NDA- New Drug Application, useful presentation for UG and PG students

1. NEW DRUG
APPLICATION (NDA)
Prepared by
Dr. Jigar Vyas
Professor
Sigma Institute of Pharmacy
1

2. INTRODUCTION
• The New Drug Application (NDA) is the
vehicle in the United States through which
drug sponsors formally propose that the FDA
approve a new pharmaceutical for sale and
marketing.
• The NDA mainly contains
– Clinical and non clinical data and analysis
– Drug chemistry information
– Description of manufacturing process
2

3. • The FDA has established the guideline for
formatting, assembling and submitting NDA.
• NDA shares many common element with the
COMMON TECHNICAL DOCUMENT (CTD)
developed by ICH.
3

4. 4

5. • The FDA requires the drug sponsors to submit the
multiple copies of NDA.
• The Archival copy
• The field copy
• The review copy
5

6. The Archival copy
 Contains all section of NDA including
 The Cover letter
 Form FDA h(application to market new drug)
 The administrative section
 The Comprehensive NDA index
 All technical section
 It must contain four copies of labelling section
6

7.  It must contain three additional copies of CMC and
method validation package in separate binder.
 The archival copy is only copy that contains the
case report form and case report tabulation
 The archival copy is a complete copy of an
application submission and must be bound in a
BLUE cover jacket.
7

8. The Review Copy
• The review copy is divided into six technical sections.
• It should be submitted with each review section
separately bound in a specific color.
• Chemistry, Manufacturing and Controls (CMC) – RED
• Nonclinical Pharmacology and Toxicology – YELLOW
• Human Pharmacokinetics and Bioavailability –
ORANGE
• Microbiology (if required) – WHITE
• Clinical Data – LIGHT BROWN
• Statistical – GREEN
8

9. • Each review section should contain the following:
– a copy of the cover letter attached to the archival copy
– a completed application form FDA 356h
– a copy of the general index of the entire application
– an index specific to that particular review section
– letters of reference or authorization, if appropriate;
– patent information.
9

10. The FIELD COPY
 Required since 1993 for use by FDA inspector during
approval for certain facilities.
 It mainly include Method validation package.
10

11. Resources for NDA Submissions
 The following resources have been gathered to
provide the legal requirements of a new drug
application.
 Guidance Documents for NDAs:
 Assistance from CDER to help meet the
requirements, and
 Internal NDA review principles, policies and
procedures.
11

12. Guidance Documents for NDAs:
 Guidance documents represent the Agency's current
thinking on a particular subject.
 These documents are prepared for FDA review staff
and applicants/sponsors to provide guidelines to the
processing, content, and evaluation/approval of
applications and also to the design, production,
manufacturing, and testing of regulated products.
12

13. Guidance documents to help prepare NDAs
include:
 Bioavailability and Bioequivalence Studies for Orally Administered
Drug Products - General Considerations. This guidance should be
useful for applicants planning to conduct bioavailability (BA) and
bioequivalence (BE) studies during the IND period for an NDA, BE
studies intended for submission in an ANDA, and BE studies conducted
in the post approval period for certain changes in both NDAs and
ANDAs.
 Container Closure Systems for Packaging Human Drugs and Biologics.
 Format and Content of the Chemistry, Manufacturing and Controls
Section of an Application.
 Format and Content of the Microbiology Section of an Application.
 Format and Content of the Clinical and Statistical Sections of an
Application.
 Format and Content of the Summary for New Drug and Antibiotic
Applications.
13

14. Cont….
• Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances.
• Documentation for the Stability of Human Drugs and
Biologics.
• Samples and Analytical Data for Methods Validation.
• Supporting Documentation in Drug Applications for the
Manufacture of Drug Products.
• NDAs: Impurities in Drug Substances.
• Format and Content of the Human Pharmacokinetics
and Bioavailability Section of an Application.
• Format and Content of the Nonclinical
Pharmacology/Toxicology Section of an Application.
14

15. Laws, Regulations, Policies and Procedures:
• The mission of FDA is to enforce laws enacted by the U.S.
Congress and regulations established by the Agency to
protect the consumer's health.
• The Federal Food, Drug, and Cosmetic Act24 are the
basic food and drug law of the U.S. With numerous
amendments.
• The law is intended to assure consumers that foods are
pure and wholesome, safe to eat, and produced under
sanitary conditions; that drugs and devices are safe and
effective for their intended uses; that cosmetics are safe
and made from appropriate ingredients; and that all
labeling and packaging is truthful, informative, and not
deceptive
15

16. Code Of Federal Regulations (CFR)
• The final regulations prepared by ICH committee
published in the Federal Register (daily published
record of proposed rules, final rules, meeting notices,
etc.) are collected in the CFR.
• The CFR is divided into 50 titles which represent
broad areas subject to Federal regulations.
• 21CFR Part 314 - Applications for FDA Approval to
Market a New Drug or an Antibiotic Drug.
16

17. New Drug Application
1
7
 Introduction
Critical component for drug approval process which
required to submit to USFDA before drug
commercialization.
The data gathered during the animal studies and
human clinical trials of an Investigational New Drug
(IND) become part of the NDA.
 Goal
The NDA provide enough information to permit FDA
reviewer to reach safety, efficacy and quality for
pharmaceutical production

18. NDA Classifications
1
8
 New Molecular Entity
 New Salt of Previously Approved Drug (not a new molecular entity)
 New Formulation of Previously Approved Drug (not a new salt OR a
new molecular entity)
 New Combination of Two or More Drugs
 Already Marketed Drug Product - Duplication (i.e., new
manufacturer)
 New Indication (claim) for Already Marketed Drug (includes switch
in marketing status from prescription to OTC)
 Already Marketed Drug Product - No Previously Approved NDA

19. New Drug Development and Review Process
Steps from Test Tube to New Drug Application Review
1
9

20. Phases of clinical testing
Phase Number of
patients
Length Purpose Percent
successfully
completing
Phase1 20-100 Several months Mainly safety
67
Phase2 Up to several
hundred
Several months
to two years
Some short-term
safety but mainly
effectiveness
45
Phase3 Several hundred 1-4 years Safety,
to several
thousand
effectiveness,
dosage
5-10
6
20

21. 2
1

22. 2
2

23. NDA Review Process
2
3

24. NDA contents
 The NDA may have as many as 20 different section
in addition to form FDA 356h itself.
 The application form FDA 356h mainly serve as
 Checklist as well as
 Certification that sponsor agree to comply with the range of
legal and regulatory requirments.
24

25. 25

26.  Before NDA is submitted to FDA, applicant usually
meet with the reviewing division in pre-NDA
meting
 Applicant present the summary of the clinical
studies and proposed format of NDA and any other
information he want to share.
 The purpose is to uncover any major unresolved
issue and to help the applicant for filing the NDA
26

27.  By this time ,the classification of the NDA for the
priority of the review should be known.
 Standard review is used for drugs with therapeutics
benefit similar to currently available drugs.
 Priority review is used for the drugs that represent
significant advances over existing treatmemt.
 Within 60 days FDA either send acceptance or
rejection letter the application
27

28. Reason for the refusal
 Form FDA 356h has not been completed
 Format is not correct
 One or more item are missing
 Manufacturing facilities is not ready for the inspection
 Environmental assessment is incomplete
 No statement regarding the compliance with IRB
 Product is already approved by NDA
28

29.  Easily correctable deficiency- notify by phone or fax
 The applicant have to submit the safety report within
4 month of the initial submission
 When the scientific or medical issue are resolved,
then FDA will inspect the manufacturing sites
 Then they will send
 Not approvable letter
 Approvable letter
 Approval letter
29

30. Approval time
 1993 - 23 month
 1996 - 14.3 month
 2001 - 6 month
30

31. 31

32. General overview
 Two copy of the application form is needed:- archive
and review copy
 Both copies include a cover letter which confirms the
agreement
 Letter contain any relevant correspondence or
meeting by date and topic
 It also contain any other information that applicant
may wish to give
32

33. Review and the archive copy
 Application form as cover letter, and it must
obligate following laws
 Labeling regulation
 Prescription drug advertising regulation
 Regulations on making changes in an application
 Local, state and federal environmental impact laws
 User fee cover sheet (included 1st volume)
 Financial disclosure forms 3454
33

34.  If the applicant is not residing or have a place of
business in the US, then application must contain
name and address of the countersigned by attorney
agent
 Application, index and summary should be bound in
single volume
34

35. Format for title
 Type of the Document_______
(IND,NDA DMF)
 Document no. __________
 Title or subject of the document _____
 Document holder_____
 Vol. Page no.________
 Date _______
35

36. Formatting, assembling and submitting
new drug and antibiotic application
36

37. A General Format of NDA
 Index
1. Archive copy (reference material):- after approval
it is retained by the FDA
2. Review copy :- divided into 5-6 sections,
containing the technical and scientific information
 Separately bound
37

38. Each section of review copy should contain a copy of
volume no. 1.1with the following
 1. A copy of the FDA cover letter
 2. A copy of the application form (FDA 356h)
 3. A copy of the index to the entire application
 4. A copy of the overall summary
 5. A copy of a letter of reference or authorization to
access NDAs, DMFs, etc
 For each section use the colored folder (name of
applicant and the drug)
38

39. It is necessary that applicant use the colored folders to bind
the specific section of the review copy.
Document Folder colour Form no.
Archival copy Light blue FD 2626
CMC data Red FD 2626 a
Nonclinical
pharmacology and
toxicology section
Yellow FD 2626 b
Human p’kinetic &
bioavailability
Orange FD 2626 c
Microbiology section White FD 2626 d
Clinical data section Light brown FD 2626 e
Statistical section Green FD 2626 f
Field copy Maroon FD 2626 h
39

40.  3. Paper Size and Binding
 Bound on left size of the page, both size should be used for
presentation of the information.
 4. Pagination
 Any method can be used , but the page no of the archive and
review should be same
 5. Volume size and identification
 Volume submitted in hard copy form should not more than 2
inch. thick.
 The front cover of each vol. should have name of applicant,
drug, and NDA number.
40

41.  The vol. no. should preprinted in the right upper
corner, and in the lower right –hand corner of each
jacket cover is the legend, “ THIS SUBMISSION:
VOL.__OF VOLS.”
 The blanks should be filled in by the applicant to
identify the specific vol. and the total no. of the
vol.submitted.
41

42.  6. Packing carton
 The box size of 14*12*9 ‘’ is recommended for shipment of
application to FDA.
 An exterior label should indicate applicant’s name, drug name &
vol. no., it is also imt. to identify which carton contain the review
copy and which the archive copy.
 Full applications should be sent to
Food and Drug Administration
Office of Drug Evaluation and Review
Central Document Room
Park Building.
Room 214 12420 Parkhnvn Drive
Rockviile, MD 20852
42

43. C. Supplements, Amendments, and Post-marketing
Reports
 The submission format for amendments to pending
application and supplement to approved application
will be the same as in an original application.
 Amendment, supplements, resubmissions, annual
reports, and other correspondence concerning full
application should be addressed to the appropriate
FDA reviewing divisions.
43

44.  Postmarketing report of adverse drug reaction,
including the 15-day “alert report” and the periodic
drug experience report, should be submmitted,
unbound, induplicate, to

Food and Drug Administration
Office of Drug Evaluation and Review
Central Document Room
12420 Parklawn Drive
Rockville, MD 20852
44

45. NDA SECTION
1. INDEX
2. LABELLING
3. APPLICATION SUMMARY
4. CHEMISTERY, MANUFACTURING AND
CONTROLL
5. NON CLINICAL PHARMACOLOGY AND
TOXICOLOGY
6. HUMAN PHARMACOKINETICS AND
BIOAVAILABILITY
45

46. 7. MICROBIOLOGY
8. CLINICAL DATA
9. SAFTY UPDATE REPORTS
10. STATASTICS
11. CASE REPORT FORM TABULATION
12. CASE REPORT FORM
13. PATENT INFORMATION
14. DEBARMENT CERTIFICATE
46

47. Section 1 - INDEX
• The NDA index is the comprehensive table of content
that enables the reviewers to find specific
information in the massive document quickly.
• It must show the location of every section in the
archival NDA by volume and by page number.
• It should guide reviewers the data in the technical
section, the summary and supporting document.
47

48. Section-2 LABELLING
• The labelling section include all draft labelling that is
intended for use on
• The Product Containers
• Cartons or Packages
• The proposed Package insert
48

49. SECTION 3 : APPLICATION SUMMARY
 The application summary is the abbreviated version
of entire application.
 The overview is one of the few elements of the
application that all reviewers receive and it should
give them clear idea of the drug and its application.
 The summary usually compries 50 to 200 pages
49

50. Section 4 : Chemistry, Manufacturing and
Control (CMC)
 The first technical section of NDA.
 It include the information on
 The composition
 Manufacturing and
 Specification of drug substance and drug product
 The Three main elements are
 The Chemistry manufacturing and control information
 Samples
 Method validation package
50

51. 4. chemistry,
manufacturing,
and control
Drug
Substanc
e
Name
Physical and
chemical
characteristic
Stability
Manufacturer
Method of
manufacturing
Tests and
analytical
method
Drug
product
Composition
and dosage
form
Manufacture
Specification
and analytical
method
Container
and closure
Stability
Investigational
formulations
51

52. The CMC information must include
 Description of drug substance
 Its stability
 Physical and Chemical characteristic
52

53. • Provide the name of the drug substance :
• Common name
• Chemical name
• Codes
• Provide the structural overview including
• Molecular structure
• Molecular formula
• Elemental composition
53

54. SECTION 5 : Non Clinical Pharmacology and
Toxicology
• The second technical section of NDA provide the
description of all animal and in vitro studies with drug.
• Includes the narrative summary od notable findings in all
studies.
• Provide individual study report including
• Pharmacology
• Toxicology
• ADME Studies
54

55. Nonclinical
pharmacology
and toxicological
summary
Pharmacology trials.
Acute toxicity trials
Multidose toxicity
trials
Carcinogenicity trials
Special toxicity trials
Reproduction trials.
Mutagenicity trials.
ADME
55

56. 1.Pharmacology trials: Further subgroup by
type of test with trials that support the
pharmacologic activity of the drug first, followed by
secondary trials and safety pharmacology trials.
2.Acute toxicity trial: Tabulate species, sex, age, dose
range, pharmacological actions and interaction with
other drug, routes of administration, vehicle, toxic
sings, lethal dose, time of death, etc.
56

57. 3.Multidose toxicity trial: Provide a table of trial including species
and strain, no. of animals, sex, age, dose, dose schedule, and route
of administration.
• Notable treatment and dose related changes in survival, %wt.
gain, toxic signs, hematology, clinical chemistries, organ weight,
and pathology should be provided.
4.Carcinogenicity trial: The following information should included ,
• For each treatment group, the no. of animal entered and
surviving 12, 15, 18, 21, 24 months.
• A summary table of tumor occurrences with deaths and tumor
type, and dose level.
57

58. 5. Reproduction trial: Tabulate fertility and reproductive
performance trials (segment 1) and perinatal and postnatal trial
(segment 3) if differences are observed from control.
• Teratology trial data (segment 2) should be tabulated showing
differences and similarities in gross viscera and skeletal
anomalies.
6. Mutagenicity trial: This data should be presented in the following
order,
-In vitro nonmammalian cell system
-In vitro mammalian cell system
-In vivo nonmammalian cell system
-In vivo mammalian cell system
58

59. 7. ADME trial: In summarizing the ADME trial,
tabulate species, strain, and dose comparison data
by the following.
-Peak level, half life and plasma protein binding
-Tissue distribution/accumulation
-Enzyme induction or inhibition
-Metabolites
-Excretion pattern and characteristics
59

60. SECTION 6 : HUMAN PHARMACOKINETICS
AND BIOAVAILABILITY
• This Technical section includes data from phase 1 safety and tolerance
studies in healthy volunteers and ADME studies.
• It should include tables of PK parameters such as
• AUC
• Cmax
• Tmax
Brief description of each
 bioavailability,
 trial objective,
 design, analytical
 statistical method used,
 results.
 Pharmacokinetic characteristics
 Dissolution profile of the drug
60

61.  summary of all in vivo biopharmaceutical trials
 trial number,
 route of administration,
 dosage form,
 batch number,
 plant and date of manufacture,
 number of subjects,
 NDA number
 date of submission,
 conclusions regarding the trial,
61

62. Summary of
pharmacokinetic
parameters
Peak concentration
AUC
Tmax
Elimination constant
Vd,
Plasma and renal
clearance,
Urinary excretion
62

63.  list of all formulations used in clinical trials
 analytical methods used to measure the-levels of the
drug and major metabolites in body fluids
 trial number,
 submission date,
 type of biological fluid,
 method used,
 sensitivity,
 range of the method
 specificity of the method for the parent compound and
metabolites.
63

64.  Dissolution data on each strength and dosage form
 date of the trials,
 dosage form and strength,
 lot number,
 dissolution apparatus,
 media/temperature,
 speed of rotation/flow,
 collection times,
 number of units tested,
 Range and mean percent dissolved
64

65.  The last portion of this section incude the report for each of trial
referenced in this section. Each report should include the following
information:
1. Objective
2. Dosage form studied
3. Investigator
4. Clinical facilities
5. Analytical facilities
6. Individual subject/patient data including demographics, con-
comitant medication, blood/urine levels, laboratory tests, and adverse
reactions
7. Documentation on the sensitivity, linearity, specificity, and
reproducibility of the analytical methods
65

66. K. Microbiology
 For anti-infective and antiviral drugs
 This section is divided into the following 11 sections.
66

67. Section 7: MCROBIOLOGY
 Required for anti-infective drug product
 Antimicribial drug differ from other classes of drugs in that they are design to
affect the microbial physiology rather than patient physiology.
This should be done for anti-infective and antiviral drug.
1. A full description of the known mechanism of action together with structure
of the drug.
2. A brief description of the antimicrobial spectrum of action and a summary of
result of in vitro susceptibility testing demonstrating the conc. of drug
required for effective use.
3. A brief description of known mechanism of resistance to the drug and result
of any in vitro trial regarding resistance and any known epidemiological trial
that demonstrate the prevalence of resistance factors.
4. A full description of the clinical microbiology laboratory test method for
effective use of the drug.
67

68. 7.
Microbiology
Mechanism of Action
Pharmacokinetics
Antimicrobial Activity
Enzyme Hydrolysis Rates
Miscellaneous trials
Assessment of Resistance
Clinical Laboratory Susceptibility Test Methods
In Vivo Animal Protection trials
In Vitro trials Conducted During the Clinical
Trials
Conclusions
Published Literature
68

69. 1.Mechanism of Action: A full description of the known
mechanism of action together with structure of the drug.
2.Pharmacokinetics: The pharmacokinetics for systemic
dosage form should be described, including absorption,
routes of excretion, protein binding, Vd, metabolites.
3.Antimicrobial activity: A brief description of the
antimicrobial spectrum of action and a summary of result
of in vitro susceptibility testing demonstrating the conc.
of drug required for effective use.
4.Enzyme Hydrolysis Rates: The stability of drug in presence
of enzyme produced by micro-organism should be
summarized.
69

70. 5.Miscellaneous trials: any miscellaneous trial, such as those
showing bacterial effect, activity of metabolite , relationship
to the known drug, should be summarized.
6.Assessment of resistence:A brief description of known
mechanism of resistance to the drug and result of any in vitro
trial regarding resistance and any known epidemiological
trial that demonstrate the prevalence of resistance factors.
7.Clinical laboratory susceptibility test method: A
detailed discussion of the development of clinical laboratory
susceptibility test method shold be provided.
70

71. 8.In vivo animal protection trial: Result of any efficacy trial in
experimentally infected animal should be summarized.
9.In vitro trial conducted during clinical trial: The susceptibility
testing of clinical isolates obtained in clinical investigation it should be
summarized.
10.Conclusion: A brief narrative summary of overall result and any
conclusion about the drug must be included in this section
11.Published literature: Included in this section is a bibliography and
copy of all published report of trials used in support of the data and
information contained in microbiological section.
71

72. L. Clinical Data Section
 Most important and most complicated section of an
NDA
 Provides the safety and efficacy data on the drug for
its intended use
72

73. Section 8 Clinical data
• The technical section of NDA comprises ten
elements.
• The document’s largest and complex section
• List of investigator and list of IND and NDA.
• Overview of investigations.
• Clinical pharmacology section
• Controlled clinical trials
• Uncontrolled clinical trials
• Other studies and information section
• Integrated summary of effectiveness data
• Integrated summary of safety information
 Drug abuse and over-dosage information
 Integrate summary of benefits and risks of drugs
73

74. 8. Clinical data
summary and
result of statistical
analysis
Clinical pharmacology
Overview of the trial
Controlled clinical
trial
Uncontrolled clinical
trial
Other trial
information
Safety summary
Extent of exposure
Adverse experiences
Clinical lab data
Summary of the other
safety assessment
Over dosage and drug
abuse
74

75. Section 9: Safty Update Reports
• A pending application must be updated when new safty
data become available that could affect any of following
• Statements in draft labelling.
• Contraindication
• Adverse event
• Warning
75

76. Section 10 : Statastics
 This technical section includes description of
statastical analysis.
 It must include copies of :
 All Clinical Trials Reports
 Integrate summary of Risk and Benefits
76

77. Section 11 :Case report form
tabulation
This section must include complete
tabulation for each patient from every phase
1 and phase 2 clinical studies and from every
clinical pharmacology study.
77

78. Section 12 Case Report form (CRFs)
 It is necessary to include complete CRF for each
patient who died during the clinical study and for
any patient who where where dropped from the
study.
 Addition CRF must be provides at the request of
FDA.
78

79. PATENT INFORMATION
 THE PATIENT INFORMATION MUST BE
INCLUDED.
 AGE
 ADDRESS
 CONTACT DETAIL
79

80. DEBARMENT CERTIFICATE
 THE COPY OF DEBAARMENT CERTIFICATE
MUST BE INCLUDE.
 FOR CERTAIN CASE STUDY, THE PATIENT CAN’T
ALLOW TO DO CERTAIN THINGS.
80