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U.S. Department of Health and Human Services

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APPENDIX C: STUDY HYPOTHESES: Independent Evaluation of FDA's First Cycle Review Performance – Final Report

Table of Contents

APPENDIX B: SPONSOR AND FDA FOCUS GROUP FINDINGS

The metrics captured for hypotheses developed and tested in the First Cycle Approval Evaluation are detailed below by the following categories:

  • Product/ disease characteristics
  • Good Review Management Practices and Principles Compliance
  • Review process issues and communication
  • Sponsor characteristics
  • FDA characteristics

Each hypothesis is accompanied by the anticipated metrics for assessment, as well as the data sources that were used or evaluated for testing.  Some hypotheses were tested, of these some had significant findings and others did not.  Some hypotheses could not be tested, either because appropriate data did not exist or the quality and quantity of such data was insufficient.  Each analysis is marked with a status that details the analysis outcome:

  • Analyzed with Findings (AF)
  • Analyzed with no Findings (ANF)
  • Not Analyzed (NA) due to insufficient data

Product/Disease Characteristic Hypotheses

Hypotheses Metric(s) Data Source Status
1. Products in the Fast-Track program have higher first-cycle approval rates
  • Approval rate*
  • Drug development designation
  • Action Packages
  • Data systems
AF
2. Products with Priority review have higher first-cycle approval rates
  • Approval rate*
  • Review designation
  • Action Packages
  • Data systems
AF
3. Products with Orphan status designation have higher first-cycle approval rates
  • Approval rate*
  • Review designation
  • Action Packages
  • Data systems
AF
4. Products with fee waived have higher first-cycle approval rates
  • Approval rate*
  • Review designation
  • Action Packages
  • Data systems
AF
5. Products with novel mechanism of action (MOA) have higher first-cycle approval rates
  • Approval rate*
  • Novel MOA
  • Action Packages
  • Data systems
ANF
6. Products for indications classified as life-threatening or for unmet medical needs have greater first-cycle approval rates
  • Approval rate*
  • Indication characteristics
  • Action Packages
  • Data systems
ANF
7. Products that have a novel MOA and are for life-threatening conditions have higher first-cycle approval rate
  • Approval rate*
  • Review designation
  • Action Packages
  • Data systems
AF
8. In-licensed drugs have greater approval rates
  • Approval rate*
  • Drug origin
  • Timing of acquisition
  • Action Packages
  • Web research
ANF
9. Novel MOA under In-licensed have greater approval rates
  • Approval rate*
  • Review designation
  • Action Packages
  • Data systems
ANF
10. Products with significant public benefits are less likely to require multiple review cycles (treating life threatening disease?)
  • Available treatments
  • Affected population
  • Others
Note – the indicator of public benefits will be further explored and defined
  • Web research
  • Review team interviews
  • Sponsor interviews
NA
11. Products for chronic conditions are more likely to require more than one review cycle
  • Chronic / Acute (based on indication)
  • Action Packages
  • Web research
ANF
12. Products with more therapeutic areas involved are likely to require multi-cycle reviews
  • Select from therapeutic area list
  • Action Packages
  • Web research
NA
13. Products addressing conditions with higher disease incidence are less likely to require multiple review cycles
  • Affected US population (appropriate ranges will be defined when data is analyzed)
  • Action Packages
  • Web research
NA
14. Products with international approval are less likely to require multiple review cycles
  • Number of years approved
  • Country or organizations that approved the drug
  • Action Packages
  • Web research
ANF
15. Applications with more Indications submitted are less likely to have single review cycle
  • List indication(s)
  • Action Packages
  • Web research
NA
16. Increasing disease severity is likely to decrease the likelihood of multiple review cycles
  • Disease severity
Note – the severity scale will be further explored and defined
  • Action Packages
  • Web research
NA
17. Products preceded by FDA approvals in same drug class are less likely to require multiple review cycles
  • Number of products in same drug class approved
  • Action Packages
  • Web research
NA
18. Products treating conditions with strong public advocacy are less likely to require multi-review cycles for approval (e.g., HIV/AIDS)
  • Based on disease condition or therapeutic area
Note – the rating of public advocacy will be further explored and defined
  • Action Packages
  • Web research
NA
19. NDAs are less likely to require multi-cycle reviews than BLAs
  • NDA/BLA historical approval rate
  • Center approval philosophy
  • Action Packages
  • Web research
  • Review team interviews
AF
20. Products that have secondary endpoints fail are more likely to require multiple review cycles
  • Y/N
  • Action Packages
  • Data systems
  • Sponsor interviews
NA
21. Applications with international clinical trial sites will increase the likelihood of multiple review cycles
  • Y/N
  • Number of international sites used
  • Counts of all non-US sites
  • Percentage of non-US sites relative to total
  • Action Packages
  • Data systems
  • Sponsor interviews
NA
22. Applications with more clinical trial sites increase the likelihood of multiple review cycles
  • Total number of sites
  • Action Packages
  • Data systems
  • Sponsor interviews
NA


GRMPs Compliance

Hypotheses Metric(s) Data Source Status
23. Implementing GRMPs will contribute to an increase in the first-cycle approval rate
  • Approval rate
  • GRMPs implementation status within and across divisions
  • Action Packages
  • Data systems
  • Review team interviews
AF
24. Product reviews that adopt all activities and timeframes in the first phase (filing and review planning) of GRMPs Guidance have greater first-cycle approval rate
  • Approval rate
  • Activities done/not done in the first phase
  • Timing compliant/delayed
  • Phase-specific Best Practices
  • Action Packages
  • Data systems
  • Review team interviews
ANF
25. Product reviews that adopt all activities and timeframes in the second phase (review) of GRMPs guidance have greater first-cycle approval rate
  • Approval rate
  • Activities done/not done in the second phase
  • Timing compliant/delayed
  • Phase-specific Best Practices
  • Action Packages
  • Data systems
  • Review team interviews
ANF
26. Product reviews that adopt all activities and timeframes in the third phase (Advisory Committee meeting) of GRMPs guidance have greater first-cycle approval rate
  • Approval rate
  • Activities done/not done in the third phase
  • Timing compliant/delayed
  • Phase-specific Best Practices
  • Action Packages
  • Data systems
  • Review team interviews
ANF
27. Product reviews that adopt all activities and timeframes in the fourth phase (Action) of GRMPs guidance have greater first-cycle approval rate
  • Approval rate
  • Activities done/not done in the fourth phase
  • Timing compliant/delayed
  • Phase-specific Best Practices
  • Action Packages
  • Data systems
  • Review team interviews
ANF
28. To be compliant with GRMPs timelines will increase initial workload
  • Review hours distribution across review phase (self-reported)
  • Total work hours (self-reported)
  • Hours spent on non-review activities (self-reported)
  • Review team interviews
NA
29. Implementing GRMPs will result in earlier interactions between FDA and sponsor
  • Communication timing (letters, emails, fax, telecom, formal meetings and response time)
  • Action Packages
  • Data systems
  • Review team interviews
AF
30. Implementing GRMPs will result in more frequent interactions between FDA and sponsor
  • Communication frequency (letters, emails, fax, telecom, formal meetings and response time)
  • Action Packages
  • Data systems
  • Review team interviews
AF
31. Implementing GRMPs will result in earlier interactions within the review team
  • Communication timing (Internal meetings, informal contact)
  • Action Packages
  • Data systems
  • Review team interviews
NA
32. Implementing GRMPs will result in more frequent interactions within review team
  • Communication frequency (Internal meetings, informal contact)
  • Action Packages
  • Data systems
  • Review team interviews
NA
33. Implementing GRMPs will increase the review quality
  • Communication frequency
  • Issues identified
  • Labeling discussion timing
  • Timing of the Office Director or Division Director receiving the Action Package
  • Timing for AC preparation
Note – the indicator of review quality will be further defined
  • Action Packages
  • Data systems
  • Review team interviews
NA
34. Implementing GRMPs will result in less compression towards the end of the review
  • Labeling discussion timing
  • Timing of the Office Director or Division Director receiving the Action Package
  • Timing for AC preparation
  • Action Packages
  • Data systems
  • Review team interviews
ANF
35. Implementing GRMPs will increase the efficiency
  • Total review effort (based on self-reported workload data)
  • Overall approval time
Note – the indicator of review efficiency will be further defined
  • Action Packages
  • Data systems
  • Review team interviews
NA
36. Implementing GRMPs will shorten review/ approval time
  • Overall approval time
  • Action Packages
  • Data systems
  • Review team interviews
NA
37. Implementing GRMPs will increase the clarity of FDA expectations (internally and externally)
  • Communication frequency
  • Issues resolution
  • Decision activities
Note – the indicator of clarity will be further defined
  • Action Packages
  • Review team interviews
  • Sponsor interviews
ANF
38. Implementing GRMPs will increase the transparency between FDA and sponsor
  • Pre-defined review schedule
Note – the indicator of review transparency will be further defined
  • Action Packages
  • Data systems
  • Review team interviews
  • Sponsor interviews
ANF
39. Implementing GRMPs will increase the consistency in review process
  • GRMPs milestones across Divisions
Note – the indicator of consistency will be further defined
  • Action Packages
  • Data systems
  • Review team interviews
ANF
40. GRMPs training could increase the review efficiency
  • Types of GRMPs training for current reviewers and new hires
  • Review efficiency (will be based on the indicator defined earlier)
  • Action Packages
  • Data systems
  • Review team interviews
NA
41. Implementing GRMPs will increase the submission quality resulting in fewer IR letters and fewer filing or review issues
  • Number of IRs
  • Number of issues
  • Number of communications
  • Submission format, issues
Note – submission quality will be further explored and defined with FDA stakeholders
  • Action Packages
  • Data systems
  • Review team interviews
  • Industry interviews
ANF

 

Issues and Communication

Hypotheses Metric(s) Data Source Status
42. Sponsor response times to information requests correlate with first-cycle approval rate
  • Approval rate
  • # of RFI/ IR and average response time
  • Perception of value of the information request
  • Action Packages
  • Sponsor interviews
ANF
43. Products in which the sponsor adequately prepares for the industry meetings are less likely to require multiple review cycles
  • Approval rate
  • Total number of meetings
  • Meeting preparation time
  • Action Packages
  • Sponsor interviews
NA
44. Early and effective interactions between FDA and Sponsor to identify, prioritize, and resolve issues early are likely to increase the first-cycle approval rate
  • Timing of pre-submission meetings (EOP2, Pre-NDA/BLA and others)
  • Format of pre-submission meetings
  • Type and count of issues discussed in the meetings (as per Retrospective Study classification system)
  • Response time between FDA and sponsor
  • Action Packages
  • Data systems
AF
45. Products that have Pre-NDA/BLA meeting prior to submission are less likely to require multiple cycle reviews
  • NDA/BLA meeting held
  • Action Packages
  • Data systems
AF
46. Products that have Pre-NDA/BLA meeting less than 6 months prior to submission are less likely to require multiple cycle reviews
  • NDA/BLA meeting timing
  • Action Packages
  • Data systems
AF
47. Products that have EOP2 meeting prior to submission are less likely to require multiple cycle reviews
  • EOP2 meeting held
  • Action Packages
  • Data systems
AF
48. Products that have both EOP2 and Pre-NDA/BLA meetings prior to submission are less likely to require multiple cycle reviews
  • EOP2 and NDA/BLA meetings held
  • Action Packages
  • Data systems
AF
49. Frequent communication is likely to increase the first-cycle approval rate
  • Number and format of interactions (meetings, telecom, emails, faxes)
  • Action Packages
  • Data systems
AF
50. Increased communication towards the end of the review cycle is likely to decrease the first-cycle approval rate
  • Number and format of interactions (meetings, telecom, emails, faxes)
  • Timing of communications
  • Action Packages
  • Data systems
AF
51. Increasing number of issues identified in pre-submission meetings and correspondence are more likely to predict multiple review cycles (Core issues not the number of issues)
  • Total number of issues raised
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
AF
52. Increasing number of issues identified during review are more likely to result in multiple review cycles (Core issues not the number of issues)
  • Total number of issues raised in review
  • Issues identified per phase (e.g., filing and primary review)
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
AF
53. Applications with increasing number of issues raised under the Trial Design phase are likely to increase the number of review cycles
  • Identify stage of program in which each issue is raised:
    • Trial Design
    • Trial Execution
    • Trial Analysis
    • Manufacturing
    • Clinical Facility Inspection
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
AF
54. Reviews requiring Advisory Committee meeting are more likely to require multiple cycle reviews
  • Y/N Advisory Committee meeting
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
AF
55. Types of Issues raised in Advisory Committee reviews may impact the number of review cycles required
  • List all issues raised
  • Type of issue raised in Advisory Committee:
    • Trial Design
    • Trial Execution
    • Trial Analysis
    • Manufacturing
    • Inspections
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
NA
56. Necessity of more complex responses (e.g., new trial data) from FDA is more likely to result in multiple review cycles
  • List responses required
  • Characterization of response (e.g., Length size of additional trials)
Note – the complexity of response will be further defined
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
ANF
57. Non-compliance of sponsor with specific FDA requests will increase the likelihood of multiple review cycles
  • List all non-compliance events (sponsor does not fulfill request of reviewer);
  • Map to Issues involved in prior column
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
ANF
58. FDA response to sponsor close to PDUFA goal date will result in multiple review cycles
  • Sample metrics would include FDA received date, first action date, performance goal date
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
ANF
59. Changes in submission requirements will increase likelihood of multiple review cycles. Such requirements include: endpoints, safety, efficacy and manufacturing standards
  • Y/N (List) of changes in submission requirements
  • Action Packages
  • Data systems
  • Review Team interviews
  • Sponsor interviews
NA
60. Products with a greater number of unsolicited amendments are less likely to be approved first-cycle
  • Number of unsolicited amendments
  • Action Packages
  • Data systems
ANF
61. Products with a change in the safety profile (as defined by FDA) for a given product class are less likely to be approved first-cycle
  • Change in safety profile
  • Action Packages
  • Data systems
NA
62. Products submitted in eCTD or electronic NDA/BLA have greater first-cycle approval
  • Submission method (electronic, paper, mixed)
  • Action Packages
  • Data systems
ANF
63. Increased communication between FDA and the sponsor for products with Priority review designation leads to greater first-cycle approval
  • Number of communications
  • Action Packages
  • Data systems
AF
64. Products with a clinical SPA review by FDA have greater first-cycle approval
  • SPA review conducted
  • Action Packages
  • Data systems
ANF
65. Products with issues reported on the 74-Day letter that were discussed pre-submission are less likely to be approved first cycle
  • 74-Day letter issues
  • Pre-submission meeting issues
  • Action letter issues
  • Action Packages
  • Data systems
ANF
66. Products with any clinical or safety issue (not a data, data format, or label request) included in the 74-Day letter are less likely to be approved first cycle
  • 74-Day letter issues
  • Action letter issues
  • Action Packages
  • Data systems
ANF
67. Products with 74-Day letter issues that are not addressed during the review are less likely to be approved first cycle
  • 74-Day letter issues
  • Action letter issues
  • Action Packages
  • Data systems
AF
68. Products with unresolved safety and efficacy issues identified pre-submission (Pre-NDA/BLA, EOP2) are less likely to be approved first cycle
  • NDA/BLA and EOP2 issues
  • Action letter issues
  • Action Packages
  • Data systems
ANF
69. Products with more sponsor meetings during the review cycle are less likely to have multiple review cycles
  • Number of sponsor meetings
  • Action Packages
  • Data systems
  • Meeting Observation
AF
70. The use of checklists by reviewers increases the first-cycle approval rate
  • Use of checklists and number of checklists
  • Action Packages
  • Data systems
ANF
71. Divisions that have structured internal team meetings and documentation practices have a higher approval rate
  • Observed meeting style/structure
  • Meeting Observation
ANF
72. High quality application (e.g., number of IRs, number of submission between application receipt date and 60-day filing date) submission have greater first-cycle approval rates
  • Review cycles and action dates
  • Total review time
  • Quality parameters (e.g., application completeness, data accuracy, technical data supported labeling, overall scorecard rating)
  • Time interval between initial submission and complete submission if initial submission incomplete
(Note: Parameters to assess quality are under development by the FDA and will evolve as data are gathered)
  • Action Packages
  • Review team interviews
  • Industry interviews
ANF
73. Large US-based companies are likely to have greater first-cycle approval rates
  • Approval rate
  • Country of origin
  • Size/ type of the sponsors
  • Size of the regulatory unit
  • Action Packages
  • Web research
AF
74. Companies with more experience with FDA have greater first-cycle approval rates
  • Approval rate
  • Number of submissions
  • Experience of regulatory staff
  • Use of consultants (e.g., CRO)
  • Action Packages
  • Web research
AF
75. Companies with more experience in the therapeutic area have greater first-cycle approval rates
  • Approval rate
  • Number of submissions in each therapeutic area
  • Action Packages
  • Web research
AF
76. Outsourcing consultant involvement is less likely to result in multiple review cycles
  • List any third parties involved; Specify nature of third party (e.g., CRO)
  • Action Packages
  • Data systems
  • Sponsor interviews
ANF
77. Sponsors whose prior submission characteristics shared with that of the current submission are less likely to require multiple review cycles
  • Number of submissions
  • By phase
  • By trial size
  • Therapeutic area
  • By type
  • By year
  • Action Packages
  • Data systems
  • Sponsor interviews
NA
78. Sponsors with experience in gaining application approvals since PDUFA are less likely to require multiple review cycles
  • Number of submission gaining approvals since PDUFA began
  • Web research
  • Sponsor interviews
AF

FDA Characteristics

Hypotheses Metric(s) Data Source Status
79. Submissions received in the fourth quarter will have the lowest first-cycle approval rate
  • Number of active applications per quarter
  • Approval rate
  • Product lists
AF
80. Products that have facility inspections early in the review cycle are more likely to increase first-cycle approval rates
  • Timing of notification of inspection
  • Type of inspection site
  • Timing of inspectors involved in the review team
  • Approval rate
  • Action Packages
  • Data systems
NA
81. Applications requiring foreign facility inspection have lower first-cycle approval rates
  • Inspection site location
  • Timing of notification of inspection
  • Type of inspection site
  • Timing of inspectors involved in the review team
  • Approval rate
  • Action Packages
  • Data systems
AF
82. Reviewer or Division workload is likely to contribute to multi-cycle review
  • Approval rate
  • Review cycles
  • Number of active applications (INDs, NMEs, BLAs and efficacy supplements) per year
  • Number of review teams or RPMs in a Division
  • Non-review activities and Priority
  • New initiatives and time spent
  • Review team interviews
NA
83. Applications that experience turnover of lead reviewers (i.e., Office Director, Clinical Team Lead) are more likely to result in multiple review cycles
  • Number of reviewer changes over course of review
  • Review team interviews
AF
84. Application that experience turnover of the RPM are more likely to result in multiple review cycles
  • Number of reviewer changes over course of review
  • Review team interviews
AF
85. Applications that are submitted to a Division in which the Division Director changes during application review result in more multi-cycle reviews
  • Division Director attrition rate
  • Review team interviews
AF
86. Applications that have more postmarketing commitment studies are less likely to require multiple review cycles
  • Review cycles
  • Number of post-marketing studies
Note – a separate task order will look into PMCs impact
  • Action Packages
  • Data systems
  • Review team interviews
AF
87. Drug-Device combinations requiring input from multiple divisions or areas are more likely to require multiple cycles
  • Drug-Device combination from multiple divisions? (Y/N)
  • Action Packages
  • Data systems
  • Review team interviews
NA
88. Drug-Drug combinations requiring input from multiple divisions or areas are more likely to require multiple cycles
  • Drug-Drug combinations from multiple divisions? (Y/N)
  • Action Packages
  • Data systems
  • Review team interviews
NA
89. Increasing numbers of consults (internal and external) are more likely to result in multiple review cycles
  • Total number of consults (internal and external) per application
  • Action Packages
  • Data systems
  • Review team interviews
ANF
90. Type and timing of consult (internal vs. external) may impact the number of review cycles required
  • List each consult, characterize as internal vs. external
  • Timing of consults
  • Action Packages
  • Data systems
  • Review team interviews
ANF
91. Number and type of issues raised in consults may impact the number of review cycles required
  • List all issues raised in consults
  • Action Packages
  • Data systems
  • Review team interviews
NA
92. Applications with dissenting opinions on the Priority review designation amongst reviewers are more likely to require multiple review cycles
  • Priority designation status disputed – Y/N?
  • Action Packages
  • Data systems
  • Review team interviews
NA
93. An experienced reviewer (2+ years of regulatory review) will have higher first-cycle approval rates
  • Approval rate
  • Reviewer experience (e.g. regulatory experience, experience in the therapeutic area)
  • Action Packages
  • Data Systems (DFS, RMS-BLA)
  • Review team interviews
NA

*Approval Rate metric will be based on specific hypothesis (e.g., for hypothesis related to the Fast-Track Program, the approval rate measured will be for approvals within this program category)



[1] Independent Evaluation of FDA's First Cycle Review Performance – Retrospective Analysis Final Report, Booz Allen Hamilton Inc., January 2006 http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119469.htm

[2] For the purposes of evaluating GRMPs compliance and impact, five key activities and associated timelines were considered based on the importance of the activity, as well as the availability of information to assess compliance with these activities: hold filing meeting, communicate filing review issues to applicant, hold mid-cycle meeting, complete primary review, and hold labeling discussions (for approval and approvable actions).

[3] Review issues are those issues identified during the filing of an application that may potentially impact approval.

[4] Action packages are a collection of important documents generated during the review of an application.

[5] The PDUFA III goals can be found at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm118925.htm.  As of September 2007, FDA began operating under PDUFA IV.  PDUFA IV goals can be found at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm

[6] Independent Evaluation of FDA's First Cycle Review Performance – Retrospective Analysis Final Report, Booz Allen Hamilton Inc., Jan. 2006 http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119469.htm
[7] Six of the 185 applications did not reach action until January 2008

[8] The 77 products analyzed in “The Independent Evaluation of FDA’s First Cycle Review Performance – Retrospective Analysis Final Report” are included in the Overall Study Cohort.

[9] A user fee waiver may be granted for a small business submitting its first application.  Also, a waiver may be granted where: it is necessary to protect the public health; assessment of the user fees would present a significant barrier to innovation due to limited resources; fees will exceed the anticipated costs incurred by FDA for conducting the application review; assessment of the fee for an application filed under section 505(b)(1) pertaining to a drug product would be inequitable because an application for a product containing the same active ingredient filed by another person under section 505(b)(2) could not be assessed user fees. (Section 736(d) of the Federal Food, Drug & Cosmetic Act (FDCA))

[10] Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA products. April 2005.

[11] Only the FY2005-FY2007 cohort could be analyzed, since the data source for earlier products was limited to  Action Packages, which contain limited if any information regarding pre-submission meetings.

[12] SOPP 8401.3.  Filing Action – Communication Options.  Version #1.  May 11, 2003

[13] PDUFA III goals were to provide the sponsor a notification of deficiencies prior to the goal date for 50% of applications in FY 2003, 70% in FY 2004, and 90% in FY 2005, FY2006, and FY 2007.

[14] Formal Meetings with Sponsors and Applicants for PDUFA Products Guidance

[15] A major deficiency is defined as a product- or application-related issue that would contribute to preventing first-cycle approval if not adequately addressed.

[16] Issues identified in either the EOP2 or Pre-NDA/BLA meeting are grouped in one pre-submission category because sponsors can take as much time as needed to resolve an issue before submitting the application, but must resolve them by the Action Date for issues identified during the review.

[17] Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) amends the FDCA to authorize FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes (section 505(o)(3)(A), 21 U.S.C. 355(o)(3)(A)). This provision took effect on March 25, 2008. The description in this report refers to policies in place prior to FDAAA implementation.

[18] Analysis not shown.

[19] Pre-submission documentation of RPM and Medical team lead were not available for all products.

[20] Contributing factor was determined by reviewing deficiencies noted on the first-cycle Action Letter.

[21] Review teams that performed each activity within one week of the guideline were considered fully compliant.  “Highly compliant” review teams performed at least 4 out of the 5 activities within one week of the guideline (80% compliant).

[22] The activities include: hold filing meeting, communicate filing review issues to applicant, mid-cycle meeting, complete primary review, and labeling discussions (for approval and approvable actions).

[23] Note: Large pharmaceutical companies had a market capitalization over $5B; large biotechnology had capitalization over $1B; small biotechnology had capitalization under $1B, small-medium pharma had less than $5B.

[24] At the Application Orientation meeting, sponsors can walk the FDA through the format of their product application. However, discussion of data, results, and conclusions is not the focus of this meeting.

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