[Congressional Record Volume 148, Number 73 (Thursday, June 6, 2002)]
[Senate]
[Pages S5195-S5200]
From the Congressional Record Online through the Government Publishing Office [www.gpo.gov]




PERFORMANCE GOALS FOR THE PRESCRIPTION DRUG USER FEE AMENDMENTS OF 2002

  Mr. KENNEDY. Mr. President, on May 23, 2002, the Senate passed the 
Conference Report to H.R. 3448, the Public Health Security and 
Bioterrorism Preparedness and Response Act of 2002. Included in Title V 
of this Conference Report is the reauthorization of the Prescription 
Drug User Fee Act, ``PDUFA''.
  Performance goals, existing outside of the statute, accompany the 
reauthorization of PDUFA. These goals represent a realistic projection 
of what the Food and Drug Administration Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research can 
accomplish with industry cooperation. The Secretary of Health and Human 
Services forwarded these goals to the chairmen of the Committee on 
Energy and Commerce of the House of Representatives and the Committee 
on Health, Education, Labor and Pensions of the Senate, in a document 
entitled ``PDUFA Reauthorization Performance Goals and Procedures.'' 
According to Section 502 of the Conference Report, ``the fees 
authorized by amendments made in this subtitle will be dedicated 
towards expediting the drug development process and the process for the 
review of human drug application as set forth in the goals in the 
Congressional Record.''
  Today I am submitting for the Record this document, which was 
forwarded to the Committee on Health, Education, Labor and Pensions on 
June 4, 2002, as well as the letter from Secretary Thompson that 
accompanied the transmittal of this document.
  I ask unanimous consent it be printed in the Record.
  There being no objection, the material was ordered to be printed in 
the Record, as follows:

                                                  The Secretary of


                                    Health and Human Services,

                                     Washington, DC, June 4, 2002.
     Hon. Edward M. Kennedy,
     Chairman, Committee on Health, Education, Labor and Pensions, 
         U.S. Senate Washington, DC.
       Dear Chairman Kennedy: As you are aware, the Prescription 
     Drug User Fee Act of 1992 (PDUFA), as reauthorized by the 
     Food and Drug Administration Modernization Act of 1997, 
     expires at the end of Fiscal Year 2002. Under PDUFA, the 
     additional revenues generated from fees paid by the 
     pharmaceutical and biological prescription drug industries 
     have been used to expedite the process for the review of 
     prescription drugs, in accordance with performance goals that 
     were developed by the Food and Drug Administration (FDA) in 
     consultation with PDUFA stakeholders.
       FDA has worked with various stakeholders, including 
     representatives from consumer, patient, and health provider 
     groups, and the pharmaceutical and biological prescription 
     drug industries, to develop a reauthorization proposal for 
     PDUFA that would build upon and enhance the success of the 
     program. Title 5, Subtitle A, of the Public Health Security 
     and Bioterrorism Preparedness and Response Act of 2002, as 
     passed by the House on May 22, 2002, and by the Senate on May 
     23, 2002, reflects the fee mechanisms and other improvements 
     developed in these discussions. The performance goals 
     referenced in Section 502 are specified in the enclosure to 
     this letter, entitled ``PDUFA Reauthorization Performance 
     Goals and Procedures.'' I believe they represent a realistic 
     projection of what FDA can accomplish with industry 
     cooperation and both the additional resources identified in 
     the bill and annual FDA appropriations that fully cover the 
     costs of pay and inflation increases for the drug and 
     biologics review process each year.
       This letter and the enclosed goals document pertain only to 
     Title 5, Subtitle A (Prescription Drug User Fees) of H.R. 
     3448, the Public Health Security and Bioterrorism 
     Preparedness and Response Act of 2002. OMB has advised that 
     there is no objection to the presentation of these views from 
     the standpoint of the Administration's program. We appreciate 
     the support of you and your staffs, the assistance of other 
     Members of the Committee, and that of the Appropriations 
     Committees, in the reauthorization of this vital program.
           Sincerely,
                                                Tommy S. Thompson.
       Enclosure.

         PDUFA Reauthorization Performance Goals and Procedures

       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 reauthorization of the prescription drug user fee program 
     in the [cite statute] are summarized as follows:


       I. Review Performance Goals--Fiscal Year 2003 Through 2007

                A. NDA/BLA submissions and resubmissions

       Review and act on 90 percent of standard original NDA and 
     BLA submissions filed during fiscal year within 10 months of 
     receipt.
       1. Review and act on 90 percent of priority original NDA 
     and BLA submissions filed during fiscal year within 6 months 
     of receipt.
       2. Review and act on 90 percent of Class 1 resubmitted 
     original applications filed during fiscal year within 2 
     months of receipt.
       3. Review and act on 90 percent of Class 2 resubmitted 
     original applications filed during fiscal year within 6 
     months of receipt.

                     Original Efficacy Supplements

       1. Review and act on 90 percent of standard efficacy 
     supplements filed during fiscal year within 10 months of 
     receipt.
       2. Review and act on 90 percent of priority efficacy 
     supplements filed during fiscal year within 6 months of 
     receipt.

                    Resubmitted Efficacy Supplements

       Fiscal Year 2003:
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements filed during fiscal year 2003 within 6 
     months of receipt and review and act on 30 percent within 2 
     months of receipt.
       2. Review and act on 90 percent of Class 2 resubmitted 
     efficacy supplements filed during fiscal year 2003 within 6 
     months of receipt.
       Fiscal Year 2004:
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements filed during fiscal year 2004 within 4 
     months of receipt and review and act on 50 percent within 2 
     months of receipt.
       2. Review and act on 90 percent of Class 2 resubmitted 
     original applications filed during fiscal year 2000 within 6 
     months of receipt.
       Fiscal Year 2005:
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements filed during fiscal year 2005 within 4 
     months of receipt and review and act on 70 percent within 2 
     months of receipt.

[[Page S5196]]

       2. Review and act on 90 percent of Class 2 resubmitted 
     efficacy supplements within 6 months of receipt.
       Fiscal Year 2006
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements filed during fiscal year 2006 within 4 
     months of receipt and review and act on 80 percent within 2 
     months of receipt.
       2. Review and act on 90 percent of class 2 resubmitted 
     efficacy supplements within 6 months of receipt.
       Fiscal Year 2007:
       1. Review and act on 90 percent of Class 1 resubmitted 
     efficacy supplements filed during fiscal year 2007 with 2 
     months of receipt.
       2. Review and act on 909 percent of Class 2 resubmitted 
     efficacy supplements within 6 months of receipt.

                   Original Manufacturing Supplements

       1. Review and act on 90 percent of manufacturing 
     supplements filed during fiscal year within 6 months of 
     receipt and review and act on 90 percent of manufacturing 
     supplements requiring prior approval within 4 months of 
     receipt.
       These review goals are summarized in the following tables:

                   ORIGINAL AND RESUBMITTED NDAS/BLAS
------------------------------------------------------------------------
        Submission cohort                Standard            Priority
------------------------------------------------------------------------
Original Applications............  90% in 10 mo........  90% in 6 mo.
Class 1 Resubmissions............  90% in 2 mo.........  90% in 2 mo.
Class 2 Resubmissions............  90% in 6 mo.........  90% in 6 mo.
------------------------------------------------------------------------


              ORIGINAL AND RESUBMITTED EFFICACY SUPPLEMENTS
------------------------------------------------------------------------
        Submission cohort                Standard            Priority
------------------------------------------------------------------------
Original Efficacy Supplements....  90% in 10 mo........  90% in 6 mo.
------------------------------------------------------------------------


                    RESUBMITTED EFFICACY SUPPLEMENTS
------------------------------------------------------------------------
        Submission cohort                 Class 1             Class
------------------------------------------------------------------------
FY 2003..........................  90% in 6 mo/30% in 2  90% in 6 mo.
                                    mo.
FY 2004..........................  90% in 4 mo/50% in 2  90% in 6 mo.
                                    mo.
FY 2005..........................  90% in 4 mo/70% in 2  90% in 6 mo.
                                    mo.
FY 2006..........................  90% in 4 mo/80% in 2  90% in 6 mo.
                                    mo.
FY 2007..........................  90% in 2 mo.........  90% in 6 mo.
------------------------------------------------------------------------


                        MANUFACTURING SUPPLEMENTS
------------------------------------------------------------------------
                                     Manufacturing
                                     supplements no      Manufacturing
                                     prior approval     supplements that
        Submission cohort           (``changes being    do require prior
                                  effected'' or ``30-       approval
                                   day supplements'')
------------------------------------------------------------------------
FY 2003-2007....................  90% in 6 mo........  90% in 4 mo.
------------------------------------------------------------------------

            ii. new molecular entity (nme) performance goals

       A. The performance goals for standard and priority original 
     NMEs in each submission cohort will be the same as for all of 
     the original NDAs (including NMEs) in each submission cohort 
     but shall be reported separately.
       B. For biological products, for purposes of this 
     performance goal, all original BKSs will be considered to be 
     NMEs.


                     iii. 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 meeting 
     (i.e., a scheduled face-to-face, teleconference, or 
     videoconference) 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.
       2. Performance Goal: FDA will provide this notification 
     within 14 days for 90% in FY 2003-2007.

                         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 date requested.
       Type A Meetings should occur within 30 calendar days of the 
     Agency receipt of the meeting request.
       Type B Meetings should occur within 60 calendar days of the 
     Agency receipt of the meeting request.
       Type C Meetings should occur within 75 calendar days of the 
     Agency receipt of the meeting request.
       2. Performance goal: 90% of meetings are held within the 
     timeframe (based on cohort year of request) from FY 03 to FY 
     07.

                           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: 90% of minutes are issued within 30 
     calendar days of date of meeting (based on cohort year of 
     meeting) in FY 03 to FY 07.

                             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;
       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;
       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 least 2 weeks in advance 
     of the scheduled meeting for Type A meetings and at least 1 
     month in advance of the scheduled meeting for Type B and Type 
     C meetings); and
       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.


                           iv. 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 in FY 03 to FY 07 (cohort of date of 
     receipt).


                      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 divisional level 
     (including a request for reconsideration by the Division 
     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 in FY 03 to FY 07.

                             C. Conditions

       1. Sponsors should first try to resolve the procedural or 
     scientific issue at the Division level. If it cannot be 
     resolved at that level, it should be appealed to the Office 
     Director level (with a copy to the Division Director) and 
     then, if necessary, to the Deputy Center Director or Center 
     Director (with a copy to the Office Director).
       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 
     deny or grant 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 in order 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 in order 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 in order to allow 
     conformance with advisory committee administrative 
     procedures.


         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 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.

[[Page S5197]]

       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 under 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 (based on 
     cohort year of request) from FY 03 to FY 07.


                 vii. continuous marketing application

       To test whether providing early review of selected 
     applications and additional feedback and advice to sponsors 
     during drug development for selected products can further 
     shorten drug development and review times, FDA agrees to 
     conduct the following two pilot programs:

 A. Pilot 1--Discipline review letters for pre-submitted ``reviewable 
                          units'' of NDAs/BLAs

       1. This pilot applies to drugs and biologics that have been 
     designated to be Fast Track drugs or biologics, pursuant to 
     section 112 of the FDA Modernization Act (21 U.S.C. 356), 
     have been the subject of an End-of-Phase 2 and/or a Pre-NDA/
     BLA meeting, and have demonstrated significant promise as a 
     therapeutic advance in clinical trials.
       2. For drugs and biologics that meet these criteria, FDA 
     may enter into an agreement with the sponsor to accept pre-
     submission of one or more ``reviewable units'' of the 
     application in advance of the submission of the complete NDA/
     BLA.
       3. If following an initial review FDA finds a ``reviewable 
     unit'' to be substantially complete for review (i.e., after a 
     ``filing review'' similar to that performed on an NDA/BLA), 
     FDA will initiate a review clock for the complete review of 
     the ``reviewable unit'' of the NDA/BLA. The review clock 
     would start from the date of receipt of the ``reviewable 
     unit.''
       4. To be considered fileable for review under paragraph 3, 
     a ``reviewable unit'' must be substantially complete when 
     submitted to FDA. Once a ``reviewable unit'' is ``filed'' by 
     FDA, except as provided in paragraph 5 below, only minor 
     information amendments submitted in response to FDA inquiries 
     or requests and routine stability and safety updates will be 
     considered during the review cycle.
       5. Major amendments to the `'reviewable unit'' are strongly 
     discouraged. However, in rare cases, and with prior 
     agreement, FDA may accept and consider for review a major 
     amendment to a ``reviewable unit.'' To accommodate these rare 
     cases, a major amendment to a ``reviewable unit'' submitted 
     within the last three months of a 6-month review cycle may, 
     at FDA's discretion, trigger a 3-month extension of the 
     review clock for the ``reviewable unit'' in question. In no 
     case, however, would a major amendment be accepted for 
     review and the review clock for the ``reviewable unit'' 
     extended if the extended review clock for the ``reviewable 
     unit'' exceeded the review clock for the complete NDA/BLA. 
     (See paragraph 10 below).
       6. After completion of review of the ``reviewable unit'' of 
     the NDA/BLA by the appropriate discipline review team, FDA 
     will provide written feedback to the sponsor of the review 
     findings in the form of a discipline review letter (DRL).
       7. The DRL will provide feedback on the individual 
     ``reviewable unit'' from the discipline review team, and not 
     final, definitive decisions relevant to the NDA/BLA.
       8. If an application is to be presented to an advisory 
     committee, the final DRL on the ``reviewable unit'' may be 
     deferred pending completion of the advisory committee meeting 
     and internal review and consideration of the advice received.
       9. The following performance goals will apply to review of 
     ``reviewable units'' of an NDA/BLA for Fast Track drugs and 
     biologics that are submitted in advance of the complete NDA/
     BLA under this pilot program:
       a. Discipline review team review of a ``reviewable unit'' 
     for a Fast Track drug or biologic will be completed and a DRL 
     issued within 6 months of the date of the submission for 30% 
     of ``reviewable units'' submitted in FY04;
       b. Discipline review team review of a ``reviewable unit'' 
     for a Fast Track drug or biologic will be completed and a DRL 
     issued within 6 months of the date of the submission for 50% 
     of ``reviewable units'' submitted in FY05;
       c. Discipline review team review of a ``reviewable unit'' 
     for a Fast Track drug or biologic will be completed and a DRL 
     issued within 6 months of the date of the submission for 70% 
     ``reviewable units'' submitted in FY06, and
       d. Discipline review team review of a ``reviewable unit'' 
     for a Fast Track drug or biologic will be completed and a DRL 
     letter issued within 6 months of the date of the submission 
     for 90% of ``reviewable units'' submitted in FY07.
       10. If the complete NDA/BLA is submitted to FDA while a 6-
     month review clock for a ``reviewable unit'' is still open, 
     FDA will adhere to the timelines and performance goals for 
     both the ``reviewable unit'' and the complete NDA/BLA. For 
     example, if a ``reviewable unit'' is submitted in January and 
     the complete NDA/BLA is submitted in April, the review goal 
     for the ``reviewable unit'' will be July and the review goal 
     for the complete NDA/BLA will be October.
       11. Any resubmission or amendment of a ``reviewable unit'' 
     submitted by the sponsor in response to an FDA discipline 
     review letter will not be subject to the review timelines and 
     performance goals proposed above. FDA review of such 
     resubmissions and amendments in advance of submission of the 
     complete NDA/BLA will occur only as resources allow.
       12. This pilot program is limited to the initial submission 
     of an NDA/BLA and is not applicable to a resubmission in 
     response to an FDA complete response letter following the 
     complete review of an NDA/BLA.
       13. Guidance: FDA will develop and issue a joint CDER/CBER 
     guidance on how it intends to implement this pilot program by 
     September 30, 2003. The guidance will describe the 
     principles, processes, and procedures that will be followed 
     during the pilot program. The guidance also will define what 
     subsections of a complete technical section would be 
     considered an acceptable ``reviewable unit'' for pre-
     submission and review and how many individual ``reviewable 
     units'' from one or more technical sections of an NDA/BLA can 
     be pre-submitted and reviewed subject to separate review 
     clocks under this program at any given time. The pilot 
     program will be implemented in FY 2004, after the final 
     guidance is issued and will continue through FY 2007.

 B. Pilot 2--Frequent scientific feedback and interactions during drug 
                              development

       1. This pilot applies to drugs and biologics that have been 
     designated to be Fast Track drugs or biologics pursuant to 
     section 112 of the FDA Modernization Act (21 U.S.C. 356), 
     that are intended to treat serious and/or life-threatening 
     diseases, and that have been the subject of an end-of-phase 1 
     meeting. The pilot program is limited to one Fast Track 
     product in each CDER and CBER review division over the course 
     of the pilot program.
       2. For drugs and biologics that meet these criteria, FDA 
     may enter into an agreement with the sponsor to initiate a 
     format program of frequent scientific feedback and 
     interactions regarding the drug development program. The 
     feedback and interactions may take the form of regular 
     meetings between the division and the sponsor at appropriate 
     points during the development process, written feedback from 
     the division following review of the sponsor's drug 
     development plan, written feedback from the division 
     following review of important new protocols, and written 
     feedback from the division following review of study 
     summaries or complete study reports submitted by the sponsor.
       3. Decisions regarding what study reports would be reviewed 
     as summaries and what study reports would be reviewed as 
     complete study reports under this pilot program would be made 
     in advance, following discussions between the division and 
     the sponsor of the proposed drug development program. In 
     making these decisions, the review division will consider the 
     importance of the study to the drug development program, the 
     nature of the study, and the potential value of limited 
     (i.e., based on summaries) versus more thorough division 
     review (i.e., based on complete study reports).
       4. Guidance: FDA will develop and issue a joint CDER/CBER 
     guidance on how it intends to implement this pilot program by 
     September 30, 2003. The guidance will describe the 
     principles, processes, and procedures that will be followed 
     during the pilot program. The pilot program will be 
     implemented in FY 2004, after the final guidance is issued 
     and will continue through FY 2007. The full (unredacted) 
     study report will be provided to the FDA Commissioner and a 
     version of the study report redacted to remove confidential 
     commercial information or other information exempt from 
     disclosure, will be made available to the public.

                  C. Evaluation of the pilot programs

       1. In FY 2004, FDA will contract with an outside expert 
     consultant(s) to evaluate both pilot programs.
       2. The consultant(s) will develop an evaluation study 
     design that identifies key questions, data requirements, and 
     a data collection plan, and a conduct a comprehensive study 
     of the pilot programs to help assess the value, costs, and 
     impact of these programs to the drug development and review 
     process. A preliminary report will be generated by the 
     consultant by the end of FY06.

[[Page S5198]]

      viii. pre- and peri-nda/bla risk management plan activities

       a. Submission and Review of pre-NDA/BLA meeting packages: A 
     pre-NDA/BLA meeting package may include a summary of relevant 
     safety information and industry questions/discussion points 
     regarding proposed risk management plans and discussion of 
     the need for any post-approval risk management studies. The 
     elements of the proposal may include:
       1. assessment of clinical trial limitations and disease 
     epidemiology
       2. assessment of risk management tools to be used to 
     address known and potential risks
       3. suggestions for phase 4 epidemiology studies, if such 
     studies are warranted
       4. proposals for targeted post-approval surveillance (this 
     would include attempts to quantify background rates of risks 
     of concern and thresholds for actions)
       The pre-NDA/BLA meeting package will be reviewed and 
     discussed by the review divisions as well as the appropriate 
     safety group in CDER or CBER.
       b. Pre-NDA/BLA meeting with industry: This meeting may 
     include a discussion of the preliminary risk management plans 
     and proposed observational studies, if warranted, as outlined 
     above. Participants in this meeting will include product 
     safety experts from the respective Center. The intent of 
     these discussions will be for FDA to get a better 
     understanding of the safety issues associated with the 
     particular drug/biologic and the proposed risk management 
     plans, and to provide industry with feedback on these 
     proposals so that they can be included in the NDA/BLA 
     submission. It is the intent of this proposal that such risk 
     management plans and the discussions around them would focus 
     on specific issues of concern, either based on already 
     identified safety issues or reasonable potential focused 
     issues of concern.
       c. Review of NDA/BLA: The NDA/BLA submitted by industry may 
     include the proposed risk management tools and plans, and 
     protocols for observational studies, based on the discussions 
     that began with the pre-NDA/BLA meeting, as described above, 
     and may be amended as appropriate to further refine the 
     proposal. These amendments would not normally be considered 
     major amendments. Both the review division and the 
     appropriate safety group will be involved in the review of 
     the application and will try to communicate comments 
     regarding the risk management plan as early in the review 
     process as practicable, in the form of a discipline review 
     letter. Items to be included in the risk management plan to 
     assure FDA of the safety and efficiency of the drug or 
     biologic are to be addressed prior to approval of an 
     application. The risk management plan may contain additional 
     items that can be used to help refine the risks and actions 
     (e.g., background rates and observational studies) and these 
     items may be further defined and completed after approval in 
     accordance with time frames agreed upon at the time of 
     product approval.
       d. Peri-Approval Submission of Observational Study Reports 
     and Periodic Safely Update Reports (PSURs): For NDA/BLA 
     applications, and supplements containing clinical data, 
     submitted on or after October 1, 2002, FDA may use user fees 
     to review an applicant's implementation of the risk 
     management plan for a period of up to two years post-approval 
     for most products and for a period of up to three years for 
     products that require risk management beyond standard 
     labeling (e.g., a black box or bolded warning, medication 
     guide, restricted distribution). This period is defined for 
     purposes of the user fee goals as the peri-approval period. 
     Issues that arise during implementation of the risk 
     management plan (e.g., whether the plan is effective) will be 
     reported to FDA either in the form of a PSUR or in a periodic 
     or annual report (21 CFR 314.80 and 314.81) (ICH Guidance 
     E2C, Clinical Safety Data Management: Periodic Safety Update 
     Reports for Marketed Drugs) and addressed during the peri-
     approval period through discussions between the applicant and 
     FDA. PSURs may be submitted and reviewed semi-annually for 
     the first two or three years post approval to allow adequate 
     time for implementation of risk management plans.
       For drugs approved under PDUFA III, FDA may use user fees 
     to independently evaluate produce utilization for drugs with 
     important safety concerns, using drug utilization databases, 
     for the first three years post approval. The purpose of such 
     utilization evaluations is to evaluate whether these products 
     are being used in a safe manner and to work pro-actively with 
     companies during the peri-approval period to accomplish 
     this. FDA will allocate $70,900,000 in user fees over 5 
     years to the activities covered in this section. FDA will 
     track the specific amounts of user fees spent on these 
     activities and will include in its annual report to 
     Congress an accounting of this spending.
       e. Guidance Document Development: By the end of Fiscal Year 
     04, CDER and CBER will jointly develop final guidance 
     documents that address good risk assessment, risk management, 
     and pharmacovigilance practices.


 ix. independent consultants for biotechnology clinical trial protocols

                   A. Engagement of expert consultant

       During the development period for a biotechnology product, 
     a sponsor may request that FDA engage an independent expert 
     consultant, selected by FDA, to participate in the Agency's 
     review of the protocol for the clinical studies that are 
     expected to serve as the primary basis for a claim.

                             B. Conditions

       1. The product must be a biotechnology product (for 
     example, DNA plasmid products, synthetic peptides of fewer 
     than 40 amino acids, monoclonal antibodies for in vivo use, 
     and recombinant DNA-derived products) that represents a 
     significant advance in the treatment, diagnosis or prevention 
     of a disease or condition, or have the potential to address 
     an unmet medical need;
       2. The product may not have been the subject of a 
     previously granted request under this program;
       3. The sponsor must submit a written request for the use of 
     an independent consultant, describing the reasons why the 
     consultant should be engaged (e.g., as a result of 
     preliminary discussions with the Agency the sponsor expects 
     substantial disagreement over the proposed protocol); and
       4. The request must be designated as a ``Request for 
     Appointment of Expert Consultant'' and submitted in 
     conjunction with a formal meeting request (for example, 
     during the end-of-Phase II meeting or a Type A, meeting).

                   C. Recommendations for consultants

       The sponsor may submit a list of recommended consultants 
     for consideration by the Agency. The selected consultant will 
     either be a special government employee, or will be retained 
     by FDA under contract. The consultant's role will be advisory 
     to FDA and FDA will remain responsible for making scientific 
     and regulatory decisions regarding the clinical protocol in 
     question.

                         D. Denial of requests

       FDA will grant the request unless the Agency determines 
     that engagement of an expert consultant would not serve a 
     useful purpose (for example it is clearly premature). FDA 
     will engage the services of an independent consultant, of 
     FDA's choosing, as soon as practicable. If the Agency denies 
     the request, it will provide a written rationale to the 
     requester within 14 days of receipt.

                       E. Performance goal change

       Due to the time required to select and screen the 
     consultant for potential conflicts of interest and to allow 
     the consultant sufficient time to review the scientific 
     issues involved, the performance goals for scheduling the 
     formal meeting (see section III) may be extended for an 
     additional sixty (60) days.

                             F. Evaluation

       During FY 2006, FDA will conduct a study to evaluate the 
     costs and benefits of this program for both sponsors and the 
     Agency.


               x. first cycle review performance proposal

     A. Notification of issues identified during the filing review

       1. Performance Goal: For original NDA/BLA applications and 
     efficacy supplements, FDA will report substantive 
     deficiencies identified in the initial filing review to the 
     sponsor by letter, telephone conference, facsimile, secure e-
     mail, or other expedient means.
       2. The timeline for such communication will be within 14 
     calendar days after the 60 day filing date.
       3. If no deficiencies were noted, FDA will so notify the 
     sponsor.
       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 provide the sponsor a notification of 
     deficiencies prior to the goal date for 50% of applications 
     in FY 2003, 70% in FY 2004, and 90% in FY 2005, FY 2006, and 
     FY 2007.

             B. Good review management principles guidance

       FDA will develop a joint CDER-CBER guidance on Good Review 
     Management Principles (GRMPs), and publish final guidance by 
     the end of FY 2003. The Good Review Management Principles 
     will address, among other elements, the following:
       1. The filing review process, including communication of 
     issues identified during the filing review that may affect 
     approval of the application.
       2. Ongoing communication with the sponsor during the review 
     process (in accordance with 21 CFR 314.102(a)), including 
     emphasis on early communication of easily correctable 
     deficiencies (21 CFR 314.102(b)).
       3. Appropriate use of Information Request and Discipline 
     Review letters, as well as other informal methods of 
     communication (phone, tax, e-mail).
       4. Anticipating/planning for a potential Advisory Committee 
     meeting.
       5. Completing the primary reviews--allowing time for 
     secondary and tertiary reviews prior to the action goal date.
       6. Labeling feedback--planning to provide labeling comments 
     and scheduling time for teleconferences with the sponsor in 
     advance of the action goal date.

                              C. Training

       FDA will develop and implement a program for training all 
     review personnel, including current employees as well as 
     future new hires, on the good review management principles.

                             D. Evaluation

       FDA will retain an independent expert consultant to 
     undertake a study to evaluate issues associated with the 
     conduct of first cycle reviews.
       1. The study will be designed to assess current performance 
     and changes that occur

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     after the guidance on GRMPs is published. The study will 
     include collection of various types of tracking data 
     regarding actions that occur during the first cycle review, 
     both from an FDA and industry perspective (e.g., IR letters, 
     DR letters, draft labeling comments from FDA to the sponsor, 
     sponsor response to FDA requests for information).
       2. The study will also include an assessment of the first 
     cycle review history of all NDAs for NMEs and all BLAs during 
     PDUFA III. This assessment will include a more detailed 
     evaluation of the events that occurred during the review 
     process with a focus on identifying best practices by FDA and 
     industry that facilitated the review process.
       3. The study will also include an assessment of the 
     effectiveness of the training program implemented by FDA.
       4. FDA will develop a statement of work for the study and 
     will provide the public an opportunity to review and comment 
     on the statement of work before the study is implemented. The 
     consultant will prepare annual reports of the findings of the 
     study and a final study report at the end of the 5-year study 
     period. The full (un-redacted) study reports will be provided 
     to the FDA Commissioner and a version of the study reports 
     redacted to remove confidential commercial information or 
     other information exempt from disclosure, will be made 
     available to the public.
       5. Development and implementation of the study of first 
     cycle review performance will be a component of the 
     Performance Management Plan conducted out of the Office of 
     the Commissioner (see section X).
       6. Administrative oversight of the study will rest in the 
     Office of the Commissioner. The Office of the Commissioner 
     will convene a joint CDER/CBER review panel on a quarterly 
     basis as a mechanism for ongoing assessment of the 
     application of Good Review Management Principles to actions 
     taken on original NDA/BLA applications.


                xi. improving fda performance management

                          A. Performance fund

       The Commissioner will use at least $7 million over five 
     years of PDUFA III funds for initiatives targeted to improve 
     the drug review process.
       1. Funds would be made available by the Commissioner to the 
     Centers based both on identified areas of greatest need for 
     process improvements as well as on achievement of previously 
     identified objectives.
       2. Funds also could be used by the FDA Commissioner to 
     diagnose why objectives are not being met, or to examine 
     areas of concern.
       3. The studies conducted under this initiative would be 
     intended to foster:
       a. Development of programs to improve access to internal 
     and external expertise
       b. Reviewer development programs, particularly as they 
     relate to drug review processes,
       c. Advancing science and use of information management 
     tools
       d. Improving both inter- and intra-Center consistency, 
     efficiency, and effectiveness
       e. Improved reporting of management objectives
       f. Increased accountability for use of user fee revenues
       g. Focused investments on improvements in the process of 
     drug review
       h. Improved communication between the FDA and industry
       4. In deciding how to spend these funds, the Commissioner 
     would take into consideration how to achieve greater 
     harmonization of capabilities between CDER and CBER.

                        B. First two initiatives

       Two specific initiatives will begin early in PDUFA III and 
     supported from performance management initiative funds (1) 
     evaluation of first cycle review performance, and (2) process 
     review and analysis within the two centers.

                   1. First Cycle Review Performance

       See the First Cycle Review Performance (See section X. for 
     details on this proposed study).

                     2. Process Review and Analysis

       a. In FY 2003, FDA will contract with an outside consultant 
     to conduct a comprehensive process review and analysis within 
     CDER and CBER. This review will involve a thorough analysis 
     of information utilization, review management, and activity 
     cost.
       b. The review is expected to take from 18-24 months, 
     although its duration will depend on the type and amount of 
     complexity of the issues uncovered during the review.
       c. The outcome of this review will be a thorough 
     documentation of the process, a re-map of the process 
     indicating where efficiencies can be gained, activity-based 
     project accounting, optimal use of review tools, and a 
     suggested path for implementing the recommendations.
       d. FDA would anticipate delivery of a report of the 
     consultant's findings and recommendations in FY 2004-2005. 
     The agency would consider these recommendations in planning 
     any redesign or process reengineering to enhance 
     performance.

                           3. Further Studies

       In subsequent years of PDUFA III, FDA may develop other 
     study plans that will focus on further analysis of program 
     design, performance features and costs, to identify potential 
     avenues for further enhancement. Future studies would be 
     likely to include a comprehensive re-analysis of program 
     costs following the implementation of new PDUFA III review 
     initiatives and the adoption of any process changes following 
     the recommendations of the year 1 and 2 studies.


          xii. electronic applications and submissions--goals

       a. The Agency will centralize the accountability and 
     funding for all PDUFA Information Technology initiatives/
     activities for CBER, CDER, ORA and OC under the leadership of 
     the FDA CIO. The July 2001 HHS IT 5-year plan states that 
     infrastructure consolidation across the department should be 
     achieved, including standardization. The Agency CIO will be 
     responsible for ensuring that all PDUFA III IT infrastructure 
     and IT investments support the Agency's common IT goals, fit 
     into a common computing environment, and follow good IT 
     management practices.
       b. The Agency CIO will chair quarterly briefings on PDUFA 
     IT issues to periodically review and evaluate the progress of 
     IT initiatives against project milestones, discuss 
     alternatives when projects are not progressing, and review 
     proposals for new initiatives. On an annual basis, an 
     assessment will be conducted of progress against PDUFA III IT 
     goals and, established program milestones, including 
     appropriate changes to plans. A documented summary of the 
     assessment will be drafted and forwarded to the Commissioner. 
     A version of the study report redacted to remove confidential 
     commercial or security information, or other information 
     exempt from disclosure, will be made available to the public. 
     The project milestones, assessment and changes will be part 
     of the annual PDUFA III IT reports.
       c. FDA will implement a common solution in CBER, CDER, ORA 
     and OC for the secure exchange of content including secure e-
     mail, electronic signatures, and secure submission of, and 
     access to application components.
       d. FDA will deliver a single point of entry for the receipt 
     and processing of all electronic submissions in a highly 
     secure environment. This will support CBER, CDER, OC and ORA. 
     The system should automate the current electronic submission 
     processes such as checking the content of electronic 
     submissions for completeness and electronically acknowledging 
     submissions.
       e. FDA will provide a specification format for the 
     electronic submission of the Common Technical Document (e-
     CTD), and provide an electronic review system for this new 
     format that will be used by CBER, CDER and ORA reviewers. 
     Implementation should include training to ensure successful 
     deployment. This project will serve as the foundation for 
     automation of other types of electronic submissions. The 
     review software will be made available to the public.
       f. Within the first 12 months, FDA will conduct an 
     objective analysis and develop a plan for consolidation of 
     PDUFA III IT infrastructure and desktop management services 
     activities that will assess and prioritize the consolidation 
     possibilities among CBER, CDER, ORA and OC to achieve 
     technical efficiencies, target potential savings and realize 
     cost efficiencies. Based upon the results of this analysis, 
     to the extent appropriate, establish common IT infrastructure 
     and architecture components according to specific milestones 
     and dates. A documented summary of the analysis will be 
     forwarded to the Commissioner. A version of the study report 
     redacted to remove confidential commercial or security 
     information, or other information exempt from disclosure, 
     will be made available to the public.
       g. FDA will implement Capability Maturity Model (CMM) in 
     CBER, CDER, ORA and OC for PDUFA IT infrastructure and 
     investments, and include other industry best practices to 
     ensure that PDUFA III IT products and projects are of high 
     quality and produced with optimal efficiency and cost 
     effectiveness. This includes development of project plans and 
     schedules, goals, estimates of required resources, issues and 
     risks/mitigation plans for each PDUFA III IT initiative.
       h. Where common business needs exist, CBER, CDER, ORA and 
     OC will use the same software applications, such as eCTD 
     software, and COTS solutions.
       i. Within six months of authorization, a PDUFA III IT 5-
     year plan will be developed. Progress will be measured 
     against the milestones described in the plan.


                      XIII. ADDITIONAL PROCEDURES

                  A. Simplification of action letters

       To simplify regulatory procedures, CBER and CDER intend to 
     amend their regulations and processes to provide for the 
     issuance of either an ``approval'' (AP) or a ``complete 
     response'' (CR) action letter at the completion of a review 
     cycle for a marketing application.

   B. Timing of sponsor notification of deficiencies in applications

       To help expedite the development of drug and biologic 
     products, CBER and CDER intend to submit deficiencies to 
     sponsors in the form of an ``information request'' (IR) 
     letter when each discipline has finished its initial review 
     of its section of the pending application.


               XIV. DEFINITIONS AND EXPLANATION OF TERMS

       A. The term ``review and act on'' is understood to mean the 
     issuance of a complete action letter after the complete 
     review of 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. A major amendment to an original application, efficacy 
     supplement, or resubmission of any of these applications, 
     submitted

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     within three months of the goal date, extends the goal date 
     by three months. A major amendment to a manufacturing 
     supplement submitted within two months of the goal date 
     extends the goal date by two months.
       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 (determined by the agency as fitting the Class 1 
     category)
       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 item 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).
       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.

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