(s) from the Center.
       g) Suggested dates and times (e.g., morning or afternoon) 
     for the meeting that are within or beyond the appropriate 
     time frame of the meeting type being requested.
       2. The Agency concurs that the meeting will serve a useful 
     purpose (i.e., it is not premature or clearly unnecessary). 
     However, requests for BPD Type 2, 3 and 4 Meetings will be 
     honored except in the most unusual circumstances.
       The Center may determine that a different type of meeting 
     is more appropriate and it may grant a meeting of a different 
     type than requested, which may require the payment of a 
     biosimilar biological product development fee as described in 
     section 744B of the Federal Food, Drug, and Cosmetic Act 
     before the meeting will be provided. If a biosimilar 
     biological product development fee is required under section 
     744B, and the sponsor does not pay the fee within the time 
     frame required under section 744B, the meeting will be 
     cancelled. If the sponsor pays the biosimilar biological 
     product development fee after the meeting has been cancelled 
     due to non-payment, the time frame described in section 
     VII.A.1 will be calculated from the date on which FDA 
     received the payment, not the date on which the sponsor 
     originally submitted the meeting request.
       Sponsors are encouraged to consult FDA to obtain further 
     information on recommended meeting procedures.
       3. FDA will develop and publish for comment draft guidance 
     on Biosimilar Initial Advisory Meetings and BPD Type 1-4 
     Meetings by end of second quarter of FY 2014.


               VIII. DEFINITIONS AND EXPLANATION OF TERMS

       A. The term ``review and act on'' means the issuance of a 
     complete action letter after the complete review of a filed 
     complete application. The action letter, if it is not an 
     approval, will set forth in detail the specific deficiencies 
     and, where appropriate, the actions necessary to place the 
     application in condition for approval.
       B. Goal Date Extensions for Major Amendments
       1. A major amendment to an original application, supplement 
     with clinical data, or resubmission of any of these 
     applications, submitted at any time during the review cycle, 
     may extend the goal date by three months.
       2. A major amendment may include, for example, 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 amendment to a previously 
     submitted REMS with ETASU. Generally, changes to REMS that do 
     not include ETASU and minor changes to REMS with ETASU will 
     not be considered major amendments.
       3. A major amendment to a manufacturing supplement 
     submitted at any time during the review cycle may extend the 
     goal date by two months.
       4. Only one extension can be given per review cycle.
       5. Consistent with the underlying principles articulated in 
     the GRMP guidance, FDA's decision to extend the review clock 
     should, except in rare circumstances, be limited to occasions 
     where review of the new information could address outstanding 
     deficiencies in the application and lead to approval in the 
     current review cycle.
       C. A resubmitted original application is a complete 
     response to an action letter addressing all identified 
     deficiencies.
       D. A Biosimilar Initial Advisory Meeting is an initial 
     assessment limited to a general discussion regarding whether 
     licensure under section 351(k) of the Public Health Service 
     Act may be feasible for a particular product, and, if so, 
     general advice on the expected content of the development 
     program. Such term does not include any meeting that involves 
     substantive review of summary data or full study reports.
       E. A BPD Type 1 Meeting is a meeting which is necessary for 
     an otherwise stalled drug development program to proceed 
     (e.g. meeting to discuss clinical holds, dispute resolution 
     meeting), a special protocol assessment meeting, or a meeting 
     to address an important safety issue.
       F. A BPD Type 2 Meeting is a meeting to discuss a specific 
     issue (e.g., proposed study design or endpoints) or questions 
     where FDA will provide targeted advice regarding an ongoing 
     biosimilar biological product development program. Such term 
     includes substantive review of summary data, but does not 
     include review of full study reports.
       G. A BPD Type 3 Meeting is an in depth data review and 
     advice meeting regarding an

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     ongoing biosimilar biological product development program. 
     Such term includes substantive review of full study reports, 
     FDA advice regarding the similarity between the proposed 
     biosimilar biological product and the reference product, and 
     FDA advice regarding additional studies, including design and 
     analysis.
       H. A BPD Type 4 Meeting is a meeting to discuss the format 
     and content of a biosimilar biological product application or 
     supplement submitted under 351(k) of the PHS Act.

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