The document provides information for filing an Investigational New Drug (IND) application in electronic Common Technical Document (eCTD) format with the US FDA. It discusses the objectives of filing an IND for the drug Riociguat to treat pulmonary hypertension. It provides background on CTD and eCTD submission formats. It also includes details on the chemistry, manufacturing, and controls of Riociguat, preclinical and clinical studies, labeling, and stability data required for the IND application in eCTD format.

1. FILLING AN IND APPLICATION IN CTD
FORMAT TO US FDA
Presented by
Neeraja Reddy Am
12971M1606
1

2. AIM
 The aim of my project work is to file an IND
for the drug product in Electronic Common
Technical Document (eCTD) format for USA
in accordance with recent regulatory changes
stipulated in draft guidelines published by
FDA on January 2013.
2

3. OBJECTIVES
PRIMARY OBJECTIVE:
 The prime motto of this project is to attain a great insight
into the guidelines regarding the eCTD submissions and
filing an IND to US FDA in eCTD format for a drug.
SECONDARY OBJECTIVE:
 Making out the difference between traditional IND and
eCTD (version 3.2.2) format and stating the importance and
benefits of filing a submission in eCTD format.
 To collect(CMC, Non Clinical, Clinical literature, etc...),
analyse, organize the data and prepare an IND in eCTD
format.
3

4. SCOPE
 The draft guidance “Guidance for Industry Providing
Regulatory Submissions in Electronic Format- Certain
Human Pharmaceutical Product Applications and
Related Submissions Using the eCTD Specifications”
published by US FDA in January 2013 stated that, the
regulatory submission to FDA has to submitted in eCTD
format for their review and approvals.
 The FD&C Act provides that the submissions shall be
submitted in electronic format “beginning to earlier than 24
months after the issuance of a [final guidance specifying the
format for such submissions]”.section 745(A). Therefore, the
electronic submission requirement will be phased in
according to the following schedule: 4

5. SCOPE
 (1) 24 months after publication of final version of this
draft revised guidance, the requirements will apply to
NDA, ANDA, and BLA submissions.
 (2) 36 months after publication of the final guidance, the
requirements will apply to IND submissions.
As IND’s has to be submitted in eCTD format from the
year of 2016 I felt this as one important emerging topic
and has chosen it as my project. I felt that carrying out
project on such emerging topics would fetch me great
opportunities in the field of regulatory affairs.
5

6. INTRODUCTION
INVESTIGATIONAL NEW DRUG APPLICATION
(IND)
 An Investigational New Drug Application (IND) is a request for
Food and Drug Administration (FDA) authorization to
administer an investigational drug to humans. Such authorization
must be secured prior to interstate shipment and administration
of any new drug that is not the subject of an approved new drug
application. IND regulations are contained in Title 21, Code of
Federal Regulations, Part 312.
6

7. Types of IND
 Investigator IND
An Investigator IND is submitted by a physician who both initiates and
conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. A physician might submit a
research IND to propose studying an unapproved drug, or an approved product
for a new indication or in a new patient population.
 Emergency Use IND
Emergency Use IND allows the FDA to authorize use of an experimental drug
in an emergency situation that does not allow time for submission of an IND in
accordance with 21 CFR, Sec. 312.23 or Sec. 312.34. It is also used for patients
who do not meet the criteria of an existing study protocol, or if an approved
study protocol does not exist.
7

8.  Treatment IND
Treatment IND is submitted for experimental drugs showing promise in
clinical testing for serious or immediately life-threatening conditions
while the final clinical work is conducted and the FDA review takes
place.
There are two IND categories:
 Commercial
 Research(non-commercial)
And my project is a commercial treatment IND.
8

9. BACKGROUND
CTD (COMMON TECHNICAL DOCUMENT)
 ICH is a joint initiative involving both regulators and industry as
equal partners in the scientific and technical discussions of the
testing procedures which are required to ensure and assess the
safety, quality and efficacy of medicines.
 The CTD was agreed upon in November 2000, in San Diego, USA. The
purpose of this Common Technical Document (CTD) is to provide a
harmonised structure and format for new product applications (marketing
authorization).
9

10. CTD (COMMON TECHNICALDOCUMENT)
 The focus of the CTD is to provide a common format for the preparation of a
well structured submission according to the modular framework described in
the ICH guidelines of the Common technical document for registration for
Human Use (ICH topic M4).
 The agreement to assemble all the Quality, Safety and Efficacy information in
a common format (called CTD - Common Technical Document ) has
revolutionised the regulatory review processes, led to harmonised electronic
submission that, in turn, enabled implementation of good review practices.
For industries, it has eliminated the need to reformat the information for
submission to the different ICH regulatory authorities.
10

11. CTD (COMMON TECHNICALDOCUMENT)
 The CTD guidance indicates where and how available information is to be
presented.
11

12. CTD (History)
 Concept first raised in 1995
 First concept paper in 1996
 Industry survey on cost and time to convert NDA to MAA
started July 1996
 Working groups began work Feb 1997
 Quality : Europe
 Safety : Japan
 Efficacy : USA
 Step 2 (Table of contents) 1999
 Step 3 and 4 (summary format, regional specific
requirements) March & Nov 2000
12

13. CTD (Implementations)
 Optional EU,FDA,MHLW
July 2001: (Canada, Switzerland)
 Mandatory EU,MHLW
July 2003 : (Canada, Switzerland)
 Highly recommended FDA
July 2003 :
13

14. ELECTRONIC COMMON TECHNICALDOCUMENT
(eCTD)
 The ICH M2 Expert Working Group (EWG) has defined, eCTD as
an interface for industry to agency transfer of regulatory information
while at the same time taking into consideration the facilitation of the
creation, review, lifecycle management and archival of the electronic
submission. The eCTD specification lists the criteria that will make
an electronic submission technically valid. The focus of the
specification is to provide the ability to transfer the registration
application electronically from industry to a regulatory authority.
Industry to industry and agency to agency transfer is not addressed.
 ICH multidisciplinary guideline 2, Electronic Standards.
14

15. XML(Extensible Markup Language) Based
eCTD
 The XML eCTD DTD (Document Type Definition) defines the overall structure of
the submission. The purpose of the XML backbone is two-fold: (1) to manage meta-
data for the entire submission and each document within the submission and (2) to
constitute a comprehensive table of contents and provide corresponding navigation
aids. Meta-data on submission level include information about submitting and
receiving organization, manufacturer, publisher, ID and kind of the submission, and
related data items.
 Examples for meta-data on document level are versioning information, language,
descriptive information such as document names and checksums.
 Extensible Markup Language (XML) is a markup language that defines a set of
rules for encoding documents in a format that is both human-readable and machine-
readable.
15

16. eCTD (electronic CTD) Submission
 An eCTD submission is a collection of data objects that follows the
eCTD specification. The main function of the eCTD submission is
data exchange. Information systems would have to be created to
process the eCTD submission. The biggest benefits are expected
when the eCTD submission is loaded into an information system that
supports the review process. However, one can view an eCTD
submission with a Web browser as it is Web ready. In the Web
environment, the eCTD submission should be usable without
processing in at least in the following ways:
 Standalone: Viewable with a Web browser.
 Network: Loadable into a Web server
16

17. RIOCIGUAT Tablets
Description:
 Riociguat is a tablet for oral administration. Riociguat is methyl
4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-
3-yl]-5-pyrimidinyl(methyl)carbamate with the following
structural formula
Druginformation
 The solubility at 25°C in water: 4 mg/L,
in ethanol: 800 mg/L, in 0.1 HCl (pH 1):
250 mg/L and in buffer (phosphate) pH 7:
3 mg/L. In the pH range of 2 to 4 the
solubility showed strong pH-dependency.
Solubility increases at lower pH values.
17

18.  Riociguat is a soluble guanylate cyclase (sGC) stimulator indicated for
the treatment of adults with :
 Persistent/recurrent Chronic Thromboembolic Pulmonary
Hypertension (CTEPH) (WHO Group 4) after surgical treatment or
inoperable CTEPH to improve exercise capacity and WHO functional
class.
 Pulmonary Arterial Hypertension (Riociguat is a white to yellowish,
crystalline, non-hygroscopic substance with a molecular weight of
422.42 g/mol. In solid form it is stable to temperature, light, and
humidity.
 PAH) (WHO Group 1) to improve exercise capacity, improve WHO
functional class and to delay clinical worsening.
18

19. Pathways to treat
19

20. Soluble guanylate cyclase
 Vasodilatator
 Synthetised by NO synthase in endothelial and epithelial cells
 Inhaled treatments with NO are unsuitable as long term therapies for PH
due to: short life, development of tolerance, non specific interactions with
biomolecules
 Toxicity with high dose
20
Nitric oxide
 Heterodimer: larger α subunit and a smaller haem-binding β subunit
 Prosthetic haem moiety on the haem binding domain with a reduced Fe2+
 GTP cGMP
 Potentiated by NO
sGC

21. NO-sGC-cGMPSignal Transduction Pathway
21

22. Results
Traditional IND Application: Content and
Format
 Form FDA 1571
 Table of Contents
 Introductory Statement and General Investigational Plan
 Investigator’s Brochure
 Investigator-sponsored IND.
 University-sponsored IND
 Clinical Protocol(s)
 General principles.
 Protocol content and format
 Chemistry, Manufacturing and Control (CMC) Information
 General principles
 CMC content and format
 cGMP compliance 22

23. Traditional INDApplication: Content and Format
 Labeling
 IND submission requirements.
 Investigational drug labeling requirements.
 Pharmacology and Toxicology Information
 General principles.
 Content and format.
 Previous Human Experience with the Investigational Drug
 Additional Information
 Drug dependence and abuse potential.
 Radioactive drugs.
 Pediatric studies.
 Other information.
23

24. INDinCTDFormat
24

25. Module1
regionalinformation
FORM 1571 Investigational New Drug Application(IND)
25

26. Environmentalassessmentform(21CFR25.23)
 This is to state that ANVS Pharma, Pvt,Ltd. abides by
the regulations stipulated in 21 CFR 25.23 for
environmental assessment. This report states that ,
manufacturing the drug product Riociguat by ANVS
Pharma is not causing any environmental pollution
and also neither releasing any obnoxious gases or
toxic materials nor causing any harm to the
environment.
26

27. Clinicalsupplylabels
 INDICATIONS
 PAH
 CETPH
 IMPORTANT SAFETY INFORMATION
 Embryo-fetal toxicity
 CONTRAINDICATIONS
 Pregnancy
 Nitrates and nitric oxide donors
 Phosphodiesterase Inhibitors
 WARNINGS AND PRECAUTIONS
 Embryo-fetal toxicity
 Hypotension
 Pulmonary Veno-Occlusive Disease
27

28. Clinicalsupplylabels(cont…)
 MOST COMMON ADVERSE REACTIONS
 Headache, dizziness, diarrhea, hypotension, constipation, etc
 PACKAGE:
 Riociguat tablets
 Description: Each carton contains one bottle containing 90 film
coated tablets.
 Dosage: As prescribed by the prescription.
 Storage: store at 250C(770F); excursions are permitted from
150C to 300C(59 to 860F).
28

29. Generalinvestigationalplan
 Research Rationale and Objectives
 Pulmonary hypertension is defined as an increase in mean pulmonary
arterial pressure (mPAP) >25 mmHg at rest as assessed by right heart
catheterization. This clinical definition includes a group of diseases that
share symptoms of dyspnea, fatigue, and reduced exercise capacity.
 Both CTEPH and PAH are characterized by increased mPAP associated with
pulmonary vascular resistance (PVR), which can lead to progressive right
ventricular dysfunction/failure, and ultimately, premature death. Based on
the pathophysiology, the pharmacologic activity of riociguat was expected
to result in beneficial clinical effects in both CTEPH and PAH.
29

30.  Proposed Clinical Research
 Relative Bioavailability and Food Effect Study of Two Oral Liquid
Formulations in Comparison to a 1mg Tablet of Riociguat to
Characterize Its Pharmacokinetic Properties in Healthy Male and Female
Adult Subjects in a Randomized, Open Label, 5 Fold Crossover Design.
 Brief title:
 Relative Bioavailability and Food Effect Study
 Brief summary
 Relative bioavailability study in order to investigate different liquid
formulations in comparison to a standard tablet
30

31.  Anticipated Risk From Study Drug
 Bone metabolism
 Reproductive toxicity
 Nursing mothers
 Female and male reproductive potential
 Over dosage
 Pregnancy
 Embryo-Fetal Toxicity
 Hypotension
31

32. Investigatorsbrochure
1. INTRODUCTORY STATEMENT
2. SUMMARY
3. PHYSICAL, CHEMICAL AND PHARMACEUTICAL
PROPERTIES AND FORMULATION
4. NONCLINICAL STUDIES
5. SUMMARY OF DATA AND GUIDANCE FOR THE
INVESTIGATOR
6. EFFECTS IN HUMANS
7. APPENDICES
32

33. Module2
summaries
 CMC Introduction
This section gives the brief overview of the drug
substance and drug product .CMC mainly focuses on the
quality of the drug. This includes analytical validations,
specifications and justification of specifications, stability
data, synthesis and formulation development, etc., that are
involved in manufacturing the drug.
33

34. Module3:quality
 Chemistry, Manufacturing & Controls
 Manufacturing process
 Raw materials & finished product testing
 May refer to drug master file or previous applications
 Provide Data Supporting the Purity, Identity and Stability of Bulk Drug &
Formulated Drug Substance
 Impurity Profile in Clinical Material Should Be Consistent with Material
Used in the Pivotal Nonclinical Toxicology Studies
 Formulation of Drug in Nonclinical Studies Should Parallel Clinical
Formulation
 GMPs as applicable for Phase 1
34

35. Chemistry manufacturing and
control
3.2. S. 3 Characterisation
Elucidation Of Structure And Other
Characteristics
HPLC: 99.90 area % (without taking the DMSO into
account)
DMSO (GC): 14.7% by weight
35

36. Chemistry manufacturing and
control3.2. S. 4 Control of Drug Substance
 Physiochemical properties : white to yellowish in colour
 Polymorphic form : crystalline
 Solubility :soluble in DMSO and insoluble in water
 Melting point :2860C
 Assay by HPLC :99.9%area(without taking DMSO into account))
3.2. S. 5 Reference Standards or Materials
3.2. S. 6 Container Closure System
The drug substance is packed in containers made of HDPE.
36

37. Chemistry manufacturing and
control
3.2. S. 7 Stability
The stability data show that the assay does not significantly deviate
from the initial value. No significant change from initial potency value
was observed at 250c/75% RH for 36 months or at 400c/75% RH for 6
months. The appearance, dissolution, and microbial purity showed no
changes over all the room temperature and accelerated storage
conditions.
37

38. Chemistry manufacturing and
control 3.2. P DRUG PRODUCT
3.2.P.1 Description and Composition of The Drug Product
 DRUG PRODUCT NAME: RIOCIGUAT
 DOSAGE FORM: Film-Coated Tablet
 ROUTE OF ADMINISTRATION: Oral
 PHARMACOLOGICAL CATEGORY: Soluble Guanylate Cyclase
(sGC), stimulator for treatment of chronic Thromboembolic pulmonary
hypertension(CTEPH) and pulmonary arterial hypertension (PAH).
38

39. Chemistry manufacturing and
control
3.2.P.2 Pharmaceutical Development
 The objective of the pharmaceutical development was to provide an
oral formulation containing riociguat micronized with high convenience
and patient compliance. Immediate release tablet formulations of small
size have been selected as dosage form.
 Riociguat tablets are film-coated to facilitate swallowing and a colour
code design was used to distinguish between the different dose strength
and to facilitate tablet identification.
39

40. 3.2.P.3 Manufacture
3.2.P.4 Control of Excipients
Excipients: Cellulose microcrystalline, Crospovidone, Hypromellose 5 cp,
Lactose monohydrate, Magnesium stearate, Sodium laurylsulfate
Film-coating: Hydroxypropylcellulose, Hypromellose 3cP, Propylene
glycol, Titanium dioxide, Ferric oxide yellow, Ferric oxide red
3.2.P.5 Control of Drug Product
3.2.P.6 Reference Standards or Materials
• Not Applicable
Chemistry manufacturing and
control
40

41. Chemistry manufacturing and
control3.2.P.7 Container closure system
The primary packaging of the container closure system used for distribution on
riociguat tablets is a 45-cc, white HDPE bottle closed with a screw cap white colour
with sealing insert.
3.2.P.8 Stability
 The results indicate that:
 There was no change in the description of the material.
 There was no increase in loss on drying indicating that the material is not
hygroscopic.
 The product compiled with the specified limits.
 The assay was within the limits indicating the stability of the product.
41

42. Module4:Non-ClinicalsafetyStudies
 Pharmacology & Toxicology
Information
 Non-clinical study summaries of pharmacological & toxicological
effects
 Rationale for Human Benefit
 Extrapolate from Animal Data Projected Doses or Blood
Concentrations for Human Efficacy
 Identification of Unintended Actions Which May Impact Safety
 Estimate Therapeutic Index from Pharm/Tox Data
42

43.  Pharmacology & Toxicology Information
 Identify Target Organ Toxicity
 Identify Non-Toxic and Toxic Dose Levels (NOAEL)
 Provide Evidence of Safety for the Duration of Phase 1 Clinical Trial
 Provide Evidence of Safety for the Dosing Regimen
 Non-Clinical Reports
Module4:Non-ClinicalsafetyStudies(cont…)
43

44. Study conducted Species Dose/dosing frequency Response/observation
Primary pharmacodynamic conscious and anesthetized
normotensive rats
Multiple dosing dose-dependent decrease in blood
pressure
Primary pharmacodynamic anesthetized and conscious
dogs
Multiple dosing dose-dependent decrease in blood
pressure
Secondary
pharmacodynamics
Rat 2.5 mg TID weak inhibitor of platelet
aggregation
No clinically relevant increase in
rat tail transection
Secondary
pharmacodynamics
eNOS knockout mice N/A positive effects in various models
of cardio-renal protectionlow-NO, high-renin rat
model of hypertension
Safety pharmacology human ether-a-go-go
related gene (hERG) K+
voltage clamp assay
up to 10 μM no effects on hERG K+
Safety pharmacology isolated Purkinje fiber
assay (rabbit)
at 10 μM slight and biologically not-
relevant APD90 prolongation
(+14%)
Safety pharmacology anesthetized and conscious
(telemetry) dogs
up to doses causing ≥25%
blood pressure
no biologically relevant QTc
effects
Pharmacology tabulated summary
44

45. Study conducted Species Dose/dosing frequency Response/observation
absolute bioavailability rat
dog
N/A protein binding of riociguat and M-1 was
low to moderate and species-dependent.
Elimination rat
dog
N/A elimination of riociguat occurred rapidly
from rat and dog plasma with half-lives
of about 1 to 3 hours.
Distribution rat [14C]riociguat and labeled
metabolites
Blood/brain and blood/testes
penetration of radioactivity was low
penetrated the placental barrier to a
moderate extent in pregnant rat.
Biotransformation rat, dog N/A No human-specific metabolic pathways
and no major species differences
Biotransformation Human liver
microsomes and
recombinant CYP
isoforms
N/A revealed several CYP isoforms capable to
form M-1 (CYP1A1, 2C8, 2J2, 3A4/5)
metabolite M-4 was catalyzed by human
UGT1A1 and UGT1A9
Excretion animal species and N/A renal and fecal/biliary routes
in vitro investigations riociguat and its
main metabolite M-1
N/A no inhibitory and no inductive potential
on major human CYP isoforms, but
revealed an inhibitory potency on
CYP1A1
no inhibitory potency towards human
glucuronosyl transferases (UGTs) or
sulfotransferases (SULTs) was observed
Pharmacokinetic tabulated summary
45

46. Study conducted Species Dose/dosing frequency Response/observation Key safety findings
Repeat-dose toxicity rats N/A penile erection due to vasodilation;
increased water consumption and urine
volume and consequently decreased urine
density
No clinical signs of
toxicity was observed
Repeat-dose toxicity rats 100 g/kg/day in a 13-week
study resulting exposures
about 7 times that at the
MRHD,
Bile duct activation and/or hyperplasia
and increased periportal inflammatory
infiltration
No clinical signs of
toxicity was observed
Repeat-dose toxicity dogs 0.3 mg/kg/day marked decreases in systolic and diastolic
blood pressure and compensatory
increases in heart rate
No clinical signs of
toxicity was observed
≥ 0.3 mg/kg/day Pathologic lesions in heart and and in
coronary vessels
No clinical signs of
toxicity was observed
Genotoxicity bacterial mutation
(Ames) assays
in vitro chromosome
aberration assays in
Chinese Hamster V79
cells, and in vivo bone
marrow micronucleus
studies in male mice
N/A Neither riociguat nor its major circulating
active metabolite was genotoxic negative
in an in vivo bone marrow cytogenetic
study conducted in male mice.
No clinical signs of
toxicity was observed
Carcinogenecity mice N/A statistically non-significant increases in No clinical signs of
Toxicology tabulated summary
46

47. Reproductive and
development toxicity
Rats
pre- and postnatal period
gestation period
N/A decreased live birth index and decreased
survival up to day 4 post-partum
increased rate of cardiac malformations
and an increase in post-implantation
loss, including early resorption. a
decrease in fetal weight, an increased
incidence of underdeveloped or missing
thyroid glands, and retarded
ossification.
No clinical signs of
toxicity was observed
N/A no effects on male and female fertility No clinical signs of
toxicity was observed
Rabbits(during the
gestation period)
lower than the maximum
human exposure
abortion and fetal toxicity No clinical signs of
toxicity was observed
M1 administered during the
gestation period
abortion and total resorption No clinical signs of
toxicity was observed
NOAEL systemic exposure to M1 was lower
than the maximum human exposure.
No clinical signs of
toxicity was observed
Other toxicity studies
(Bone toxicity)
adult rats 26-week
steady state systemic
exposures
during adolescence, increased bone
remodeling/hyperostosis in the femur
No clinical signs of
toxicity was observed
No bone effects were seen when
treatment was initiated in adult, full
grown rats
Toxicology tabulated summary
47

48. Module5:clinicalEfficacy
 Protocol(s)
 Must include at least the initial protocol
 Phase I – protocol outline:
 No. subjects planned
 Eligibility requirements
 Dosing
 Safety assessments
 Phase II & III – detailed protocols
48

49. Purpose
InvestigationoftheeffectofRiociguat,administeredas2.5mgIR-tabletsTIDover14days,on
bonemetabolism.
Condition Intervention Phase
Effect of Riociguat on Bone
Metabolism
Drug: Riociguat
Drug : Placebo
Phase 1
Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics
Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator,
Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Investigation of the Effect of Riociguat, Administered
as 2.5 mg IR-tablets TID Over 14 Days, on Bone
Metabolism in a Randomized, Placebo-controlled,
Double-blind, 2-fold Cross-over Design in Healthy
Male Subjects
49

50.  Form 1572: Statement Of Investigator
 This form represents Statement of the Investigator conducting clinical
research under the IND application.
 Investigator CV
 Sponsor’s CV
 Previous human experience reports
Module5:clinicalEfficacy(cont..)
50

51.  3.2. A APPENDICES
 3.2. R REGIONAL INFORMATION
Not applicable
 3.3 LITERATURE REFERENCES
51

52. discussion
 Key IND Requirements
 First-In-Humans (FIH) Study Protocol
 Rationale for Intended Use (In Vitro & In Vivo
Pharmacology)
 Toxicology Studies Supporting the Starting Dose
& Duration of the FIH Study
 Assurance of Quality of Drug Substance & Drug
Product Used in Toxicology Studies & in the FIH
Study
52

53. “TheINDPackage…”
53

54. discussion
54

55. discussion (cont..)
Managing IND Application
Maintenance Phase
Review Process
Submission Process
Pre-Filing Phase
55

56. Managing INDApplication
The pre-filing phase :
 key activity is the collection of all reports which will need to be filed with the IND
 Pre-IND meetings can be held either as face-to-face meetings or by teleconference.
 The principal aim of the pre-IND meeting is to avoid any judgements by the FDA
which would preclude the conduct of the clinical trial, or might result in a clinical
hold on review of the IND. By familiarising the FDA with your drug and your
intended clinical plans, you are trying to ensure a clear path to the clearance of your
IND.
Submission Process:
 one month prior to submission data is strongly advised.
 a surprise submission will not help with building your relationship with the project
manager.
56

57. Managing INDApplication
Review Process:
 The comments to the IND come in two categories.
 forward-looking comments and recommendations.
 comments which are “Clinical Hold” issues
Even if there is no approval letter, the FDA will issue a written summary of the suggestions,
comments, and requirements for the study to proceed within the next 4-7 working days.
Maintenance Phase:
 IND must be maintained over time by filing, at a minimum, Annual Reports to the IND. The
purpose of the Annual Report is inform the FDA of the drug’s progress in development;
however even if there has been no progress, an Annual Report to the IND must be filed in
order to keep the IND open. If the IND is not maintained, then the FDA will eventually
terminate the IND. If the IND is terminated and drug development starts again, then the entire
IND would have to be refiled.
57

58. IND Format
 The format of an IND can take multiple shapes: from a submission in
eCTD format to a paper submission in traditional format or a mixture
thereof can be acceptable. The granularity of traditional format is guided
by 21CFR312.23(a)-(f) (termed “Items” 1-8) which need to be authored
for IND. Item 1 (Cover letter; FDA Form 1571), Item 2 (Table of
Contents), Item 3 (Introductory Statement), and Item 4 (General
Investigational Plan), are unique to an IND. Item 5 (Investigator’s
Brochure), Item 6 (Protocol), Item 7 (Chemistry, Manufacturing, and
Control [CMC] Information) and Item 8 (Pharmacology and Toxicology
Information) can be reused in other regulatory submissions if appropriately
structured. A common hybrid IND submission type presents Item 7 in
CTD granularity under 3.2.S for Drug Substance and 3.2.P for Drug
Product and consists of eight principal sections ;
58

59. Traditional INDApplication: Content and Format
59

60. CTD INDApplication :content and format
60

61. Table representing mapping of Traditional IND and IND
in CTD format
Traditional IND
(Title)
IND in CTD Format
Module No (Title)
Item 1
(Form 1 FDA 1571)
1.1
(Application Form)
Item 2
(Table of Contents)
1.1
(Table of Contents)
Item 3
(Introduction)
2.5
(Clinical Overview)
Item 4
(General Investigational Plan)
1.13.9
(General Investigational Plan)
Item 5
(Investigator’s Brochure)
1.14.4.1
(Investigator’s Brochure)
61

62. Table representing mapping of Traditional IND and IND
in CTD format
Traditional IND
(Title)
IND in CTD Format
Module No (Title)
Item 6
(Protocol)
5.3
(Specific Study)
Item 7
(Chemistry, Manufacturing, and Control
Information)
3.2.S; 3.2.P
(Quality)
Item 8
(Pharmacology and Toxicology Information)
2.4, 2.6
(Nonclinical Overview; Nonclinical Written and
Tabulated Summaries)
Item 9
(Previous Human Experience)
2.5, 2.7
(Clinical Overview; Clinical Summary)
62

63. General comparison between paper and electronic
format of CTD
Paper CTD eCTD
Complied electronically with volumes, tabs,
slip-sheets, then printed to paper
Complied electronically with edocuments in
folders
Paper volumes must be A4 edocuments can be A4 or US letter size
CTD navigation by TOC’s and volume eCTD navigation by XML backbone
Cross references includes target CTD section
number
Cross references are hyperlinked to targets
Manual document navigation by TOCs, page
numbers and caption cross-reference
Electronic document navigation by TOCs,
hyperlinks and bookmarks
Submitted in binders in boxes on pallets by
trucks
Submitted on CD (or DVD) or by email or
portal.
63

64. Comparison between NeeS and eCTD in a Dossier
Format
NeeS eCTD
More often handled as individual dossiers Standard across industry
Can be viewed in EURS Typically viewed via viewing tool
Validation rules all category
A – potential to automate
Can see what has changed when
No lifecycle, no metadata Contains metadata, application history
Heavily reliant on file/folder structure Tool can be deployed throughout
organisation
64

65. NeeS vs. eCTD in terms of Software
NeeS eCTD
All software required already on desktop or
easilydeployable
Need specialist software
Can quickly adapt your organisation to build
and validate NeeS (including affiliates)
Deployment centrally only – or at all offices
dealing with dossiers
No need for expensive corporate wide
enterprise system
Potentially complex IT architecture and
performance issues
–Connectivity, access to content
–Re-use of content
–Resource availability
–Training
No additional software costs Expensive
65

66. discussionandConclusion(cont..)
Advantages of the eCTD format:
 Suitable for managing CMC dossiers for other regions through
customized CMC document creation and for building CMC
dossier content progressively over time.
 Can be used for all phases of development
 Allows consistent authorising practices for both investigational
and marketing dossiers.
 Bookmarks and headings, because of ICH restrictions on levels,
can cover more subtopic in a more granular document approach
rather than a single document covering many topics.
 Mistakes are easily addressed without subjecting old content to
re-review by the Agency
 More advantageous in maintaining the life cycle management.
66

67. Conclusion
 The purpose of my thesis is to provide helpful considerations in
developing a company strategy for submitting the IND information in
eCTD format. Since there are no official guidelines for eCTD INDs,
my thesis provides options derived from guidance’s to help
companies determine how to organize and present IND information
using the principles of the eCTD format.
 Since, most companies conduct clinical trials globally, this option of
IND in eCTD format provides opportunities to avoid reworking the
same information into multiple different formats for clinical trial
applications in other countries.
 Simply the life cycle management can be made easy with application
of eCTD format to the IND. And also, the thesis mainly emphasis on
the organization of the information which makes the reviewer work
easy and which may result in early approval or response
67

68. REFERENCES
 Guidance for Industry Providing Regulatory Submissions in Electronic Format — Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD
Specifications , U.S. Department of Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research (CDER) Center for Biologics
Evaluation and Research (CBER) June 2008 Electronic Submissions Revision 2
 http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedan
dapproved/approvalapplications/investigationalnewdrugindapplication/ucm07109
8.htm
 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope
dandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/de
fault.htm
 Guidance for Industry M2 eCTD: Electronic Common Technical Document
Specification U.S. Department of Health and Human Services Food and Drug
Administration
 Center for Drug Evaluation and Research (CDER), Center for Biologics
Evaluation and Research (CBER), April 2003
68

69. REFERENCES
 Guidance for Industry Providing Regulatory Submissions in Electronic Format — Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD
Specifications , U.S. Department of Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research (CDER) Center for Biologics
Evaluation and Research (CBER) June 2008 Electronic Submissions Revision 2
 http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedan
dapproved/approvalapplications/investigationalnewdrugindapplication/ucm07109
8.htm
 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope
dandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/de
fault.htm
 Guidance for Industry M2 eCTD: Electronic Common Technical Document
Specification U.S. Department of Health and Human Services Food and Drug
Administration
 Center for Drug Evaluation and Research (CDER), Center for Biologics
Evaluation and Research (CBER), April 2003
69

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