CONTENTS

5 EXECUTIVE SUMMARY
5 Overview of US drug approval regulations and procedures
5 Complete Response Letters and impact on approval
6 Take-home messages to avoid Complete Response Letters

8 REGULATIONS AND PROCEDURES OF RELEVANCE TO COMPLETE RESPONSE LETTERS
8 The FDA regulatory burden is increasing
13 US drug submissions process
18 References

20 COMPLETE RESPONSE LETTERS AND IMPACT ON APPROVAL
20 Trends in Complete Response Letters
29 FDA advisory committee meetings and Complete Response Letters
34 References

35 TAKE-HOME MESSAGES TO AVOID COMPLETE RESPONSE LETTERS
35 Common deficiencies that trigger a Complete Response Letter
38 Case studies
39 Neutroval (tbo-filgrastim)
40 Bydureon (exenatide)
41 Nucynta ER (tapentadol)
42 Lamictal (lamotrigine)
43 Menveo (meningococcal ACWY vaccine)
44 Horizant (gabapentin enacarbil)

46 APPENDIX
46 About the author
46 Scope
46 Methodology

LIST OF FIGURES
8 Figure 1: Full-time equivalent FDA staff, FY2000–10
10 Figure 2: Number of postmarketing requirements by drug approval year, 2000–11
20 Figure 3: Approvals, Complete Response Letters, and withdrawals as a percentage of total applications, FY2009–12
22 Figure 4: Approval delay (months) for submissions that received a single Complete Response Letter
30 Figure 5: Number and percentage of NME/BLA submissions referred to advisory committee, FY2008–11
32 Figure 6: Comparison of advisory committee votes and approval status
36 Figure 7: Common deficiencies that trigger a Complete Response Letter

LIST OF TABLES
9 Table 1: Number of NDAs/BLAs and FDA workload, FY2009–11
11 Table 2: Number of postmarketing requirements by drug approval year, 2000–11
21 Table 3: Number of drug submissions, Complete Response Letters, resubmissions, and approvals, FY2009–12
25 Table 4: Company comments and action taken after receiving a Complete Response Letter