oversight

Prescription Drugs: FDA Has Met Most Performance Goals for Reviewing Applications

Published by the Government Accountability Office on 2012-03-30.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

             United States Government Accountability Office

GAO          Report to Congressional Requesters




March 2012
             PRESCRIPTION
             DRUGS
             FDA Has Met Most
             Performance Goals for
             Reviewing
             Applications




GAO-12-500
                                             March 2012

                                             PRESCRIPTION DRUGS
                                             FDA Has Met Most Performance Goals for Reviewing
                                             Applications
Highlights of GAO-12-500, a report to
congressional requesters




Why GAO Did This Study                       What GAO Found
The Food and Drug Administration             FDA met most performance goals for priority and standard NDAs and BLAs
(FDA) within the Department of Health        received from FY 2000 through FY 2010. FDA meets its performance goals by
and Human Services (HHS) is                  completing its review and issuing an action letter—such as an approval or a
responsible for overseeing the safety        response detailing deficiencies that are preventing the application from being
and efficacy of drugs and biologics          approved—for a specified percentage of applications within a designated period
sold in the United States. New drugs         of time. FDA designates NDAs and BLAs as either priority—if the product would
and biologics must be reviewed by            provide significant therapeutic benefits when compared to available drugs—or
FDA before they can be marketed, and         standard. FDA met the performance goals for both priority and standard NDAs
the Prescription Drug User Fee Act
                                             and BLAs for 10 of the 11 fiscal years GAO examined; FDA did not meet either of
(PDUFA) authorizes FDA to collect
                                             the goals for FY 2008. Although FDA had not yet issued an action letter for all of
user fees from the pharmaceutical
industry to support its review of
                                             the applications it received in FY 2011 and results are therefore preliminary, FDA
prescription drug applications,              was meeting the goals for both priority and standard NDAs and BLAs on which it
including new drug applications (NDA),       had taken action. Meanwhile, FDA review time for NDAs and BLAs—the time
biologic license applications (BLA), and     elapsed between FDA’s receipt of an application and issuance of an action
efficacy supplements that propose            letter—increased slightly from FY 2000 through FY 2010. In addition, the
changes to the way approved drugs            percentage of NDAs and BLAs receiving an approval letter at the end of the first
and biologics are marketed or used.          review cycle generally increased, although that percentage has decreased for
Under each authorization of PDUFA            priority NDAs and BLAs since FY 2007.
since 1992, FDA committed to
                                             FDA met most of its performance goals for efficacy supplements from FY 2000
performance goals for its drug and
biologic reviews.                            through FY 2010. Specifically, FDA met the performance goals for both priority
                                             and standard efficacy supplements for 10 of the 11 fiscal years GAO examined.
In preparation for the next PDUFA            FDA review time generally increased during the analysis period for both priority
reauthorization, GAO was asked to            and standard efficacy supplements. The percentage of priority efficacy
examine FDA’s drug and biologic              supplements receiving an approval letter at the end of the first review cycle
review processes. In this report, we         fluctuated from FY 2000 through FY 2010, ranging between 47 percent and
(1) examine trends in FDA’s NDA and          80 percent during this time. The results for standard efficacy supplements
BLA review performance for fiscal            showed a steadier increase with the percentage of first-cycle approval letters
years (FY) 2000 through 2010,
                                             rising from 43 percent for FY 2000 applications to 69 percent for FY 2010
(2) examine trends in FDA’s efficacy
                                             applications.
supplement review performance for
FYs 2000 through 2010, and                   The industry groups and consumer advocacy groups we interviewed noted a
(3) describe issues stakeholders have        number of perceived issues related to FDA’s review of drug and biologic
raised about the drug and biologic           applications. The most commonly mentioned issues raised by industry and
review processes and steps FDA is            consumer advocacy stakeholder groups were actions or requirements that can
taking that may address these issues.        increase review times (such as taking more than one cycle to approve
To do this work, GAO examined FDA            applications) and insufficient communication between FDA and stakeholders
drug and biologic review data,               throughout the review process. Industry stakeholders also noted a perceived lack
reviewed FDA user fee data,
                                             of predictability and consistency in reviews. Consumer advocacy group
interviewed FDA officials, and
                                             stakeholders noted issues related to inadequate assurance of the safety and
interviewed two industry groups and
five consumer advocacy groups. All of        effectiveness of approved drugs. FDA is taking steps that may address many of
the stakeholder groups participated in       these issues, including issuing new guidance, establishing new communication-
at least half of the meetings held by        related performance goals, training staff, and enhancing scientific decision
FDA to discuss the reauthorization of        making.
the prescription drug user fee program.      In commenting on a draft of this report, HHS generally agreed with GAO’s
View GAO-12-500. For more information,       findings and noted that they reflect what the agency reported for the same time
contact Marcia Crosse at (202) 512-7114 or   period. HHS also called attention to activities FDA has undertaken to improve the
crossem@gao.gov.
                                             prescription drug review process.
                                                                                     United States Government Accountability Office
Contents


Letter                                                                                      1
               Background                                                                   4
               FDA Met Most Performance Goals for Original NDAs and BLAs
                 While FDA Review Time Increased Slightly                                   8
               FDA Met Most Performance Goals for Original Efficacy
                 Supplements While FDA Review Time Increased Slightly                     15
               Stakeholders Noted Issues with the Prescription Drug Review
                 Process and FDA Is Taking Steps That May Address Many of
                 Those Issues                                                             20
               Concluding Observations                                                    26
               Agency Comments                                                            27

Appendix I     FDA NDA and BLA Review Performance for Fiscal Years (FYs)
               2000 through 2011                                                          29



Appendix II    FDA Efficacy Supplement Review Performance for Fiscal Years
               (FYs) 2000 through 2011                                                    36



Appendix III   Full-time Equivalent (FTE) FDA Staff Supporting Prescription Drug
               User Fee Activities, FYs 2000 through 2010                                 41



Appendix IV    Comments from the Department of Health and Human Services                  43



Appendix V     GAO Contact and Staff Acknowledgments                                      46



Tables
               Table 1: FDA’s NDA, BLA and Efficacy Supplement Performance
                        Goals, FYs 2000 through 2011 Cohorts                                8
               Table 2: FDA Review Performance for Priority Original NDAs and
                        BLAs Including Innovative Drugs, FYs 2000 through 2011            29
               Table 3: FDA Review Performance for Standard Original NDAs and
                        BLAs Including Innovative Drugs, FYs 2000 through 2011            31



               Page i                           GAO-12-500 Prescription Drug Performance Goals
          Table 4: Percentages of Closed and Open NDAs and BLAs, FYs
                   2000 through 2011                                                 33
          Table 5: FDA Review Performance for NDA and BLA
                   Resubmissions Including Innovative Drugs, FYs 2000
                   through 2011                                                      34
          Table 6: FDA Review Performance for Oncology Drugs Including
                   Those Granted Accelerated Approval, FYs 2000 through
                   2011                                                              35
          Table 7: FDA Review Performance for Priority Efficacy
                   Supplements, FYs 2000 through 2011                                36
          Table 8: FDA Review Performance for Standard Efficacy
                   Supplements, FYs 2000 through 2011                                38
          Table 9: Percentages of Closed and Open Efficacy Supplements,
                   FYs 2000 through 2011                                             40


Figures
          Figure 1: Percentage of Priority and Standard Original NDAs and
                   BLAs FDA Reviewed within 6 Months and 10 Months,
                   Respectively, FYs 2000 through 2010                               10
          Figure 2: Average FDA Review Time (in Calendar Days) for Priority
                   and Standard Original NDAs and BLAs, FYs 2000 through
                   2010                                                              12
          Figure 3: Percentage of Priority and Standard Original NDAs and
                   BLAs Receiving FDA First-Cycle Approvals, FYs 2000
                   through 2010                                                      14
          Figure 4: Percentage of Priority and Standard Original Efficacy
                   Supplements FDA Reviewed within 6 Months and 10
                   Months, Respectively, FYs 2000 through 2010                       16
          Figure 5: Average FDA Review Time (in Calendar Days) for Priority
                   and Standard Original Efficacy Supplements, FYs 2000
                   through 2010                                                      18
          Figure 6: Percentage of Priority and Standard Original Efficacy
                   Supplements Receiving FDA First-Cycle Approvals, FYs
                   2000 through 2010                                                 20




          Page ii                          GAO-12-500 Prescription Drug Performance Goals
Abbreviations

BLA               biologic license application
CBER              Center for Biologics Evaluation and Research
CDER              Center for Drug Evaluation and Research
FDA               Food and Drug Administration
FDAAA             Food and Drug Administration Amendments Act of 2007
FTE               full-time equivalent
FY                fiscal year
HHS               Department of Health and Human Services
NDA               new drug application
NME               new molecular entity
PDUFA             Prescription Drug User Fee Act
REMS              Risk Evaluation and Mitigation Strategy



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Page iii                                  GAO-12-500 Prescription Drug Performance Goals
United States Government Accountability Office
Washington, DC 20548




                                   March 30, 2012

                                   The Honorable Richard Burr
                                   Ranking Member
                                   Subcommittee on Children and Families
                                   Committee on Health, Education, Labor, and Pensions
                                   United States Senate

                                   The Honorable Tom Coburn
                                   Ranking Member
                                   Permanent Subcommittee on Investigations
                                   Committee on Homeland Security and Governmental Affairs
                                   United States Senate

                                   The Food and Drug Administration (FDA) within the Department of Health
                                   and Human Services (HHS) is responsible for overseeing the safety and
                                   efficacy of drugs and biological products sold in the United States. 1 In
                                   1992, Congress passed the Prescription Drug User Fee Act (PDUFA) to
                                   provide additional resources for FDA to support the process of reviewing
                                   applications for new drugs. 2 PDUFA authorized FDA to collect user fees
                                   from the pharmaceutical and biotechnology industries to supplement its
                                   annual appropriation for salaries and expenses; these user fees include
                                   application fees, annual establishment registration fees, and annual
                                   product fees. The prescription drug user fee program has been
                                   reauthorized every 5 years since 1992, most recently as part of the Food
                                   and Drug Administration Amendments Act of 2007 (FDAAA), which
                                   authorizes FDA to collect user fees for fiscal years (FY) 2008 through
                                   2012. 3 User fees have become a larger part of FDA’s funding for drug
                                   review processes, rising from 26.1 percent of costs in FY 1993—the first
                                   year FDA collected user fees for drugs—to 61.5 percent in FY 2010, the
                                   most recent year for which data are available. In FY 2010, PDUFA user


                                   1
                                    Biological products—which include vaccines, blood products, and proteins—are derived
                                   from living sources such as humans, animals, and microorganisms, while drugs are
                                   chemically synthesized. Unless otherwise indicated, throughout this report we use the
                                   term “drug” to refer to both chemically synthesized drugs and therapeutic biological
                                   products.
                                   2
                                    Pub. L. No. 102-571, tit. I, 106 Stat. 4491 (1992).
                                   3
                                    Pub. L. No. 110-85, tit. I, 121 Stat. 823 (2007). Fees are collected and available for
                                   obligation only to the extent and in the amount provided in advance in appropriations acts.



                                   Page 1                                     GAO-12-500 Prescription Drug Performance Goals
fees collected by FDA—including application, establishment, and product
fees—totaled more than $529 million, including over $172 million in
application fees. 4

Application fees are collected for a variety of drug and biologic application
types, including new drug applications (NDA), biologic license
applications (BLA), and efficacy supplements to approved NDAs and
BLAs; the amount of the user fee varies for different types of
applications. 5 An NDA is an application to market a new drug—either an
innovative drug or a variation of a previously marketed drug. A BLA is an
application to market a new biologic. FDA categorizes innovative drugs
that have not previously been marketed in any dosage or form as new
molecular entities (NMEs); FDA also considers nearly all BLAs to be
innovative drugs. An efficacy supplement to an NDA or BLA is submitted
to propose changes to the way an approved drug is marketed or used,
such as adding or modifying an indication or claim, revising the dose or
dose regimen, providing for a new route of administration, or changing the
marketing status from prescription to over-the-counter use.

Under each authorization of the prescription drug user fee program, FDA
committed to performance goals related to the review of drug
applications. 6 FDA meets its performance goals by completing its review
and issuing an action letter (i.e., an approval, denial, or complete
response) for a specified percentage of applications within a designated
period of time. 7 These performance goals, as well as user fee amounts,


4
 For the remainder of this report, we use the term “user fees” to refer to user fees
submitted with drug applications such as NDAs, BLAs, and efficacy supplements.
5
 For applications submitted in FY 2012, the fee for the review of an application (e.g., an
NDA or BLA) that requires clinical data is $1,841,500. The user fee for applications that do
not require clinical data is half this amount ($920,750), as is the fee for efficacy
supplements requiring clinical data. Some applications—such as those for orphan
designated products to treat rare diseases or conditions—are exempt from user fees. In
addition, abbreviated new drug applications, which are applications for the approval of
generic drugs, are not subject to user fees.
6
 See Pub. L. No. 110-85, § 101(c), 121 Stat. 823, 825 (2007). The performance goals are
identified in letters sent by the Secretary of Health and Human Services to the Chairman
of the Senate Committee on Health, Education, Labor, and Pensions and the Chairman of
the House Committee on Energy and Commerce, and are published on FDA’s website.
Each fiscal year, FDA is required to submit a report on its progress in achieving those
goals and future plans for meeting them. See 21 U.S.C. § 379h-2(a).
7
 A complete response letter describes any deficiencies that must be corrected in order for
an application to be approved.




Page 2                                     GAO-12-500 Prescription Drug Performance Goals
are negotiated between FDA and industry stakeholders and submitted to
congressional committees prior to each reauthorization. FDA’s authority
to collect user fees for drugs expires on October 1, 2012, and the
prescription drug user fee program will need to be reauthorized in order
for FDA to continue to collect user fees. In preparation for the
reauthorization of the prescription drug user fee program, you requested
that we examine FDA’s prescription drug review process. In this report,
we (1) examine trends in FDA’s NDA and BLA review performance for
FYs 2000 through 2010, (2) examine trends in FDA’s efficacy supplement
review performance for FYs 2000 through 2010, and (3) describe the
issues stakeholders have raised about the prescription drug review
processes and steps FDA is taking that may address these issues. We
provide additional details on FDA’s NDA and BLA review performance in
appendix I and efficacy supplement review performance in appendix II.
You also asked us to provide information on the number of full-time
equivalent (FTE) staff involved in the prescription drug review process;
this information is provided in appendix III.

To determine the trends in FDA’s review performance for NDAs, BLAs,
and efficacy supplements to approved NDAs and BLAs for FYs 2000
through 2010, we examined data obtained from FDA on the review
process for all such applications submitted to FDA in those years.
Additionally, we reviewed data on FY 2011 applications in order to
provide preliminary performance results for that year. FDA had not yet
completed its first review for a majority of the FY 2011 applications at the
time we received FDA’s data; as these reviews are completed, the
preliminary results are likely to change. 8 We reviewed the data for
reasonableness and consistency, including screening for missing data,
outliers, and obvious errors. We also interviewed FDA officials about
steps they take to ensure data reliability. We determined that these data
were sufficiently reliable for our purposes. Our analyses focused on the
proportion of drug applications in each fiscal year for which FDA met or
did not meet the applicable performance goal(s); the FDA review time
(i.e., the time counted toward user fee performance goals, from the date
of receipt of an application to the date FDA issued an action letter to end
the first review cycle); the time to final decision (i.e., the total time
between submission of an application and the sponsor’s withdrawal of the


8
 Specifically, FDA had completed its first review for only 39 percent of original NDAs and
BLAs and 34 percent of original efficacy supplements for FY 2011 at the time we received
FDA’s data, which include reviews by CBER and CDER through November 30, 2011.




Page 3                                    GAO-12-500 Prescription Drug Performance Goals
             application or FDA’s issuance of an approval or denial action letter in the
             last completed review cycle); and the percentage of first-cycle decisions
             that were approvals. 9 We also reviewed user fee data from FDA’s annual
             PDUFA financial reports to Congress for FYs 1993 through 2010 and
             interviewed FDA staff regarding drug review processes and the data we
             received from FDA.

             To describe the issues stakeholders have raised about the drug review
             processes and what steps FDA is taking that may address these issues,
             we interviewed two industry groups representing drug manufacturers and
             five consumer advocacy groups. 10 All of these groups have participated in
             at least half of the meetings held by FDA to discuss the reauthorization of
             the prescription drug user fee program. We performed content analyses
             of the interviews to determine the most pressing issues based on how
             often each issue was raised. To describe steps FDA is taking that may
             address some of these issues, we examined publicly available FDA
             documents, including the draft agreement between FDA and industry on
             the user fees and performance goals for FYs 2013 through 2017.

             We conducted this performance audit from October 2011 through March
             2012 in accordance with generally accepted government auditing
             standards. Those standards require that we plan and perform the audit to
             obtain sufficient, appropriate evidence to provide a reasonable basis for
             our findings and conclusions based on our audit objectives. We believe
             that the evidence obtained provides a reasonable basis for our findings
             and conclusions based on our audit objectives.


             Drug applications—including NDAs, BLAs, and efficacy supplements—
Background   are reviewed primarily by FDA’s Center for Drug Evaluation and
             Research (CDER), with a smaller proportion reviewed by the Center for
             Biologics Evaluation and Research (CBER). 11 Prior to submission of an


             9
              The first review cycle begins when FDA receives an application from a sponsor and ends
             when FDA issues an action letter. If FDA does not approve the application during the first
             review cycle, a new review cycle begins if the sponsor resubmits the application to FDA.
             10
               When we refer to consumer advocacy groups, we are referring to groups that advocate
             on behalf of consumers and patients.
             11
               FDA also reviews other types of drug applications that are beyond the scope of our
             work, such as manufacturing supplements that describe changes to production processes,
             equipment, or facilities used to produce an approved drug.




             Page 4                                   GAO-12-500 Prescription Drug Performance Goals
application, sponsors may choose to seek accelerated approval status if
the drug is intended to treat a serious or life-threatening illness (such as
cancer) and has the potential to provide meaningful therapeutic benefit to
patients over existing treatments. 12 Sponsors of a drug with accelerated
approval status may be granted approval on the basis of clinical trials
conducted using a surrogate endpoint—such as a laboratory
measurement or physical sign—as an indirect or substitute measurement
for a clinically meaningful outcome such as survival. 13 According to FDA,
the agency generally also speeds its review of drug applications with
accelerated approval status by granting them priority review, although
priority review can also be granted to an application without accelerated
approval status. 14 FDA grants priority review for applications that it
expects, if approved, would provide significant therapeutic benefits,
compared to available drugs, in the treatment, diagnosis, or prevention of
a disease. Applications for which there are no perceived significant
therapeutic benefits beyond those for available drugs are granted
standard review.

The review process involves evaluating scientific and clinical data in the
application submitted by a sponsor to determine whether the drug meets
statutory and regulatory standards for safety and effectiveness,
manufacturing and controls, and labeling. For example, sponsors must
demonstrate “substantial evidence” of effectiveness for the claimed
indications of the drug in order for FDA to approve the drug. 15 FDA
communicates with sponsors—through telephone conversations, letters,
or meetings—issues that arise during its review of an application that may




12
  See 21 C.F.R. §§ 314.500-314.560, 601.40-601.46.
13
  FDA may require that a drug granted accelerated approval undergo postmarketing
studies to verify the drug’s clinical benefit. Additionally, if FDA concludes that a drug can
be safely used only if distribution or use is restricted, FDA will require postmarketing
restrictions, such as restricting distribution to certain facilities or physicians with special
training or experience. FDA may withdraw approval of a drug granted accelerated
approval if postmarketing studies fail to verify clinical benefit or the sponsor fails to adhere
to the postmarketing restrictions, or for other reasons.
14
  FDA assesses all applications for priority review eligibility; the sponsor does not need to
request priority review. If priority review is granted, the sponsor is notified within 60 days
of the start of the review period.
15
  See 21 U.S.C. § 355(d); 42 U.S.C. § 262(j).




Page 5                                      GAO-12-500 Prescription Drug Performance Goals
prevent FDA from approving the application. 16 In response, sponsors can
submit additional information to FDA in the form of amendments to the
application. Certain applications are also subject to review by an
independent advisory committee. 17 FDA convenes advisory committees
to provide independent expertise and technical assistance to help the
agency make decisions about drug products. Additionally, FDA might
require the sponsor to submit a Risk Evaluation and Mitigation Strategy
(REMS) for the drug under review to ensure that the benefits of the drug
outweigh its risks. 18

FDA review time for an original application is calculated as the time
elapsed from the date FDA receives the application and associated user
fee to the date it issues an action letter; it is calculated using only the first
review cycle and therefore does not include any time that may elapse
while FDA is waiting for a sponsor to respond to FDA’s first-cycle action
letter or any review time that elapses during subsequent review cycles. 19
In order to close the review cycle for NDAs, BLAs, and efficacy
supplements, FDA must complete its review and issue an approval letter,
a denial letter, or a “complete response” letter (i.e., a letter delineating
any problems FDA identified in the application that prevented it from




16
  For example, FDA issues a letter to sponsors to inform them of filing review issues that
were identified during FDA’s initial review of an application. Additionally, approximately
midway through its review of an application, FDA provides feedback to sponsors on the
general progress and status of the application.
17
   FDA convenes an advisory committee meeting for all applications for NMEs and original
BLAs, unless an adequate justification is documented explaining the decision to not hold a
meeting. For other applications, an advisory committee may be convened if (1) the clinical
trial design used novel clinical or surrogate endpoints, (2) the application raises significant
issues regarding the safety or effectiveness of the drug, or (3) the application raises
significant public health questions on the role of the drug in the diagnosis, cure, mitigation,
treatment, or prevention of a disease. See 21 U.S.C. § 355(n), (s).
18
  See 21 U.S.C. § 355-1; 42 U.S.C. § 262(a)(2)(D). Examples of elements that may be
required as part of a REMS include medication guides, patient package inserts,
communication plans to health care providers, prescriber or pharmacy certification, and
restrictions on distribution.
19
  If the user fee is not paid within 5 days of receipt of the application, FDA will suspend
the review. The review clock is reset to start the first review cycle on the date that the user
fee is received.




Page 6                                      GAO-12-500 Prescription Drug Performance Goals
being approved). 20 The review cycle will also be closed if the application
is withdrawn by the sponsor. The date on which one of these actions
occurs is used to determine whether the review was completed within the
PDUFA goal time frame. 21 If FDA issues a complete response letter, the
sponsor may choose to submit a revised application to FDA. These are
known as resubmissions and their review is covered under the user fee
paid with the original submission. Resubmissions are classified as
Class 1 or Class 2 according to the complexity of the information they
contain, with Class 2 being the most complex. 22

Although the prescription drug performance goals have continued to
evolve with each reauthorization of the prescription drug user fee
program, the goals for NDAs, BLAs, and efficacy supplements have
remained fairly stable for recent cohorts—a cohort being comprised of all
the submissions of a certain type filed in the same fiscal year (see
table 1). For standard NDAs, BLAs, and efficacy supplements, the current
goal was phased in until it reached the current level (90 percent of
reviews completed within 10 months) in FY 2002. Similarly, the goal for
Class 1 NDA and BLA resubmissions was phased in, reaching its current
level of 90 percent of reviews completed within 2 months in FY 2001.
FDA can extend the review time frame for NDAs, BLAs, or Class 2




20
  According to FDA officials, FDA rarely issues a denial letter. If FDA issues a complete
response letter to conclude its review of an application, FDA provides the sponsor an
opportunity to meet with reviewing officials to discuss what further steps need to be taken
by the sponsor before the application can be approved. FDA may consider a sponsor’s
failure to take action within 1 year after the issuance of a complete response letter to be a
request by the sponsor to withdraw the application, unless the sponsor has requested an
extension of time to resubmit the application.
21
  Prior to August 2008, FDA also issued “approvable” and “not approvable” letters.
Historically an approvable letter was issued when FDA determined that an application
could be approved if the sponsor submitted additional information or agreed to certain
conditions, while a not approvable letter indicated that FDA was not able to approve an
application due to major deficiencies. Beginning in August 2008, FDA started issuing
complete response letters in lieu of approvable and not approvable letters.
22
  Class 1 resubmissions contain only certain information such as draft or final printed
labeling, safety or stability updates, or other minor clarifying information. Class 2
resubmissions are those containing any information not specified in the definition of
Class 1 resubmission, including any item that would require presentation to an advisory
committee.




Page 7                                     GAO-12-500 Prescription Drug Performance Goals
                                             resubmissions by 3 months if it receives a major amendment to the
                                             application from the sponsor within 3 months of the goal date. 23

Table 1: FDA’s NDA, BLA and Efficacy Supplement Performance Goals, FYs 2000 through 2011 Cohorts

                                                    Percentage of reviews to be completed within the PDUFA goal time frame
Fiscal year cohorts                          2000       2001       2002      2003     2004   2005   2006   2007    2008     2009     2010    2011
Priority NDA, BLA, or efficacy supplement,
percentage within 6 months                        90       90         90         90     90     90     90     90       90       90      90       90
Standard NDA, BLA, or efficacy
supplement, percentage within
         a
10 months                                         50       70         90         90     90     90     90     90       90       90      90       90
Class 1 NDA or BLA resubmission,
                          b
percentage within 2 months                        70       90         90         90     90     90     90     90       90       90      90       90
Class 2 NDA or BLA resubmission,
percentage within 6 months                        90       90         90         90     90     90     90     90       90       90      90       90
                                             Source: GAO analysis of FDA data.

                                             Note: A review cohort includes all the drug submissions relating to a particular performance goal that
                                             were submitted in a given fiscal year. For example, all NDAs received by FDA from October 1, 2010,
                                             to September 30, 2011, make up the NDA review cohort for FY 2011.
                                             a
                                              For FYs 2000 and 2001, FDA also had a goal to complete 90 percent of these reviews within
                                             12 months.
                                             b
                                             For FY 2000, FDA also had a goal to complete 90 percent of these reviews within 4 months.


                                             FDA met most of its performance goals for priority and standard original
FDA Met Most                                 NDA and BLA submissions for the FYs 2000 through 2010 cohorts.
Performance Goals                            However, the average FDA review time increased slightly during this
                                             period for both priority and standard NDAs and BLAs. The percentage of
for Original NDAs and                        FDA first-cycle approvals for both priority and standard NDAs and BLAs
BLAs While FDA                               generally increased from FY 2000 through FY 2010; however, the
Review Time                                  percentage of first-cycle approvals has decreased for priority NDAs and
                                             BLAs since FY 2007.
Increased Slightly


                                             23
                                               A major amendment is one that contains one or both of the following: (1) a substantial
                                             amount of new data or new information not previously submitted to, or reviewed by, FDA
                                             (e.g., a major new clinical safety or efficacy study report); or (2) a new analysis or major
                                             reanalysis of studies previously submitted for the pending application. A major
                                             amendment can be solicited or unsolicited. Prior to FY 2003, FDA did not extend the
                                             review time frame for efficacy supplements. Amendments cannot be submitted for Class 1
                                             resubmissions.




                                             Page 8                                            GAO-12-500 Prescription Drug Performance Goals
FDA Met Most                FDA met most of its performance goals for priority and standard original
Performance Goals for       NDA and BLA submissions during our analysis period by issuing the
Original NDAs and BLAs      proportion of action letters specified in the performance goals within the
                            goal time frames. Specifically, for priority original NDAs and BLAs, FDA
for FYs 2000 through 2010   met the performance goals for 10 of the 11 completed cohorts we
                            examined (see fig. 1). FDA also met the performance goals for 10 of the
                            11 completed standard NDA and BLA cohorts we examined. However,
                            FDA did not meet the goals (i.e., issue the specified proportion of action
                            letters within the goal time frames) for priority or standard NDAs and
                            BLAs in the FY 2008 cohort. FDA and industry stakeholders we
                            interviewed suggested that the reason FDA did not meet the goals for this
                            cohort was that extra time was required for implementation of REMS
                            requirements, which were introduced as part of the implementation of
                            FDAAA. Although the FY 2011 cohort was still incomplete at the time we
                            received FDA’s data, FDA was meeting the goals for both priority and
                            standard original NDAs and BLAs on which it had taken action. 24




                            24
                              Approximately 32 percent of priority original NDAs and BLAs and 70 percent of standard
                            original NDAs and BLAs received in FY 2011 were still under review at the time we
                            received FDA’s data, which include reviews by CBER and CDER through November 30,
                            2011. As a result, it was too soon to tell what the final results for this cohort would be. The
                            percentage of priority and standard original drug submissions reviewed within 6 months
                            and 10 months, respectively, may increase or decrease as those reviews are completed.




                            Page 9                                      GAO-12-500 Prescription Drug Performance Goals
Figure 1: Percentage of Priority and Standard Original NDAs and BLAs FDA Reviewed within 6 Months and 10 Months,
Respectively, FYs 2000 through 2010




                                       Notes: A review cohort includes all of the drug submissions relating to a particular performance goal
                                       that were submitted in a given fiscal year. Only original NDAs and BLAs that had received an action
                                       letter from FDA at the time we received FDA’s data were included in this analysis; the data include
                                       reviews by CBER and CDER through November 30, 2011. The review cycle for original submissions
                                       starts when FDA receives a submission and ends when FDA issues an action letter or the sponsor
                                       withdraws the submission.
                                       Priority and standard designations are associated with different lengths of time allotted (6 and
                                       10 months, respectively) for FDA to complete its review of original drug submissions and issue an
                                       action letter. If FDA completed its review of a priority submission in 6 months or less, it met the
                                       priority goal time frame. If FDA completed its review of a standard submission in 10 months or less, it
                                       met the standard goal time frame. Our calculations include extensions of the goal time frame, where
                                       applicable. Goal time frames can be extended by 3 months if the sponsor submits a major
                                       amendment to the application within 3 months of the goal date.
                                       For FYs 2000 and 2001, FDA also had a goal to complete 90 percent of standard reviews within
                                       12 months.




                                       Page 10                                         GAO-12-500 Prescription Drug Performance Goals
                          For the subset of priority NDAs and BLAs that were for innovative drugs,
                          FDA met the performance goals for 9 of the 11 completed cohorts—all
                          cohorts except FYs 2008 and 2009. For the subset of standard NDAs and
                          BLAs that were for innovative drugs, FDA also met the performance goals
                          for 9 of the 11 completed cohorts—all cohorts except FYs 2007 and 2008.
                          For the incomplete FY 2011 cohort, FDA was meeting the goals for the
                          subsets of both priority and standard NDAs and BLAs that were for
                          innovative drugs.

                          If FDA issues a complete response letter to the sponsor noting
                          deficiencies with the original submission, the sponsor can resubmit the
                          application with the deficiencies addressed. For Class I NDA and BLA
                          resubmissions, FDA met the performance goals for 8 of the 11 completed
                          cohorts we examined. 25 For Class 2 NDA and BLA resubmissions, FDA
                          met the performance goals for 10 of the 11 completed cohorts we
                          examined. Although the FY 2011 cohort was still incomplete at the time
                          we received FDA’s data, FDA was meeting the goals for both the Class 1
                          resubmissions and the Class 2 resubmissions on which it had taken
                          action.


Average FDA Review Time   Overall, average FDA review time—the time elapsed from when FDA
Increased Slightly for    received a submission until it issued an action letter—increased slightly
Original NDAs and BLAs    from FY 2000 through FY 2010 for both priority and standard NDAs and
                          BLAs. There was a larger increase in average review time for both types
from FY 2000 through      of applications beginning in FY 2006. However, average review time
FY 2010                   began decreasing after FY 2007 for standard applications and after
                          FY 2008 for priority applications, bringing the review times back near the
                          FY 2000 levels (see fig. 2). As mentioned previously, FDA and industry
                          stakeholder groups noted the implementation of REMS requirements as a
                          contributing factor to increased review times for the FY 2008 cohort.
                          Although the FY 2011 cohort was still incomplete at the time we received
                          FDA’s data, average FDA review time for applications on which FDA had




                          25
                            The performance we report for FDA’s review of resubmissions may not match the
                          performance reported in FDA’s annual PDUFA performance reports because our analysis
                          was limited to resubmissions made in FYs 2000 through 2011 for original NDAs and BLAs
                          that were also submitted in FYs 2000 through 2011. Resubmissions made in FYs 2000
                          through 2011 for original NDAs and BLAs submitted prior to FY 2000 were not captured
                          by our analysis.




                          Page 11                                GAO-12-500 Prescription Drug Performance Goals
taken action was 186 days for priority NDAs and BLAs and 308 days for
standard NDAs and BLAs. 26

Figure 2: Average FDA Review Time (in Calendar Days) for Priority and Standard
Original NDAs and BLAs, FYs 2000 through 2010




Note: A review cohort includes all of the drug submissions relating to a particular performance goal
that were submitted in a given fiscal year. Only original NDAs and BLAs that had received an action
letter from FDA at the time we received FDA’s data were included in this analysis; the data include
reviews by CBER and CDER through November 30, 2011. The review cycle for original submissions
starts when FDA receives a submission and ends when FDA issues an action letter or the sponsor
withdraws the submission. Priority and standard designations are associated with different lengths of
time allotted (6 and 10 months, respectively) for FDA to complete its review of original drug
submissions and issue an action letter.




26
  Approximately 32 percent of priority original NDAs and BLAs and 70 percent of standard
original NDAs and BLAs received in FY 2011 were still under review at the time we
received FDA’s data, which include reviews by CBER and CDER through November 30,
2011. As a result, it was too soon to tell what the final results for this cohort would be. The
average FDA review time for this cohort may increase or decrease as those reviews are
completed.




Page 12                                        GAO-12-500 Prescription Drug Performance Goals
                             Trends in average FDA review time for the subset of NDAs and BLAs that
                             were for innovative drugs were similar to trends for all priority or standard
                             NDAs and BLAs. For the subset of priority NDAs and BLAs that were for
                             innovative drugs, average FDA review times were sometimes longer and
                             sometimes shorter than those for all priority NDAs and BLAs; review
                             times for the subset of standard NDAs and BLAs that were for innovative
                             drugs were generally slightly longer than review times for all standard
                             NDAs and BLAs.

                             We were unable to calculate the average time to final decision for original
                             NDAs and BLAs—that is, the average time elapsed between submission
                             of an application and the sponsor’s withdrawal of the application or FDA’s
                             issuance of an approval or denial action letter in the last completed
                             review cycle. Time to final decision includes FDA review time as well as
                             time that elapsed between review cycles while FDA was waiting for the
                             sponsor to resubmit the application. We were unable to complete this
                             calculation because most cohorts were still open for these purposes
                             (i.e., fewer than 90 percent of submissions had received a final action
                             such as approval, denial, or withdrawal). Specifically, for priority NDAs
                             and BLAs, only four cohorts (FYs 2001, 2002, 2005, and 2006) had at
                             least 90 percent of submissions closed, and for standard NDAs and
                             BLAs, only one cohort (FY 2002) had at least 90 percent of submissions
                             closed. (See app. I, table 4 for details.) As a result, there were too few
                             completed cohorts available to calculate the time to final decision in a
                             meaningful way. FDA may opt to consider an application withdrawn (and
                             thus closed) if the sponsor fails to resubmit the application within 1 year
                             after FDA issues a complete response letter. When we examined the
                             open applications using this criterion, we identified 194 open NDAs and
                             BLAs in FYs 2000 through 2010 for which FDA had issued a complete
                             response letter in the most recent review cycle but had not yet received a
                             resubmission from the sponsor. FDA had issued the complete response
                             letter more than 1 year earlier for 162 (84 percent) of these applications.


Percentage of FDA            The percentage of priority NDAs and BLAs receiving an approval letter at
First-Cycle Approvals        the end of the first review cycle exhibited a sharp 1-year decline from
Generally Increased from     FY 2000 to FY 2001, then increased substantially from FY 2001 through
                             FY 2007, before decreasing again from FY 2007 through FY 2010 (see
FY 2000 through FY 2010      fig. 3). The percentage of first-cycle approvals for standard NDAs and
but Decreased for Priority   BLAs showed a similar 1-year decline from FY 2000 to FY 2001, then
NDAs and BLAs Since          varied somewhat but generally increased from FY 2002 through FY 2010.
FY 2007                      Although review of the FY 2011 cohort was incomplete at the time we
                             received FDA’s data, 93 percent of the priority NDAs and BLAs that had


                             Page 13                            GAO-12-500 Prescription Drug Performance Goals
received a first-cycle action letter had been approved, as had 42 percent
of the standard NDAs and BLAs. 27

Figure 3: Percentage of Priority and Standard Original NDAs and BLAs Receiving
FDA First-Cycle Approvals, FYs 2000 through 2010




Note: A review cohort includes all of the drug submissions relating to a particular performance goal
that were submitted in a given fiscal year. Only original NDAs and BLAs that had received an action
letter from FDA at the time we received FDA’s data were included in this analysis; the data include
reviews by CBER and CDER through November 30, 2011. The review cycle for original submissions
starts when FDA receives a submission and ends when FDA issues an action letter or the sponsor
withdraws the submission. Priority and standard designations are associated with different lengths of
time allotted (6 and 10 months, respectively) for FDA to complete its review of original drug
submissions and issue an action letter.




27
  Approximately 32 percent of priority original NDAs and BLAs and 70 percent of standard
original NDAs and BLAs received in FY 2011 were still under review at the time we
received FDA’s data, which include reviews by CBER and CDER through November 30,
2011. As a result, it was too soon to tell what the final results for this cohort would be. The
percentage of first-cycle approvals for this cohort may increase or decrease as those
reviews are completed.




Page 14                                        GAO-12-500 Prescription Drug Performance Goals
                          Trends for FYs 2000 through 2010 in the percentage of first-cycle
                          approvals were similar for the subset of NDAs and BLAs that were for
                          innovative drugs when compared to trends for all priority or standard
                          NDAs and BLAs. For the subset of priority NDAs and BLAs for innovative
                          drugs, the percentage of first-cycle approvals was generally higher than
                          for all priority NDAs and BLAs. For standard submissions, the percentage
                          of first-cycle approvals for innovative drugs was generally lower than for
                          all standard NDAs and BLAs; for some cohorts (e.g., FYs 2000, 2004–
                          2006, and 2008) this difference was substantial.


                          FDA met most of its performance goals for priority and standard original
FDA Met Most              efficacy supplements to approved NDAs and BLAs for the FYs 2000
Performance Goals         through 2010 cohorts. However, the average FDA review time generally
                          increased during this period for both priority and standard efficacy
for Original Efficacy     supplements. The percentage of FDA first-cycle approvals fluctuated for
Supplements While         priority efficacy supplements but generally increased for standard efficacy
FDA Review Time           supplements for the FYs 2000 through 2010 cohorts.

Increased Slightly
FDA Met Most              FDA met most of its performance goals for efficacy supplements to
Performance Goals for     approved NDAs and BLAs during our analysis period. Specifically, FDA
Original Efficacy         met the performance goals for both priority and standard efficacy
                          supplements for 10 of the 11 completed cohorts we examined (see fig. 4).
Supplements in FYs 2000   Although the FY 2011 cohort was still incomplete at the time we received
through 2010              FDA’s data, based on efficacy supplements on which it had taken action,
                          FDA was meeting the goal for both priority and standard efficacy
                          supplements. 28




                          28
                            Approximately 50 percent of priority and 70 percent of standard efficacy supplements
                          received in FY 2011 were still under review at the time we received FDA’s data, which
                          include reviews by CBER and CDER through November 30, 2011. As a result, it was too
                          soon to tell what the final results for this cohort would be. The percentage of priority and
                          standard efficacy supplements reviewed within 6 and 10 months, respectively, may
                          increase or decrease as those reviews are completed.




                          Page 15                                    GAO-12-500 Prescription Drug Performance Goals
Figure 4: Percentage of Priority and Standard Original Efficacy Supplements FDA Reviewed within 6 Months and 10 Months,
Respectively, FYs 2000 through 2010




                                        Notes: A review cohort includes all of the efficacy supplement submissions relating to a particular
                                        performance goal that were submitted in a given fiscal year. Only original efficacy supplements that
                                        had received an action letter from FDA at the time we received FDA’s data were included in this
                                        analysis; the data include reviews by CBER and CDER through November 30, 2011. The review
                                        cycle for efficacy supplements starts when FDA receives a submission and ends when FDA issues an
                                        action letter or the sponsor withdraws the submission.
                                        Priority and standard designations are associated with different lengths of time allotted (6 and
                                        10 months, respectively) for FDA to complete its review of original efficacy supplement submissions
                                        and issue an action letter. If FDA completed its review of a priority submission in 6 months or less, it
                                        met the priority goal time frame. If FDA completed its review of a standard submission in 10 months
                                        or less, it met the standard goal time frame. Our calculations include extensions of the goal time
                                        frame, where applicable. Goal time frames can be extended by 3 months if the sponsor submits a
                                        major amendment to the application within 3 months of the goal date. Prior to FY 2003, FDA did not
                                        extend the goal time frame for efficacy supplement submissions.
                                        For FYs 2000 through 2001, FDA also had a goal to complete 90 percent of standard reviews within
                                        12 months.




                                        Page 16                                          GAO-12-500 Prescription Drug Performance Goals
Average FDA Review Time   Average FDA review time generally increased during our analysis period
Generally Increased for   for both priority and standard efficacy supplements. Specifically, average
Original Efficacy         FDA review time for priority efficacy supplements increased from
                          173 days in the FY 2000 cohort to a peak of 205 days in the FY 2009
Supplements from          cohort and then fell in the FY 2010 cohort to 191 days (see fig. 5). For
FYs 2000 through 2010     standard efficacy supplements, average FDA review time rose from
                          285 days in the FY 2000 cohort to a peak of 316 days in the FY 2008
                          cohort and then fell in the FY 2010 cohort to 308 days. Although the
                          FY 2011 cohort was still incomplete at the time we received FDA’s data,
                          average FDA review time for efficacy supplements on which FDA had
                          taken action was 195 days for priority submissions and 284 days for
                          standard submissions. 29




                          29
                            Approximately 50 percent of priority and 70 percent of standard efficacy supplements
                          received in FY 2011 were still under review at the time we received FDA’s data, which
                          include reviews by CBER and CDER through November 30, 2011. As a result, it was too
                          soon to tell what the final results for this cohort would be. The average FDA review time
                          for this cohort may increase or decrease as those reviews are completed.




                          Page 17                                   GAO-12-500 Prescription Drug Performance Goals
Figure 5: Average FDA Review Time (in Calendar Days) for Priority and Standard
Original Efficacy Supplements, FYs 2000 through 2010




Note: A review cohort includes all of the efficacy supplement submissions relating to a particular
performance goal that were submitted in a given fiscal year. Only original efficacy supplements that
had received an action letter from FDA at the time we received FDA’s data were included in this
analysis; the data include reviews by CBER and CDER through November 30, 2011. The review
cycle for efficacy supplements starts when FDA receives a submission and ends when FDA issues an
action letter or the sponsor withdraws the submission. Priority and standard designations are
associated with different lengths of time allotted (6 and 10 months, respectively) for FDA to complete
its review of original efficacy supplement submissions and issue an action letter.


As with NDA and BLA submissions, we were unable to calculate the
average time to final decision for efficacy supplements in any meaningful
way because there were too few completed cohorts. Specifically, for
priority efficacy supplements, only four cohorts (FYs 2000, 2001, 2004,
and 2007) had at least 90 percent of submissions closed, and for
standard efficacy supplements, only one cohort (FY 2005) had at least 90
percent of submissions closed. (See app. II, table 9 for details.) FDA may
opt to consider an application withdrawn (and thus closed) if the sponsor
fails to resubmit the application within 1 year after FDA issues a complete
response letter. When we examined the open applications using this
criterion, we identified 196 open efficacy supplements in FYs 2000
through 2010 for which FDA had issued a complete response letter in the
most recent review cycle but had not yet received a resubmission from


Page 18                                        GAO-12-500 Prescription Drug Performance Goals
                           the sponsor. FDA had issued the complete response letter more than
                           1 year earlier for 168 (86 percent) of these submissions.


Percentage of FDA          The percentage of priority efficacy supplements receiving an approval
First-Cycle Approvals      decision at the end of the first review cycle fluctuated for FYs 2000
Fluctuated for Priority    through 2010, ranging between 47 percent and 80 percent during this
                           time (see fig. 6). The results for standard efficacy supplements showed a
Efficacy Supplements but   steadier increase than for priority submissions. Specifically, the
Generally Increased for    percentage of first-cycle approvals rose from 43 percent in the FY 2000
Standard Efficacy          cohort to 69 percent in the FY 2010 cohort. Although the FY 2011 cohort
Supplements from           was still incomplete at the time we received FDA’s data, 63 percent of
FYs 2000 through 2010      first-cycle action letters for standard submissions and 92 percent of
                           first-cycle action letters for priority submissions issued by that time were
                           approvals. 30




                           30
                             Approximately 50 percent of priority and 70 percent of standard efficacy supplements
                           received in FY 2011 were still under review at the time we received FDA’s data, which
                           include reviews by CBER and CDER through November 30, 2011. As a result, it was too
                           soon to tell what the final results for this cohort would be. The percentage of first-cycle
                           approvals for this cohort may increase or decrease as those reviews are completed.




                           Page 19                                    GAO-12-500 Prescription Drug Performance Goals
                       Figure 6: Percentage of Priority and Standard Original Efficacy Supplements
                       Receiving FDA First-Cycle Approvals, FYs 2000 through 2010




                       Note: A review cohort includes all of the efficacy supplement submissions relating to a particular
                       performance goal that were submitted in a given fiscal year. Only original efficacy supplements that
                       had received an action letter from FDA at the time we received FDA’s data were included in this
                       analysis; the data include reviews by CBER and CDER through November 30, 2011. The review
                       cycle for efficacy supplements starts when FDA receives a submission and ends when FDA issues an
                       action letter or the sponsor withdraws the submission. Priority and standard designations are
                       associated with different lengths of time allotted (6 and 10 months, respectively) for FDA to complete
                       its review of original efficacy supplement submissions and issue an action letter.




                       The industry groups and consumer advocacy groups we interviewed
Stakeholders Noted     noted a number of issues related to FDA’s review of prescription drug
Issues with the        applications. The most commonly mentioned issues raised by industry
                       and consumer advocacy stakeholder groups were actions or
Prescription Drug      requirements that stakeholders believe can increase review times and
Review Process and     insufficient communication between FDA and stakeholders throughout the
FDA Is Taking Steps    review process. Industry stakeholders also noted a lack of predictability
                       and consistency in reviews. Consumer advocacy group stakeholders
That May Address       noted issues related to inadequate assurance of the safety and efficacy of
Many of Those Issues   approved drugs. FDA is taking steps that may address many of these
                       issues.



                       Page 20                                        GAO-12-500 Prescription Drug Performance Goals
Stakeholders Noted        Most of the seven stakeholder groups we interviewed told us that there
Actions or Requirements   are actions and requirements that can lengthen FDA’s review process.
That They Believe Can     For example, four of the five consumer advocacy group stakeholders
                          noted that FDA does not require sponsors to submit electronic
Increase Review Times     applications; three of these stakeholders noted that requiring electronic
                          applications could make the review process faster. Additionally, the two
                          industry stakeholders told us that they believe FDA should approve more
                          applications during the first review cycle. We found that an average of
                          44 percent of all original NDAs and BLAs submitted in FYs 2000 through
                          2010 were approved during the first review cycle, while 75 percent were
                          ultimately approved.

                          In addition, the two industry stakeholders that we interviewed raised
                          requirements that can make review times longer, but the consumer
                          advocacy group stakeholders did not agree with these points. For
                          example, both industry stakeholders noted that working out the
                          implementation of REMS requirements introduced in FDAAA slowed
                          FDA’s review process. One industry stakeholder stated that discussions
                          about REMS often happened late in the review process, resulting in an
                          increase in review times; another noted that REMS requirements have
                          not been standardized, contributing to longer review times. In contrast,
                          one consumer advocacy group stakeholder that we interviewed
                          suggested that standardized REMS requirements or a “one size fits all”
                          approach would not be meaningful as a risk management strategy. The
                          industry and consumer advocacy group stakeholders also disagreed on
                          another issue that can potentially lengthen the review process—FDA’s
                          process for using outside scientific expertise for the review of
                          applications. 31 The two industry stakeholders we interviewed stated that
                          the rules surrounding consultation with an advisory committee—
                          particularly those related to conflicts of interest—can extend the time it
                          takes FDA to complete the review process. In contrast, two of the
                          consumer advocacy group stakeholders we interviewed specifically stated


                          31
                            Both industry stakeholders stated that FDA’s ability to consult with advisory committees
                          is inefficient in part due to the associated rules, including the conflict-of-interest provisions
                          in FDAAA and transparency provisions in the Federal Advisory Committee Act. FDAAA
                          placed a cap on the number of conflict-of-interest waivers that FDA can grant annually,
                          and although one stakeholder did not think the number of waivers FDA grants each year
                          approaches this cap, the stakeholder suggested that the very existence of a cap could
                          discourage FDA from granting waivers. See 21 U.S.C. § 379d-1(c). The Federal Advisory
                          Committee Act places a particular emphasis on open meetings, chartering, and public
                          involvement. See 5 U.S.C. app. 2, §§ 9, 10.




                          Page 21                                      GAO-12-500 Prescription Drug Performance Goals
that FDA should be concerned with issues of conflict of interest in
advisory committees used during the drug review process.

FDA has taken or plans to take several steps that may address issues
stakeholders noted can lengthen the review process, including issuing
new guidance, commissioning and issuing assessments of the review
process, training staff, and establishing programs aimed at helping
sponsors. For example, according to the draft agreement with industry for
the upcoming prescription drug user fee program reauthorization, FDA
would issue guidance on the standards and format for submitting
electronic applications and would begin tracking and reporting on the
number of electronic applications received. 32 In addition, according to the
draft agreement, FDA would publish both an interim and a final
assessment of the review process for innovative drugs and then hold
public meetings for stakeholders to present their views on the success of
the program, including its effect on the efficiency and effectiveness of
first-cycle reviews. FDA would also provide training to staff on reviewing
applications containing complex scientific issues, which may improve
FDA’s ability to grant first-cycle approvals where appropriate. In addition,
FDA would issue guidance on assessing the effectiveness of REMS for a
particular drug and would hold public meetings to explore strategies to
standardize REMS, where appropriate. However, we did not identify any
examples of steps FDA has taken to address industry stakeholder issues
with leveraging outside expertise during the drug review process in any of
the recently released strategy, assessment, and guidance documents we
reviewed. 33




32
  In February 2012, FDA issued draft guidance on providing applications in electronic
format. See U.S. Department of Health and Human Services, Food and Drug
Administration, Draft Guidance for Industry on Providing Regulatory Submissions in
Electronic Format—Standardized Study Data (Silver Spring, Md.: February 2012).
33
  We considered documents published in 2010 or later to be recently released. In a
previous study, GAO found that while FDA faced barriers to recruiting advisory committee
candidates without conflicts of interest, the agency may be able to mitigate these barriers
by expanding its outreach efforts. See GAO, FDA Advisory Committees: Process for
Recruiting Members and Evaluating Potential Conflicts of Interest, GAO-08-640
(Washington, D.C.: Sept. 30, 2008).




Page 22                                   GAO-12-500 Prescription Drug Performance Goals
Stakeholders Cite       Most of the two industry and five consumer advocacy group stakeholders
Insufficient            that we interviewed told us that there is insufficient communication
Communication between   between FDA and stakeholders throughout the review process. For
                        example, both of the industry stakeholders noted that FDA does not
FDA and Stakeholders    clearly communicate the regulatory standards that it uses to evaluate
throughout the Review   applications. In particular, the industry stakeholders noted that the
Process                 regulatory guidance documents issued by FDA are often out of date or
                        the necessary documents have not yet been developed. Additionally, both
                        industry stakeholders and two consumer advocacy group stakeholders
                        noted that after sponsors submit their applications, insufficient
                        communication from FDA prevents sponsors from learning about
                        deficiencies in their applications early in FDA’s review process. According
                        to these four stakeholders, if FDA communicated these deficiencies
                        earlier in the process, sponsors would have more time to address them;
                        this would increase the likelihood of first-cycle approvals. Finally, three
                        consumer advocacy group stakeholders also noted that FDA does not
                        sufficiently seek patient input during reviews. One stakeholder noted that
                        it is important for FDA to incorporate patient perspectives into its reviews
                        of drugs because patients might weigh the benefits and risks of a certain
                        drug differently than FDA reviewers.

                        FDA has taken or plans to take several steps that may address
                        stakeholders’ issues with the frequency and quality of its communications
                        with stakeholders, including conducting a review of its regulations,
                        establishing new review programs and communication-related
                        performance goals, providing additional staff training, and increasing its
                        efforts to incorporate patient input into the review process. FDA is in the
                        process of reviewing its regulations to identify burdensome, unclear,
                        obsolete, ineffective, or inefficient regulations and is soliciting stakeholder
                        input on additional rules that could be improved. In addition, according to
                        the draft agreement with industry, FDA would establish a review model
                        with enhanced communication requirements for innovative drugs,
                        including requirements to hold pre- and late-cycle submission meetings
                        with sponsors as well as to update sponsors following FDA’s internal




                        Page 23                             GAO-12-500 Prescription Drug Performance Goals
                         midcycle review meetings. 34 Additionally, under the draft user fee
                         agreement, FDA would inform sponsors of the planned review timeline
                         and any substantive review issues identified thus far within 74 days of
                         receipt for 90 percent of original NDAs, BLAs, and efficacy supplements.
                         FDA would also issue guidance, develop a dedicated drug development
                         training staff, and provide training on communication for all CDER staff
                         involved in the review of investigational new drugs. 35 Finally, FDA would
                         increase its utilization of patient representatives as consultants to provide
                         patient views early in the product development process and to ensure
                         those perspectives are considered in regulatory discussions. More
                         specifically, FDA would expect to start with a selected set of disease
                         areas and meet with the relevant patient advocacy groups and other
                         interested stakeholders to determine how to incorporate patient
                         perspectives into FDA’s decision making.


Industry Stakeholders    The two industry stakeholders that we interviewed also told us that there
Report a Lack of         is a lack of predictability and consistency in FDA’s reviews of drug
Predictability and       applications. For example, both stakeholders noted that there is
                         sometimes inconsistent application of criteria across review divisions or
Consistency in Reviews   offices. Further, both industry stakeholders we interviewed noted that
                         FDA lacks a structured benefit-risk framework to refer to when making




                         34
                           At the presubmission meeting, FDA and the sponsor will agree on the content of a
                         complete application, including preliminary discussions on the need for REMS; the
                         agreement and discussion will be summarized at the end of the meeting and will be
                         reflected in the FDA meeting minutes. Following the internal midcycle review meeting,
                         FDA will call the sponsor with an update on the status of the review of its application; this
                         update will include any significant issues identified to date; any information requests;
                         information regarding safety concerns and preliminary thoughts regarding risk
                         management; proposed dates for the late-cycle meeting; updates regarding plans for any
                         potential advisory committee meetings; and other projected milestone dates for the
                         remainder of the review cycle. At the late-cycle meeting, potential topics for discussion
                         include major deficiencies identified to date; issues to be discussed at any planned
                         advisory committee meetings; current assessment of the need for a REMS or other risk
                         management actions; information requests from the review team to the sponsor; and
                         additional data or analyses the sponsor may wish to submit.
                         35
                           Investigational new drugs are drugs permitted by FDA to be tested in humans but that
                         have not been approved for marketing.




                         Page 24                                    GAO-12-500 Prescription Drug Performance Goals
                           decisions, which they believe would improve the predictability of the
                           review process. 36

                           FDA has taken or plans to take steps that may address stakeholders’
                           issues with the predictability and consistency of its reviews of drug
                           applications. For example, FDA plans to provide training related to the
                           development, review, and approval of drugs for rare diseases, which may
                           help to improve the consistency of FDA’s review of those drugs. In
                           addition, FDA has appointed a Deputy Commissioner for Medical
                           Products to oversee and manage CBER, CDER, and the Center for
                           Devices and Radiological Health (CDRH) in an attempt to improve
                           integration and consistency between the centers. Furthermore, FDA has
                           agreed to create a 5-year plan to develop and implement a structured
                           benefit-risk framework in the review process. FDA will also revise its
                           internal guidance to incorporate a structured benefit-risk framework and
                           then train its review staff on these revisions.


Consumer Advocacy          Three of the five consumer advocacy group stakeholders that we spoke
Group Stakeholders         with raised issues about whether FDA is adequately ensuring the safety
Suggest That FDA May       and efficacy of the drugs it approves for marketing. All three of these
                           stakeholders told us that FDA should place greater priority on safety and
Provide Inadequate         efficacy over review speed. In addition, three stakeholders told us that
Assurance of the Safety    FDA does not gather enough data on long-term drug safety and efficacy
and Efficacy of Approved   through methods such as postmarket surveillance. One stakeholder
Drugs                      suggested that FDA should more effectively utilize its Sentinel System for




                           36
                             In mentioning a structured benefit-risk framework, industry stakeholders were referring
                           to an established process for weighing the potential benefits of a new drug against the
                           potential risks it poses.




                           Page 25                                   GAO-12-500 Prescription Drug Performance Goals
               adverse event reporting. 37 These concerns have also been extensively
               discussed elsewhere. 38

               FDA has taken or plans to take steps that may address stakeholders’
               issues with the safety and efficacy of approved drugs, including
               publishing a regulatory science strategic plan. This document describes
               various plans FDA has for emphasizing safety and efficacy, such as
               developing assessment tools for novel therapies, assuring safe and
               effective medical innovation, and integrating complex data (including
               postmarket data) to allow for better analyses. 39 FDA has also published a
               report identifying needs that, if addressed, would enhance scientific
               decision making in CDER. 40 Some of the needs identified included
               improving access to postmarket data sources and exploring the feasibility
               of different postmarket analyses; improving risk assessment and
               management strategies to reinforce the safe use of drugs; and developing
               and improving predictive models of safety and efficacy in humans. Finally,
               in the draft agreement with industry, FDA has committed to conducting
               both an interim and a final assessment of the strengths, limitations, and
               appropriate use of the Sentinel System for helping FDA determine the
               regulatory actions necessary to manage safety issues.


               FDA met most of the performance goals for the agency to review and
Concluding     issue action letters for original NDA and BLA submissions, Class 1 and
Observations   Class 2 resubmissions, and original efficacy supplements for the



               37
                 The Sentinel System is a national electronic system FDA has been developing that will
               draw on existing automated health care data from multiple sources—such as electronic
               health record systems, administrative and insurance claims databases, and registries—to
               monitor the safety of medical products continuously and in real time.
               38
                 See GAO, Drug Safety: FDA Has Begun Efforts to Enhance Postmarket Safety, but
               Additional Actions Are Needed, GAO-10-68 (Washington, D.C.: Nov. 9, 2009); and Drug
               Safety: Improvement Needed in FDA’s Postmarket Decision-making and Oversight
               Process, GAO-06-402 (Washington, D.C.: Mar. 31, 2006). Also see Institute of Medicine
               of the National Academies, The Future of Drug Safety: Promoting and Protecting the
               Health of the Public (Washington, D.C.: 2007).
               39
                See U.S. Department of Health and Human Services, Food and Drug Administration,
               Advancing Regulatory Science at FDA (Silver Spring, Md.: August 2011).
               40
                See U.S. Department of Health and Human Services, Food and Drug Administration,
               The CDER Science Prioritization and Review Committee (SPaRC): Identifying CDER’s
               Science and Research Needs Report (Silver Spring, Md.: July 2011).




               Page 26                                 GAO-12-500 Prescription Drug Performance Goals
                  FYs 2000 through 2010 cohorts. FDA review times increased slightly for
                  original NDAs, BLAs, and efficacy supplements during this period while
                  changes in the percentage of first-cycle approvals varied by application
                  type. While FDA has met most of the performance goals we examined,
                  stakeholders we spoke with point to a number of issues that the agency
                  could consider to improve the drug review process; FDA is taking or has
                  agreed to take steps that may address these issues, such as issuing new
                  guidance, establishing new communication-related performance goals,
                  training staff, and enhancing scientific decision making. It is important for
                  the agency to continue monitoring these efforts in order to increase the
                  efficiency and effectiveness of the review process and thereby help
                  ensure that safe and effective drugs are reaching the market in a timely
                  manner.


                  HHS reviewed a draft of this report and provided written comments, which
Agency Comments   are reprinted in appendix IV. HHS generally agreed with our findings and
                  noted that they reflect what the agency reported for the same time period.
                  HHS also called attention to activities FDA has undertaken to improve the
                  prescription drug review process. It highlighted FDA’s performance in
                  approving innovative drugs in FY 2011. HHS also noted steps FDA will
                  take to contribute to medical product innovation including expediting the
                  drug development pathway and streamlining and reforming FDA
                  regulations. Finally, HHS discussed enhancements to the drug review
                  program that were included in the proposed recommendations for the
                  2012 reauthorization of the prescription drug user fee program, such as
                  establishing a new review program for innovative drugs, enhancing
                  benefit-risk assessment, and requiring electronic submissions and
                  standardization of electronic application data to improve efficiency. HHS
                  also provided technical comments, which we incorporated as appropriate.


                  As agreed with your office, unless you publicly announce the contents of
                  this report earlier, we plan no further distribution until 30 days from the
                  report date. At that time, we will send copies of this report to the
                  Secretary of Health and Human Services, the Commissioner of the Food
                  and Drug Administration, and other interested parties. In addition, the
                  report will be available at no charge on the GAO website at
                  http://www.gao.gov.




                  Page 27                             GAO-12-500 Prescription Drug Performance Goals
If you or your staff have any questions about this report, please contact
me at (202) 512-7114 or crossem@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this report. GAO staff who made key contributions to this
report are listed in appendix V.




Marcia Crosse
Director, Health Care




Page 28                           GAO-12-500 Prescription Drug Performance Goals
Appendix I: FDA NDA and BLA Review
                                                 Appendix I: FDA NDA and BLA Review
                                                 Performance for Fiscal Years (FYs) 2000
                                                 through 2011


Performance for Fiscal Years (FYs) 2000
through 2011
Table 2: FDA Review Performance for Priority Original NDAs and BLAs Including Innovative Drugs, FYs 2000 through 2011

                                                                                             Fiscal year cohorts
                                                                                                                                                a
                                                 2000     2001       2002      2003       2004   2005   2006   2007     2008   2009   2010   2011
Total number of priority NDA      All              34         14        15           23     27     32     34       28     36     25     20     22
and BLA original submissions      I.D
                                        b
                                                   20         12        11           17     20     21     16       16     18     17     11     14
Number of submissions that       All                 0         0          0          0      0      0      0        0      0      0      0       7
were pending (i.e., not complete I.D                 0         0          0          0      0      0      0        0      0      0      0       4
for PDUFA purposes)
Number of submissions that        All              34         14        15           23     27     32     34       28     36     25     20     15
were complete for PDUFA           I.D              20         12        11           17     20     21     16       16     18     17     11     10
purposes
     Number of completed          All              32         13        15           23     27     31     32       26     28     23     20     14
     submissions reviewed         I.D              19         12        11           17     20     20     15       16     14     15     11      9
                        c
     within 6-month goal
     Percentage of completed      All              94         93      100        100       100     97     94       93     78     92    100     93
     submissions reviewed         I.D              95       100       100        100       100     95     94    100       78     88    100     90
     within 6-month goal
     PDUFA goal percentage        All              90         90        90           90     90     90     90       90     90     90     90     90
                                  I.D              90         90        90           90     90     90     90       90     90     90     90     90
     Met PDUFA goal               All            Yes        Yes       Yes        Yes      Yes    Yes    Yes    Yes       No    Yes    Yes     Yes
                                  I.D            Yes        Yes       Yes        Yes      Yes    Yes    Yes    Yes       No     No    Yes     Yes
Average FDA review time         All               187       193       184        185       183    188    175    193      197    206    207    172
(in days) for priority original I.D               188       195       186        186       185    197    177    191      201    206    210    171
submissions that were reviewed
            d
within goal
Average FDA review time           All             283       303          —           —      —    254    286    261      405    335      —     382
(in days) for priority original   I.D             237         —          —           —      —    254    267        —    380    335      —     382
submissions that were not
                       d
reviewed within goal
                                             e
Percentage of first-cycle actions that were:
     Approved                     All              44         14        47           52     59     66     68       68     56     52     50     93
                                  I.D              35         17        55           59     55     71     75       75     61     53     73    100
                           f
     Complete response            All              56         71        47           43     33     31     29       29     42     48     50      0
                                  I.D              65         75        36           35     40     29     19       19     33     47     27      0
     Withdrawn                    All                0        14          7          4      7      3      3        4      3      0      0       7
                                  I.D                0         8          9          6      5      0      6        6      6      0      0       0
                                         g
Percentage of final actions that were:
     Approved                     All              97         86        93           94     91     93     94       96     97    100    100     93
                                  I.D              94         92        91           92     93     95     87       94     94    100    100    100
     Withdrawn                    All                3        14          7          6      9      7      6        4      3      0      0       7
                                  I.D                6         8          9          8      7      5     13        6      6      0      0       0
                                                 Source: GAO analysis of FDA data.




                                                 Page 29                                            GAO-12-500 Prescription Drug Performance Goals
Appendix I: FDA NDA and BLA Review
Performance for Fiscal Years (FYs) 2000
through 2011




Note: Percentages are rounded to the nearest whole number and may not add to 100 due to
rounding.
a
 For the FY 2011 priority NDA/BLA original submission cohort, 7 out of 22 submissions (32 percent)
were still under review at the time we received FDA’s data, which include reviews by CBER and
CDER through November 30, 2011. Therefore, values indicated for FY 2011 in the table above may
change as these reviews are completed.
b
 “I.D.” stands for innovative drugs, a subset of all priority original NDAs and BLAs that includes nearly
all BLAs and those NDAs designated as new molecular entities (NMEs).
c
 Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal
time frames can be extended by 3 months if the sponsor submits a major amendment to the
application within 3 months of the goal date. For priority NDA/BLA original submissions in FYs 2000
through 2011, 62 out of 311 submissions (20 percent) received PDUFA goal extensions. The
percentage was slightly higher for innovative drugs in these cohorts, with 24 percent receiving
PDUFA goal extensions.
d
 Average review time for the first review cycle for original submissions. Resubmissions are subject to
different PDUFA goal time frames. Dashes (—) indicate cohorts for which no submissions met the
criteria.
e
 Includes only those submissions that had received a first-cycle FDA action letter at the time we
received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.
f
 Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the
same purpose as the complete response letters currently used. We grouped these three types of
letters together in our analysis.
g
 Includes only those submissions that had received a final FDA action letter (i.e., approval) in their
last completed review cycle or were withdrawn by the sponsor at the time we received FDA’s data,
which include reviews by CBER and CDER through November 30, 2011.




Page 30                                         GAO-12-500 Prescription Drug Performance Goals
                                                  Appendix I: FDA NDA and BLA Review
                                                  Performance for Fiscal Years (FYs) 2000
                                                  through 2011




Table 3: FDA Review Performance for Standard Original NDAs and BLAs Including Innovative Drugs, FYs 2000 through 2011

                                                                                  Fiscal year cohorts
                                                                                                                                          a
                                                 2000   2001     2002   2003    2004    2005      2006   2007   2008   2009   2010    2011
Total number of standard NDA       All             97       87     90      89     101        76     89     91    105    123     84      79
and BLA original submissions       I.D
                                         b
                                                   24       34     21      25      23        22     26     34     32     36     18      24
Number of submissions that       All                0       0      0        0       0         0      0      0      0      0       0     55
were pending (i.e., not complete I.D                0       0      0        0       0         0      0      0      0      0       0     19
for PDUFA purposes)
Number of submissions that         All             97       87     90      89     101        76     89     91    105    123     84      24
were complete for PDUFA            I.D             24       34     21      25      23        22     26     34     32     36     18        5
purposes
    Number of completed            All             81       81     89      88      99        75     87     82     92    118     83      23
    submissions reviewed           I.D             18       30     20      24      23        21     26     30     26     35     18        5
                        c
    within 10-month goal
    Percentage of completed        All             84       93     99      99      98        99     98     90     88     96     99      96
    submissions reviewed           I.D             75       88     95      96     100        95    100     88     81     97    100     100
    within 10-month goal
                              d
    PDUFA goal percentage          All             50       70     90      90      90        90     90     90     90     90     90      90
                                   I.D             50       70     90      90      90        90     90     90     90     90     90      90
    Met PDUFA goal                 All           Yes     Yes     Yes      Yes    Yes        Yes   Yes    Yes      No    Yes    Yes     Yes
                                   I.D           Yes     Yes     Yes      Yes    Yes        Yes   Yes     No      No    Yes    Yes     Yes
Average FDA review time            All            297    312      310     300     307       322    320    310    307    309    314     306
(in days) for standard original    I.D            297    321      308     306     319       327    332    320    308    306    314     303
submissions that were reviewed
            e
within goal
Average FDA review time            All            386    356      372   1124      354       445    364    599    453    522    405     350
(in days) for standard original    I.D            411    355      372   1124       —        445     —     477    473    530      —       —
submissions that were not
                     e
reviewed within goal
                                             f
Percentage of first-cycle actions that were:
    Approved                       All             32       21     37      37      50        39     47     42     42     44     54      42
                                   I.D              8       21     33      40      35        18     31     41     25     36     50      20
                         g
    Complete response              All             59       71     62      58      47        59     49     54     51     53     44      58
                                   I.D             83       74     67      52      57        82     62     59     66     58     44      80
    Withdrawn                      All              9       8      1        4       4         1      3      4      7      3       2       0
                                   I.D              8       6      0        8       9         0      8      0      9      6       6       0




                                                  Page 31                                     GAO-12-500 Prescription Drug Performance Goals
                                              Appendix I: FDA NDA and BLA Review
                                              Performance for Fiscal Years (FYs) 2000
                                              through 2011




                                                                                        Fiscal year cohorts
                                                                                                                                                       a
                                             2000      2001      2002        2003      2004   2005   2006     2007   2008     2009     2010    2011
                                         h
Percentage of final actions that were:
    Approved                       All            90      89        98            93     95     95     96       94      91       95       96      100
                                   I.D            90      91        94            89     87     90     89      100      85       92       92      100
    Withdrawn                      All            10      11          2           7      5      5       4       6        9        5        4           0
                                   I.D            10       9          6           11     13     10     11       0       15        8        8           0
                                              Source: GAO analysis of FDA data.

                                              Note: Percentages are rounded to the nearest whole number and may not add to 100 due to
                                              rounding.
                                              a
                                               For the FY 2011 standard NDA/BLA original submission cohort, 55 out of 79 submissions
                                              (70 percent) were still under review at the time we received FDA’s data, which include reviews by
                                              CBER and CDER through November 30, 2011. As a result, it was too soon to tell what the final
                                              results for this cohort would be. Therefore, values indicated for FY 2011 in the table above may
                                              change as these reviews are completed.
                                              b
                                               “I.D.” stands for innovative drugs, a subset of all priority original NDAs and BLAs that includes nearly
                                              all BLAs and those NDAs designated as new molecular entities (NMEs).
                                              c
                                               Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal
                                              time frames can be extended for 3 months if the sponsor submits a major amendment to the
                                              application within 3 months of the goal date. For standard NDA/BLA original submissions from
                                              FYs 2000 through 2011, 168 out of 1,110 submissions (15 percent) received PDUFA goal extensions.
                                              The percentage was higher for innovative drugs in these cohorts, with 22 percent receiving PDUFA
                                              goal extensions.
                                              d
                                               In FYs 2000 and 2001, standard original submissions were also subject to a 12-month goal time
                                              frame that is not shown in our analysis.
                                              e
                                               Average review time for the first review cycle for original submissions. Resubmissions are subject to
                                              different PDUFA goal time frames. Dashes (—) indicate cohorts for which no submissions met the
                                              criteria.
                                              f
                                               Includes only those submissions that had received a first-cycle FDA action letter at the time we
                                              received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.
                                              g
                                               Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the
                                              same purpose as the complete response letters currently used. We grouped these three types of
                                              letters together in our analysis.
                                              h
                                               Includes only those submissions that had received a final FDA action letter (i.e., approval) in their
                                              last completed review cycle or were withdrawn by the sponsor at the time we received FDA’s data,
                                              which include reviews by CBER and CDER through November 30, 2011.




                                              Page 32                                            GAO-12-500 Prescription Drug Performance Goals
                                       Appendix I: FDA NDA and BLA Review
                                       Performance for Fiscal Years (FYs) 2000
                                       through 2011




Table 4: Percentages of Closed and Open NDAs and BLAs, FYs 2000 through 2011

                                                                                 Fiscal year cohorts
                                       2000      2001      2002       2003      2004   2005   2006     2007   2008      2009     2010     2011
Priority NDAs and BLAs
 Percentage of submissions that
            a
 were closed                               85     100        100           78     82     91     94       89      81        76       55       68
 Percentage of submissions that
                b
 were still open                           15         0          0         22    18      9       6      11       19        24       45       32
    Percentage of submissions
    that were under FDA review
    (i.e., pending)                        0          0          0         0      0      0       0        4        3        0       20       32
    Percentage of submissions for
    which FDA had issued a complete
    response and the sponsor had not
    resubmitted the application            15         0          0         22     18     9       6        7      17        24       25        0
Standard NDAs and BLAs
 Percentage of submissions that
            a
 were closed                               89       83         90          80     85     76     81       71      73        70       65       13
 Percentage of submissions that
                b
 were still open                           11       17         10          20     15     24     19       29      27        30       35       87
    Percentage of submissions that
    were under FDA review
    (i.e., pending)                        0          0          0         0      1      0       1        1        6        3       11       72
    Percentage of submissions for
    which FDA had issued a complete
    response and the sponsor had not
    resubmitted the application            11       17         10          20     14     24     18       27      21        27       24       15
                                       Source: GAO analysis of FDA data.

                                       Note: Percentages are rounded to the nearest whole number.
                                       a
                                        We defined a submission as closed if it was approved or withdrawn in the last completed review
                                       cycle. Although denial is an action available to FDA officials to close the review of an application, no
                                       NDAs or BLAs were denied for FYs 2000 through 2011.
                                       b
                                        We defined a submission as open if the most recent review cycle was still underway (i.e., pending) or
                                       if FDA had issued a complete response letter in the most recent review cycle and the sponsor still
                                       had the option of resubmitting the application under the original user fee. Submissions that have
                                       received a complete response letter are considered complete for purposes of determining whether
                                       FDA met the PDUFA performance goals, but the review is not closed. Prior to August 2008, FDA also
                                       issued “approvable” and “not approvable” letters, which served the same purpose as the complete
                                       response letters currently used. We grouped these three types of letters together in our analysis.




                                       Page 33                                           GAO-12-500 Prescription Drug Performance Goals
                                         Appendix I: FDA NDA and BLA Review
                                         Performance for Fiscal Years (FYs) 2000
                                         through 2011




Table 5: FDA Review Performance for NDA and BLA Resubmissions Including Innovative Drugs, FYs 2000 through 2011

                                                                                    Fiscal year cohorts
                                                                                                                                         a
                                         2000      2001       2002      2003       2004   2005   2006   2007    2008   2009   2010   2011
Total number of Class 1 NDA and All           3       19         22           22     18     19     20      21     18     16     12     10
                   b
BLA resubmissions               I.D
                                    c
                                              0         6        11            2     2      2       4       5     4      2       1       2
Number of resubmissions that       All        0         0          0           0     0      0       0       0     0      0       0       2
were pending (i.e., not complete   I.D        0         0          0           0     0      0       0       0     0      0       0       0
for PDUFA purposes)
Number of resubmissions that       All        3       19         22           22     18     19     20      21     18     16     12       8
were complete for PDUFA            I.D        0         6        11            2     2      2       4       5     4      2       1       2
purposes
    Number of completed            All        3       18         22           21     18     17     20      16     17     13     12       8
    resubmissions reviewed         I.D        0         6        11            2     2      2       4       5     4      2       1       2
    within 2-month goal
    Percentage of completed        All    100         95       100            95    100     89    100      76     94     81    100    100
    resubmissions reviewed         I.D      —        100       100           100    100    100    100     100    100    100    100    100
    within 2-month goal
                                              d
    PDUFA goal percentage          All     70         90         90           90     90     90     90      90     90     90     90     90
                                   I.D      70        90         90           90     90     90     90      90     90     90     90     90
    Met PDUFA goal                 All    Yes        Yes       Yes           Yes   Yes     No    Yes      No    Yes     No    Yes     Yes
                                   I.D    Yes        Yes       Yes           Yes   Yes    Yes    Yes      Yes   Yes    Yes    Yes     Yes
Total number of Class 2 NDA        All        2       24         35           44     58     32     38      46     34     52     41     53
                       b
and BLA resubmissions              I.D        1       14         16           23     22     11      8      22     14     21     11     17
Number of resubmissions that       All        0         0          0           0     0      0       0       0     0      0       0     21
were pending (i.e., not complete   I.D        0         0          0           0     0      0       0       0     0      0       0       5
for PDUFA purposes)
Number of resubmissions that       All        2       24         35           44     58     32     38      46     34     52     41     32
were complete for PDUFA            I.D        1       14         16           23     22     11      8      22     14     21     11     12
purposes
    Number of completed            All        2       24         35           44     57     30     36      43     29     48     39     32
    resubmissions reviewed         I.D        1       14         16           23     22     10      8      20     11     20     10     12
                e
    6-month goal
    Percentage of completed        All    100        100       100           100     98     97     95      93     85     92     95    100
    resubmissions reviewed         I.D    100        100       100           100    100     91    100      91     79     95     91    100
    6-month goal
    PDUFA goal percentage          All      90        90         90           90     90     90     90      90     90     90     90     90
                                   I.D      90        90         90           90     90     90     90      90     90     90     90     90
    Met PDUFA goal                 All    Yes        Yes       Yes           Yes   Yes    Yes    Yes      Yes    No    Yes    Yes     Yes
                                   I.D    Yes        Yes       Yes           Yes   Yes    Yes    Yes      Yes    No    Yes    Yes     Yes
                                         Source: GAO analysis of FDA data.

                                         Note: Percentages are rounded to the nearest whole number.




                                         Page 34                                             GAO-12-500 Prescription Drug Performance Goals
                                                 Appendix I: FDA NDA and BLA Review
                                                 Performance for Fiscal Years (FYs) 2000
                                                 through 2011




                                                 a
                                                  The FY 2011 cohort was not complete at the time we received FDA’s data, which include reviews by
                                                 CBER and CDER through November 30, 2011. Therefore, values indicated for FY 2011 in the table
                                                 above may change as these reviews are completed.
                                                 b
                                                  Our analysis was limited to resubmissions made in FYs 2000 through 2011 for original NDAs and
                                                 BLAs that were also submitted in FYs 2000 through 2011. Resubmissions made in FYs 2000 through
                                                 2011 for original NDAs and BLAs submitted prior to FY 2000 were not captured by our analysis.
                                                 c
                                                  “I.D.” stands for innovative drugs, a subset of all priority original NDAs and BLAs that includes nearly
                                                 all BLAs and those NDAs designated as new molecular entities (NMEs).
                                                 d
                                                  In FY 2000, Class 1 resubmissions were also subject to a 4-month goal time frame which is not
                                                 shown in our analysis.
                                                 e
                                                  Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal
                                                 time frames for Class 2 resubmissions can be extended for 3 months if the sponsor submits a major
                                                 amendment to the resubmission within 3 months of the goal date. For Class 2 NDA/BLA
                                                 resubmissions in these cohorts, 45 out of 463 submissions (9.7 percent) received goal extensions.



Table 6: FDA Review Performance for Oncology Drugs Including Those Granted Accelerated Approval, FYs 2000 through
2011

                                                                                           Fiscal year cohorts
                                                                                                                                                        a
                                                 2000       2001      2002      2003     2004   2005   2006    2007     2008     2009     2010     2011
Total number of NDA and BLA           All               7       7          6         3     13     10      8       11        8       12       11       15
original submissions for              A.A.
                                             b
                                                        1       2          2         2     1      3       2        0        1        2        0         1
oncology drugs
                                  c
Number of first-cycle approvals       All               3       4          3         3     8      7       4        6        5        5        6         6
                                      A.A.              1       1          2         2     1      3       2       —         1        2       —          1
                         d
Number of final approvals             All               5       5          4         3     8      8       5        7        7        5        9         6
                                      A.A.              1       2          2         2     1      3       2       —         1        2       —          1
                                                 Source: GAO analysis of FDA data.
                                                 a
                                                  For the FY 2011 cohort, 55 out of 79 standard NDA and BLA submissions (70 percent) and 7 out of
                                                 22 priority submissions (32 percent) were still under review at the time we received FDA’s data, which
                                                 include reviews by CBER and CDER through November 30, 2011. Therefore, values indicated for
                                                 FY 2011 in the table above may change as these reviews are completed.
                                                 b
                                                     “A.A.” designates the subset of oncology drug submissions granted accelerated approval status.
                                                 c
                                                  Includes only those submissions that had received a first-cycle FDA approval letter at the time we
                                                 received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.
                                                 Includes tentative approvals (one each in FYs 2005, 2007, and 2009). Dashes (—) indicate cohorts
                                                 for which no submissions met the criteria.
                                                 d
                                                  Includes only those submissions that had received an approval letter in their last completed review
                                                 cycle at the time we received FDA’s data, which include reviews by CBER and CDER through
                                                 November 30, 2011. Dashes (—) indicate cohorts for which no submissions met the criteria.




                                                 Page 35                                           GAO-12-500 Prescription Drug Performance Goals
Appendix II: FDA Efficacy Supplement
                                                Appendix II: FDA Efficacy Supplement Review
                                                Performance for Fiscal Years (FYs) 2000
                                                through 2011


Review Performance for Fiscal Years (FYs)
2000 through 2011
Table 7: FDA Review Performance for Priority Efficacy Supplements, FYs 2000 through 2011

                                                                                           Fiscal year cohorts
                                                                                                                                                      a
                                               2000      2001      2002      2003        2004   2005   2006   2007     2008   2009     2010     2011
Total number of priority efficacy
supplements                                         21     10         38            37     50     42     45       45     38      42       19        26
 Number of submissions that were
 pending (i.e., not complete for
 PDUFA purposes)                                    0        0          0           0      0       0      0        0     0        0        0        13
 Number of submissions that were
 complete for PDUFA purposes                        21     10         38            37     50     42     45       45     38      42       19        13
    Number of completed
    submissions reviewed within
                b
    6-month goal                                    21       9        36            37     47     41     44       41     35      36       19        13
    Percentage of completed
    submissions reviewed within
    6-month goal                                100        90         95       100         94     98     98       91     92      86     100       100
 PDUFA goal percentage                              90     90         90            90     90     90     90       90     90      90       90        90
    Met PDUFA goal                             Yes       Yes        Yes        Yes       Yes    Yes    Yes       Yes   Yes      No      Yes       Yes
Average FDA review time (in days) for
priority efficacy supplements that
                          c
were reviewed within goal                       173       182       169        182        171    176    182      180    189    182      191       195
Average FDA review time (in days) for
priority efficacy supplements that
                               c
were not reviewed within goal                       ─     347       303             ─     356    289    393      309    249    341         ─         ─
                                           d
Percentage of first-cycle actions that were:
    Approved                                        76     60         47            70     72     64     80       58     63      62       63        92
                         e
    Complete response                               14     30         42            30     24     33     20       42     34      33       37          8
    Withdrawn                                       10     10         11            0      4       2      0        0     3        5        0          0
                                      f
Percentage of final actions that were:
    Approved                                        89     86         82       100         95     96    100      100     96      90     100       100
    Withdrawn                                       11     14         18            0      5       4      0        0     4       10        0          0
                                                Source: GAO analysis of FDA data.

                                                Note: Percentages are rounded to the nearest whole number and may not add to 100 due to
                                                rounding.
                                                a
                                                 For the FY 2011 priority efficacy supplement cohort, 13 out of 26 submissions (50 percent) were still
                                                under review at the time we received FDA’s data, which include reviews by CBER and CDER through
                                                November 30, 2011. As a result, it was too soon to tell what the final results for this cohort would be.
                                                Therefore, values indicated for FY 2011 in the table above may change as these reviews are
                                                completed.
                                                b
                                                 Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal
                                                time frames can be extended for 3 months if the sponsor submits a major amendment to the
                                                application within 3 months of the goal date. For priority efficacy supplements in FYs 2000 through
                                                2011, 24 out of 400 submissions (6 percent) received PDUFA goal extensions.




                                                Page 36                                             GAO-12-500 Prescription Drug Performance Goals
Appendix II: FDA Efficacy Supplement Review
Performance for Fiscal Years (FYs) 2000
through 2011




c
  Average review time for the first review cycle for original submissions. Resubmissions are subject to
different PDUFA goal time frames. Dashes (—) indicate cohorts for which no submissions met the
criteria.
d
 Includes only those submissions that had received a first-cycle FDA action letter at the time we
received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.
e
 Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the
same purpose as the complete response letters currently used. We grouped these three types of
letters together in our analysis.
f
 Includes only those submissions that had received a final FDA approval letter in their last completed
review cycle or were withdrawn by the sponsor at the time we received FDA’s data, which include
reviews by CBER and CDER through November 30, 2011.




Page 37                                         GAO-12-500 Prescription Drug Performance Goals
                                                    Appendix II: FDA Efficacy Supplement Review
                                                    Performance for Fiscal Years (FYs) 2000
                                                    through 2011




Table 8: FDA Review Performance for Standard Efficacy Supplements, FYs 2000 through 2011

                                                                                           Fiscal year cohorts
                                                                                                                           a         a         a          a
                                          2000          2001     2002       2003        2004   2005   2006   2007     2008     2009       2010      2011
Total number of standard efficacy
supplements                                167           164       131        113        156    116    149    147      112        117       128       107
 Number of submissions that were
 pending (i.e., not complete for
 PDUFA purposes)                                0           0          0         0        0      0      0        0        1          2         1        75
 Number of submissions that were
 complete for PDUFA purposes               167           164       131        113        156    116    149    147      111        115       127         32
    Number of completed
    submissions reviewed within
                 b
    10-month goal                          152           150       126        110        151    114    147    133        99       111       125         32
    Percentage of completed
    submissions reviewed within
                  c
    10-month goal                           91            91         96         97        97     98     99       90      89        97         98      100
                             d
 PDUFA goal percentage                      50            70         90         90        90     90     90       90      90        90         90        90
    Met PDUFA goal                        Yes           Yes        Yes        Yes       Yes    Yes    Yes    Yes        No        Yes       Yes       Yes
Average FDA review time
(in days) for standard efficacy
supplements that were reviewed
            e
within goal                                278           278       282        283        287    283    292    290      297        297       306       284
Average FDA review time
(in days) for standard efficacy
supplements that were not
                     e
reviewed within goal                       370           395       394        426        463    397    994    499      470        499       399          ─
                                            f
Percentage of first-cycle actions that were:
    Approved                                43            50         53         55        55     72     67       71      70        63         69        63
                         g
    Complete response                       51            41         44         45        41     25     28       28      27        35         27        25
    Withdrawn                                   6           9          3         0        4      3      5        1        3          2         5        13
                                      h
Percentage of final actions that were:
    Approved                                87            87         93       100         93     94     93       96      96        96         94        83
    Withdrawn                               13            13           7         0        7      6      7        4        4          4         6        17
                                                    Source: GAO analysis of FDA data.

                                                    Note: Percentages are rounded to the nearest whole number and may not add to 100 due to
                                                    rounding.
                                                    a
                                                     For the FYs 2008 through 2011 standard efficacy supplement cohorts, certain submissions were still
                                                    under review at the time we received FDA’s data, which include reviews by CBER and CDER through
                                                    November 30, 2011. For FY 2008, 1 out of 112 submissions (less than 1 percent) was still under
                                                    review. For FY 2009, 2 out of 117 submissions (approximately 2 percent) were still under review. For
                                                    FY 2010, 1 out of 128 submissions (less than 1 percent) was still under review. For FY 2011, 75 out
                                                    of 107 submissions (70 percent) were still under review. As a result, it was too soon to tell what the
                                                    final results for this cohort would be. Therefore, values indicated for these cohorts in the table above
                                                    may change as these reviews are completed.




                                                    Page 38                                           GAO-12-500 Prescription Drug Performance Goals
Appendix II: FDA Efficacy Supplement Review
Performance for Fiscal Years (FYs) 2000
through 2011




b
 Our calculations include extensions of the PDUFA goal time frame, where applicable. PDUFA goal
time frames can be extended for 3 months if the sponsor submits a major amendment to the
application within 3 months of the goal date. For standard efficacy supplements in FYs 2000 through
2011, 90 out of 1,528 submissions (6 percent) received PDUFA goal extensions.
c
 FYs 2008 through 2011 calculations exclude submissions for which FDA had not yet issued an
action letter.
d
 In FYs 2000 and 2001, standard efficacy supplement submissions were also subject to a 12-month
goal time frame that is not shown in our analysis.
e
 Average review time for the first review cycle for original submissions. Resubmissions are subject to
different PDUFA goal time frames.
f
 Includes only those submissions that had received a first-cycle FDA action letter at the time we
received FDA’s data, which include reviews by CBER and CDER through November 30, 2011.
g
 Prior to August 2008, FDA also issued “approvable” and “not approvable” letters, which served the
same purpose as the complete response letters currently used. We grouped these three types of
letters together in our analysis.
h
 Includes only those submissions that had received a final FDA approval letter in their last completed
review cycle or were withdrawn by the sponsor at the time we received FDA’s data, which include
reviews by CBER and CDER through November 30, 2011.




Page 39                                         GAO-12-500 Prescription Drug Performance Goals
                                          Appendix II: FDA Efficacy Supplement Review
                                          Performance for Fiscal Years (FYs) 2000
                                          through 2011




Table 9: Percentages of Closed and Open Efficacy Supplements, FYs 2000 through 2011

                                                                                     Fiscal year cohorts
                                          2000      2001      2002       2003      2004   2005   2006   2007     2008     2009     2010     2011
Priority efficacy supplements
 Percentage of submissions that were
       a
 closed                                       100    100          84          89     92     83     89      93       76       76       74      46
 Percentage of submissions that were
           b
 still open                                    0         0        16          11     8      17     11       7       24       24       26      54
    Percentage of submissions that were
    under FDA review (i.e., pending)           0         0          0         0      0      0      0        0        0        0        0      50
    Percentage of submissions for which
    FDA had issued a complete
    response and the sponsor had not
    resubmitted the application                0         0        16          11     8      17     11       7       24       24       26           4
Standard efficacy supplements
 Percentage of submissions that were
       a
 closed                                        83      89         84          86     75     91     82      88       83       80       82      22
 Percentage of submissions that were
           b
 still open                                    17      11         16          14     25     9      18      12       17       20       18      78
    Percentage of submissions that were
    under FDA review (i.e., pending)           0         0          0         0      0      0      0        0        1        2        1      70
    Percentage of submissions for which
    FDA had issued a complete
    response and the sponsor had not
    resubmitted the application                17      11         16          14     25     9      18      12       16       18       17           7
                                          Source: GAO analysis of FDA data.

                                          Note: Percentages may not add to totals due to rounding.
                                          a
                                           We defined a submission as closed if it was approved or withdrawn in the last completed review
                                          cycle. Although denial is an action available to FDA officials to close the review of a submission, no
                                          efficacy supplements were denied in FYs 2000 through 2011.
                                          b
                                           We defined a submission as open if the most recent review cycle was still underway (i.e., pending) or
                                          if FDA issued a complete response letter in the most recent review cycle (i.e., the sponsor still had
                                          the option of resubmitting the application under the original user fee). Submissions that have received
                                          a complete response letter are considered complete for purposes of determining whether FDA met
                                          the PDUFA performance goals, but the review is not closed. Prior to August 2008, FDA also issued
                                          “approvable” and “not approvable” letters, which served the same purpose as the complete response
                                          letters currently used. We grouped these three types of letters together in our analysis.




                                          Page 40                                           GAO-12-500 Prescription Drug Performance Goals
Appendix III: Full-time Equivalent (FTE)
                                                         Appendix III: Full-time Equivalent (FTE) FDA
                                                         Staff Supporting Prescription Drug User Fee
                                                         Activities, FYs 2000 through 2010


FDA Staff Supporting Prescription Drug User
Fee Activities, FYs 2000 through 2010

                                                                                      Number of FTEs in each fiscal year
FDA centers and offices                                       2000 2001 2002         2003    2004       2005    2006    2007    2008    2009    2010
Center for Drug Evaluation and Research (CDER)
 Office of the Center Director (OCD)                            44      38     20      19       13        17      19      22      29      38       49
                                       a
 Office of Regulatory Policy (ORP)                             N/A       4     23      26       37        33      45      46      47      49       53
                                           a,b
 Office of Executive Programs (OEP)                            N/A       3     39      55       58        58      54      53      57      63       70
 Office of Management (OM)                                      65      66     64      57       46        41      43      45      50      62       75
                                            b
 Office of Communications (OCOMM)                               83      87     71      68       72        76      81      53      57      66       72
                           b
 Office of Compliance (OC)                                      27      24     30      31       62        39      47      83     101     173      202
                                                         c
 Office of Information Technology (OIT/OIM)                     99     104     95      87       86        78      88      40      38      40       44
                                                 d
 Office of Translational Sciences (OTS)                        N/A     N/A    N/A     N/A      N/A       N/A     N/A     147     210     286      323
                               e
 Office of New Drugs (OND)                                     705     676    541     593      697       700     725     732     740     858      892
                                                     c
 Office of Planning and Informatics (OPI)                      N/A     N/A    N/A     N/A      N/A       N/A     N/A      40      48      66       78
 Office of Counter-Terrorism and Emergency
                        e
 Coordination (OCTEC)                                          N/A     N/A     13      33       43        35      39      23      23      24       12
 Office of Surveillance & Epidemiology
        d,e
 (OSE)                                                         N/A     N/A     98      99      118       115     136     113      92     134      167
                                   b
 Office of Medical Policy (OMP)                                 53      52     54      58       62        47      61      43      46      56       64
                                                     d
 Office of Pharmaceutical Science (OPS)                        332     320    302     303      379       394     398     299     308     358      376
                                                                                                                                                    f
                                       CDER Total 1,408 1,374 1,350                 1,429    1,673      1,633   1,736   1,739   1,846   2,273   2,477
Center for Biologics Evaluation and Research (CBER)
 Center Director’s Office, Office of
 Management (OM), Office of Information
 Management (OIM) & Office of
 Communication, Outreach and Development
 (OCOD)                                                        114     123    124     131      108       106     108     116     128     140      166
 Office of Blood Research & Review                              38      46     48      53       50        55      50      56      57      67       69
 Office of Cellular, Tissue & Gene Therapies                       0     0      0      54       69        66      69      75      78      82       92
 Office of Vaccines Research & Review                          134     136    161     194      201       193     200     217     224     229      238
 Office of Therapeutics Research & Review                      157     169    189     141        0         0       0       0       0       0        0
 Office of Biostatistics & Epidemiology                         15      17     22      22       14        16      18      24      30      40       45
 Office of Compliance & Biologics Quality                       42      42     42      49       36        33      33      34      37      45       44
                                       CBER Total              500     533    586     644      478       469     478     522     554     603      654




                                                         Page 41                                     GAO-12-500 Prescription Drug Performance Goals
                                           Appendix III: Full-time Equivalent (FTE) FDA
                                           Staff Supporting Prescription Drug User Fee
                                           Activities, FYs 2000 through 2010




                                                                                Number of FTEs in each fiscal year
FDA centers and offices                            2000 2001 2002              2003    2004     2005    2006    2007     2008     2009         2010
Office of Regulatory Affairs (ORA)
                                     ORA Total       180     180       153      147     147      145     142     144      146      194          174
Office of the Commissioner (OC)
                                      OC Total       257     253       248      212     206      203     218     168      211      283          282
                    b,g
Shared Service (SS)
                                      SS Total       N/A     N/A       N/A      N/A     104       90     117     165      168      173          173
               All Centers and Offices Total 2,345 2,340 2,337                 2,432   2,608   2,540   2,691    2,738   2,925    3,526     3,760
                                           Source: GAO analysis of FDA data.

                                           Note: One FTE represents 40 hours of work per week conducted by a federal government employee
                                           over the course of 1 year. FTEs do not include contractors and therefore provide a partial measure of
                                           staffing resources.
                                           a
                                               ORP and OEP were created in FY 2001.
                                           b
                                            In FY 2007, Medical Library staff were transferred from OCOMM to SS, Division of Training staff
                                           were transferred from OCOMM to OEP, and the Division of Scientific Investigations was transferred
                                           from OMP to OC.
                                           c
                                               OPI was created in FY 2007 through transfers from OIT; other OIT staff were realigned to OIM.
                                           d
                                               OTS was created in FY 2007 through transfers from OSE and OPS.
                                           e
                                               OCTEC and OSE were created in FY 2002 through transfers from OND.
                                           f
                                               CDER total in FY 2010 includes Commissioner’s Fellows.
                                           g
                                               SS FTEs were not separated from the center FTEs until FY 2004.




                                           Page 42                                             GAO-12-500 Prescription Drug Performance Goals
Appendix IV: Comments from the
             Appendix IV: Comments from the Department
             of Health and Human Services



Department of Health and Human Services




             Page 43                                GAO-12-500 Prescription Drug Performance Goals
Appendix IV: Comments from the Department
of Health and Human Services




Page 44                                GAO-12-500 Prescription Drug Performance Goals
Appendix IV: Comments from the Department
of Health and Human Services




Page 45                                GAO-12-500 Prescription Drug Performance Goals
Appendix V: GAO Contact and Staff
                  Appendix V: GAO Contact and Staff
                  Acknowledgments



Acknowledgments

                  Marcia Crosse, (202) 512-7114 or crossem@gao.gov
GAO Contact
                  In addition to the contact named above, Robert Copeland, Assistant
Staff             Director; Carolyn Fitzgerald; Cathleen Hamann; Karen Howard; Hannah
Acknowledgments   Marston Minter; Lisa Motley; Aubrey Naffis; and Rachel Schulman made
                  key contributions to this report.




(291008)
                  Page 46                             GAO-12-500 Prescription Drug Performance Goals
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