1. Results
Section 505(b)(2) of the Food, Drug, and Cosmetic act is a key component of the 1984
Hatch-Waxman Amendments that allows the FDA to rely on evidence not owned by the
applicant. This portion of the Act, in combination Section 115(a) of the Food and Drug
Administration ModernizationAct of 1997, which allows for approvals to be based on one study
and confirmatory evidence, has had the effect of streamlining clinical development programs,
particularly during the 'lifecycle' portion of drug development.
This study abstracts information related to the development programs from publicly available
Summary Basis of Approvals (SBOAs). Providing a high-level summary of differences between
the programs of different NDA/Chemical classifications, as well as an evaluation of intra-class
differences will provide important insights to both Regulators and pharmaceutical industry
Sponsors. These data will provide new knowledge on critical points in development programs, as
well as identify potential areas for improvement that may improve the efficiency of these
processes.
Principal Aims
• To determine what types of studies are used in different lifecycle strategies
• To determine how many studies are needed on average for each strategy to establish
substantial evidence for approval
Methods
•505(b)(2) Database
– A listing of 505(b)(2) programs was compiled from the website* Food and Drug
Administration / NDA and BLA Calendar Year Approvals (access date: 5/1/16).
– Key demographic features and content from drug development programs were identified
and entered into an EXCEL database by a primary reviewer; All fields of the database were
verified by a second reviewer.
•Analysis
– Demographic features and program content from nonclinical, clinical pharmacology, and
clinical programs will be summarized by chemical classification with descriptive statistics.
– Key Endpoints (by Chemical Classification) will be:
• Average Number of Studies Required for Substantial Evidence
• Sources of Contributory Evidence
• Subjects in the Phase 2b/3a and Total Development Program
• Complete Responses and Review Extensions
• Waivers and Post-Marketing Requirements
Introduction
Alignment of the Regulatory and Lifecycle Strategies in New Drug Applications
Submitted Under 505(b)(2) of the Food, Drug, and Cosmetic Act
• Manufacturing issues were a common reason for both Complete Responses
and Review Extensions. These trends were seen across chemical classes,
demonstrating that it is an important concern for all NDAs.
• Considering the high cost and time consuming nature of clinical trials,
knowing if and how many clinical trials need to be completed for an NDA to
be approved will be valuable information for Applicants. Based on the data
we have collected thus far, we have begun to see trends emerging on these
issues.
• The data represent our analyses to date. As the assessment of NDAs
becomes complete, our evaluations may suggest issues for improvements in
development programs. These changes will increase the efficiency of the
505 (b)(2) development process for Sponsors and help to expedite their
reviews.
Table 1: Chemical Classification Corresponding Number and Name
Chemical Classification # Corresponding Chemical Classification Name
Class 1 New Molecular Entity
Class 2 New Active Ingredient (New Salt, New Noncovalent Derivative, New Ester)
Class 3 New Dosage Form
Class 4 New Combination
Class 5 New Formulation or New Manufacturer, Same or New Indication
Class 6 New Indication or Claim, Same Applicant
Class 7 Drug Already Marketed but Without an Approved NDA
Table 3 Waiver and PMR vs Chemical Classification
Chemical Classification
Characteristics
(N)
1(N=4) 2 (N=1) 3 (N=15) 4 (N=3) 5 (N=6) 7 (N=3)
Waiver
Clinical 3 1 9 3 6 2
Clinical Pharm 1 NA 5 3 1 1
Pharm 1 0 1 1 0 1
PMR
Clinical 3 1 7 3 1 0
Clinical Pharm 1 0 6 1 2 0
Pharm 1 0 3 1 1 1
Conclusions
0
1
2
3
NumberofNDAs
D
A
A
A
P
D
A
IP
D
C
R
P
D
D
D
P
D
G
IEP
D
H
P
D
M
EP
D
M
IP
D
N
C
E
D
N
P
D
PA
R
P
D
PP
D
TO
P
Division
Chemical Classification
1
2
3
4
5
7
Table 2: NDAs by Chemical
Classification, reviewed to date
Chemical
Classification
N (%)
1 4 (12.5)
2 1 (3.1)
3 15 (46.9)
4 3 (9.4)
5 6 (18.7)
7 3 (9.4)
Total (to date) 32 (100)
Complete response/Extension
0
5
10
15
NumberofNDAs
Complete response Extension
1 2 3 4 5 7
Chemical Classification
1 2 3 4 5 7
Chemical Classification
Y/N
N
Y
Figure 4: Complete Responses and Review Extensions by Chemical
Classification
Manufacturing issues were a typical reason for Review Extension. Inadequate Safety Data in the
original NDA submission resulted in both Complete Responses and Review Extensions.
Figure 1: NDAs reviewed and Chemical
Classification by Clinical Division
0
5
10
15
NumberofNDAs
1 2 3 4 5 7
Chemical Classification
Clin References
L = Literature
L, P
Monograph, P
NA
P = Reference Drug
Figure 2: Source of Contributory
Evidence by Chemical Classification
Clin Requirements
0
1
2
3
4
5
6
NumberofNDAs
N Y
1 2 3 4 5 7
Chemical Classification
1 2 3 4 5 7
Chemical Classification
Total # +Ph2b/3a trials
1
2
3
6
Most programs required evidence from
clinical studies except some of those in Class
3 that relied on Relative Bioavailability
studies. Evidence of efficacy and safety from
Marketed Unapproved drugs typically came
from the literature.
Figure 3: Requirement for evidence from
Clinical Studies by Chemical Classification
Acknowledgements: We are very grateful to Dr. ShaAvhree Buckman-
Garner (OTS) and Drs. Dunn and Unger (ODE1) for their support!
Table 2. Number of Subjects per Program and in 'Positive' Phase2b/3a Studies' Used for
Substantial Evidence of Approval
Relatively large programs for Class 4 were due to placebo-controlled factorial studies that provided evidence of
efficacy/safety and to satisfy the Combination Rule. One Class 4 program had a cardiac outcome study, which
skewed the average in this small sample of programs.
Chemical
Classification # of Subjects in (mean±SD)
On test treatment in
+ Ph2b/3a trials
Total in + Ph2b/3a
trials
On test treatment in
whole program
Total in whole program
1 402 ± 205 737 ± 423 737 ± 133 1141 ± 210
2 0 0 102 ± 0 102 ± 0
3 108 ± 128 381 ± 447 602 ± 761 742 ± 907
4 561 ± 608 1132 ± 997 2767 ± 761 5159 ± 7410
5 296 ± 274 633 ± 476 361 ± 365 649 ± 618
7 0 0 0 0
*
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAa
ndBLAApprovalReports/ucm373413.htm
Margaret VanHeusen 1,2,4, Xiao Fang, MS 1,3,4, Christopher D. Breder, MD PhD 1,2
1Division of Neurology Products, ODE1/OND/CDER, 2Program in Regulatory Science, AAP/CAS Johns Hopkins University, 3Office of Biostatistics, University of Texas Medical Branch, 4ORISE Fellowship Program