3. Introduction
3
Non- Clinical development Phase primarily aims to identify
which candidate therapy has the greatest probability of success,
assess it’s safety & Build solid scientific foundations before
transition to the Clinical development Phase.
Also, during this phase candidate compound should meet non
medical objectives, including defining the intellectual property
rights & making enough medicinal product available for clinical
studies.
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4. GLOBAL SUBMISSION OF
IND
4
INTRODUCTION
The investigational new drug application is the result of a
successful preclinical development programme
IND is also a vehicle through which a sponsor
advances to next stage of drug development known as clinical
trials.
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5. 5
There are 2 main categories
1. Commercial:-
• Permits sponsor to collect data on ‘clinical safety&
effectiveness’ needed for application for marketing in the
form of NDA.
2. Non-commercial (Research) :-
• Permits sponsor to use drug in research to obtain
‘advanced scientific knowledge’of new drug .
• No plan to market the product .
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6. 6
Types of IND
1. Investigator INDs: It is submitted by Physician who both
initiates & conduct an investigation and under whose
immediate direction the investigational drug is administered
or dispensed.
2. Emergency Use INDs: It allows FDA to authorize use of
experimental drug in an emergency situation that does not
allow time for submission of an IND in a normal way.
3. Treatment IND (Expanded access IND): Submitted for
experimental drugs showing promise in clinical testing of
serious conditions while final work is conducted & FDA
review takes place.
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7. Criteria for IND application
A clinical study is required for an IND if it is
intended to support a :
• New indication.
• Change in approved route of administration or dosage level.
• Change in approved patient population (e.g. pediatric) or a
population at greater or increase in risk (elderly
,HIV positive , immuno compromised )
• Significant change in the promotion of an approved
drug
7
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8. Format And Content Of IND
1) Cover sheet (Form FDA1571).
2) Atable of contents.
3) Introductory statement & General Investigational plan.
4) Investigator’s Brochure.
5) Protocols.
6) Chemistry , Manufacturing &Control information.
7) Pharmacology and toxicology information.
8) Previous human experience with investigational
product.
9) Additional Information
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9. IND Application must contain information in
three broad areas:
a) Animal Pharmacology & Toxicology Studies:
Preclinical data to permit an assessment as to whether the
product is reasonably safe for initial testing in humans. If any
previous experience with the drug in humans.
b) Manufacturing Information:
Information regarding to the composition, manufacturer,
stability &controls used for manufacturing drug substance and
product.
c) Clinical Protocols and Investigator Information:
Detailed protocols proposed clinical studies to assess whether
initial phase trials will expose subjects to unnecessary risks.
Information and qualification of Clinical Investigators –
professionals .
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11. • After pre-clinical investigations when the new molecule has
been screened for pharmacological activity and acute toxicity
potential in animals the sponsor requires permission from FDA
for its clinical trials in humans.
• The sponsor submits the application for conduct of human
clinical trials called Investigational New Drug (IND)
application to FDA.
• Once IND application is submitted , the sponsor must wait
for 30 days before initiating any clinical trial.
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12. • Clinical trials in humans can begin only after IND is
reviewed by the FDA and a local institutional review board (IRB).
• IRBs approve clinical trial protocol, informed consent of all
participants and appropriate steps to prevent subjects from
harm.
• If the FDA accepts the IND request within 30 days of
submission, clinical testing of the new molecule on human
may begin by the investigator.
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13. • At this point, the molecule under the legal status of FDA
becomes a new drug subject to specific requirements of drug
regulatory system.
• If at any time during clinical testing, the data furnished to FDA
indicate the IP to be toxic under the criterion of FDA’s Benefit/Risk
ratio, FDA can terminate clinical trial and its actions are not subject
to any judicial review.
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14. Application submission:-
• Most of INDs are paper submission. While only 12%INDs
submitted electronically,28% of IND Amendments are
submitted electronically a result of maintaining a growing
number of INDs submitted electronically to date.
TIMELINE:
• 30 days after FDA receives the application , unless FDA
notifies the sponsor that the investigations described in the
application are subject to a clinical hold.
• Any earlier notification issued with approval clinical
investigations in IND may begins.
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15. GLOBAL SUBMISSION OF NDA
• Vehicle through which drug sponsors formally propose that the
regulatory body (FDA) approve a new pharmaceutical for sale &
marketing.
• The data gathered during the ‘animal studies’ & ‘Human clinical
trials’ of an Investigational new product become part of NDA.
The goal of NDA are to provide enough information to permit FDA
reviewers to establish the following :
• Safety & Effectiveness of drug ? - Proper labelling ?
• Are the methods used for manufacturing (GMP) the Drug &
Controls used to maintain the drug’s quality adequate to preserve
the drug’s identity, strength, quality &purity ?
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16. The goal of NDA are to provide enough information to permit
FDAreviewers to establish the following :
• Safety & Effectiveness of drug ?
• Proper labelling ?
• Are the methods used for manufacturing (GMP) the Drug &
Controls used to maintain the drug’s quality adequate to
preserve the drug’s identity, strength, quality &purity ?
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17. Classification of NDA
• Centre for drug evaluation and Research(CDER) classifies new drug
applications according to the type of drug being submitted and its
intended use:
a . New molecular entity
b. New salt of previously approved drug
c. New formulation of previously approved drug
d. New combination of two or more drugs
e.Already marketed drug product- Duplication (i.e., new
manufacturer)
f.New indication (claim) for already marketed drug (includes
switching marketing status from prescription to OTC)
g.Already marketed drug product ( no previously approved
NDA)
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18. Format and Contents of NDA
As outlined in Form no.-FDA-356th , Application to Market a
New drug for Human use .NDA consists of many different
sections:
• Index
• Labelling
• Application Summary
• CMC (chemistry, manufacturing & controls
• Non clinical- (Animal) Pharmacology & Toxicology
• Human pharmacokinetics & Bioavailability.
• Microbiology (for antimicrobial drugs only)
• Clinical data
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19. • Safety Update Report
• Statistics
• Case report Tabulations
• Case report forms
• Patent information
• Patent certification
• Other information.
Format:
It involves 3 copies;
1. Archival Copy
2. Review Copy
3. Field Copy
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20. 1.ARCHIVAL COPY
• It is a complete copy of an application for submission.
• It should include a cover letter to:
i. Confirm any agreements or understanding between
FDA& applicant.
ii. Identify a contact person regarding the application.
iii. Identify the reviewing division of FDA
iv. Convey any other important information about
application .
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21. 2.REVIEW COPY
• Divided into 6 technical sections shown with specific colour:
• Chemistry, manufacturing & controls(CMC)
• Non clinical pharmacology & toxicology
• Human pharmacokinetics & Bioavailability-
• Microbiology (if required )
• Clinical data –
• Statistical
• Separately bound copy of the Quality Section
• It is directly send to appropriate field office .
3.FIELD COPY
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22. NDA CONTENTS
Index : - Comprehensive table of contents
Show the location of every section in archival NDA by volume &
page number
Labelling : -Draft labelling used on Product container, Cartons or
packages, proposed package insert.
Application Summary : An abbreviated version of entire
application.
Involves few elements of application that all reviewers
review.
Gives a clear idea of Drug &its application.
-
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23. CMC: First technical section of NDA
Includes information on Composition, manufacturing and
specifications of drug substance & drug product.
Non clinical pharmacology & toxicology:
Provides a description of all animal & in vitro studies with drug.
Provide individual study reports, including pharmacology,
toxicology &ADME studies.
Human pharmacokinetics& Bioavailability : Includes data from
phase I safety & tolerance studies in healthy volunteers
&ADME studies. PK parameter , giving value of Cmax , AUC,
tmax , Ke , Vd
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24. Microbiology: Required for anti-infective drug product. Used in
case of involvement of antimicrobial drugs.
Clinical Data: Largest document & complex section
• List of investigators& list of INDs and NDAs
• Background/overview of clinical investigations
• Clinical pharmacology
• Controlled & Uncontrolled clinical trials
• Other studies & information.
Safety update reports: Safety updates should be submitted 4
months after initial application, following the receipt of an
approval letter & any other time that FDArequests.
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25. Statistics: Description & documentation of Statistical analyses
performed to evaluation of controlled clinical trials &other safety
information.
Case Report Form Tabulations:Complete tabulations for each
patient from every well controlled phase II &phase III and from
every phase I clinical pharmacology studies & also Safety data .
Case Report Forms(CRFs): Complete CRFs of each patient who
died during a clinical study & patients who were dropped from
study.
Others:Patent information &certification,
Establishment description, Debarment & Field copy certification,
User fee cover sheet , Financial disclosure.
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27. TIMELINE
Review time frames:
• Within 180 days of receipt of an application, FDA will review
approval , approvable or not approval letter ,this period is called
the ‘review clock’
• Applicant may withdraw at this period & later resubmit it .
• The time period may be extended by mutual agreement between
FDA& applicant .
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28. Filling timeline frames:
• Within 60 days after FDA receives , a determination is made
whether application may be filed.
• This determines whether sufficient information is provided to
proceed with in depth review.
• If FDA files the application ,applicant will be notified in written
.the date of filling will be the date 60 days after FDA received
application.
• The date of filling begins the 180 days period of review ,if FDA
refuses it then applicant can meet with FDA& discuss.
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29. ABBREVIATED NEW DRUG APPLICATION
(ANDA)
• An ANDA contains data submitted to U.S food & drug
administration (FDA’s CDER) ,office of generic drugs request for
review and ultimate approval of a generic drug.
• Once ANDA is approved ,an applicant may manufacture
&market the generic drug product to provide a Safe, Effective,
Low cost alternative to public.
• A generic drug product is one compared with innovator drug
product in Dosage form, Strength, Route of administration
Quality, Performance characteristics & intended use.
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30. • All approved products, both innovator & generic are listed in
Orange Book.
• Use of bioequivalence as the base for approving generic drug
products was established by the "Drug Price Competition and
Patent Term Restoration Act of 1984," also known as the
HATCH-WAXMANACT.
• It is because of this Act that there is the availability of less costly
generic drugs into the market without conducting costly and
duplicative clinical trials.
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31. FORMAT & CONTENT OFANDA
a .Application summary
b. Chemistry, Manufacturing and controls section
c. Non clinical pharmacology and toxicology section
d. Human pharmacokinetics & bioavailability section
e. Clinical and statically section
f. MicrobThe patent certification involved in
ANDA that includes:
g. iology section
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32. Paragraph I
- That the
patent
information has
not been
submitted to
FDA.
Paragraph
II
- That the
patent has
expired
Paragraph III
- That the
patent will
expire (on date
of marketing)
Paragraph IV
- Patent is invalid,
unenforceable or
will not be
infringed by
manufacture, use or
sale of generic drug.
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33. Bioequivalence:
Ageneric drug is considered to be Bioequivalent to Branded Drug if,
The rate & extent of absorption do not show a significant
difference from listed drug or
Extent of absorption does not show a significant difference in
rate is intentional or not medically significant.
NON
EQUIVALENT
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36. ➢Introduction to Dossier and Registration Dossier
➢Contents of the Dossiers
➢Goals of Dossiers
➢List of Dossier used in p’ceutical industries
➢Format of Dossier
➢Importance of effective Dossier management
➢What is IMPD?
➢Objective and General structure of IMPD
➢Types of IMPD
➢What IMPD shouldAccompany
➢References
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37. • Dossier: The word 'Dossier' has the english meaning as a collection
or file of documents on the particular subject, especially a file
containing detailed information about a person or a topic.
• Example: Patient Medication Record(PMR)
• Any formulation is prepared for human use or the benefit of the
recipient is called as “Pharmaceutical product for human use”.
• Process of critiquing and assessing the dossier of pharmaceutical
product containing its detailed about administrative, chemistry,
preclinical & clinical information and the permission granted by the
regulatory agencies of a country with a view to support its
marketing or approval in a country is called as “Marketing
approval” or Registration Dossier.
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38. • “Registration Dossier” of the pharmaceutical product is a
document that contains all technical data (administrative, quality,
nonclinical, and clinical) of a pharmaceutical product to be
approved / registered / marketed in a country.
• It is more commonly called as New Drug Application (NDA) in
the USA or Marketing Authorization Application (MAA) in
European Union (EU) and other countries as simply Registration
Dossier.
• It is used for licensing approval/ market authorization of a drug.
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40. • Is the drug safe and effective in its proposed use(s) when used as
directed, and do the benefits of the drug outweigh the risks?
•Is the drug’s proposed labelling appropriate, and what it contain?
•Are the methods used in manufacturing (Good Manufacturing
Practice, GMP) drug and the controls used to maintain the drug’s
quality adequate to preserve the drug’s identity, strength, quality, and
purity?
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41. List of Common Dossiers which are used in
Pharmaceutical Industries
● Following are the some common forms of Dossiers which
are widely and commonly used in the pharmaceutical industries.
1. CTD Dossier.
2. e-CTD Dossier
3. ACTD Dossier
4. Country Specific Registration Dossier.
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42. The Dossier is submitted in the form of Common Technical
Document i.e CTD
The CTD is divided into five modules, in which the Module 1
(Administrative Information) is region specific and remaining all the
four modules are common for all the regions.
Following are the modules of CTD:
Module 1: Administrative Module Module 2: CTD summary
Module 3: Quality reports
Module 4: Pre-Clinical study reports Module 5: Clinical study
reports
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43. ● Below is the figure of the CTD dossier which shows the
Modules 1-5 it is consider as one of the format of Dossier.
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44. The registration dossier for medicines is an important document
which is submitted for review to regulatory agencies by pharma
companies for approval to market their medicines.
Utmost care should be taken during its compilation and filing as it
plays a direct role in earliest possible availability of medicines in the
market which in turn translates into business for the company.
Regulatory affairs professionals need to ensure the safety, quality and
efficacy of the medicines for which they are filing registration
dossier.
• Note : The dossiers could be anything among DMF
, ASMF
,
ANDA, NDAor MAA.
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45. IMPD is an abbreviated term for investigational medicinal
product
dossier.
IMPD resembles to the Module 3 of CTD in structure.
IMPD is serve as a basis for approval of clinical trials by the
competent authorities in the EU.
The Clinical Trials Directive (2001/20/EC) came into force in
April 2001, harmonizing the laws, regulation and administrative
provision of member states relating to implementation of GCP in
the conduct on medicinal products for human use.
The directive introduced a harmonized procedure for the
authorization to perform a clinical study in any one of the EU
Member States.
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46. ● IMPD is file containing detailed information/records about
particular drug product.
● IMPD is one of several pieces of investigational medicinal product
(IMP) related data require whenever the performance of a clinical
trail is intended in one or more EU member states.
● The IMPD includes summaries of information related to the
Quality, Manufacture and Control of the any Investigational
Medicinal Product (IMP) (including reference product and
placebo) data from non-clinical studies and its clinical use.
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47. Objectives: Since Clinical trials are often be designed as multi-
center studies, potentially involving different members states, it is the
aim of this guideline to define harmonized requirements of the
documentation to be submitted throughout the European Community.
General Structure of IMPD: The IMPD has a single general
structure which is common for both the types of IMPD :
Quality Data (CMC)
Non clinical pharmacological data and toxicological data
Previous clinical trial data and human experience data
Overall risk and benefit assessment.
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48. Following are the two types of IMPD:
1. Full IMPD
2. Simplified IMPD
Full IMPD: When applying for clinical trial authorization, full
IMPD is required when little or NO information about an IMP has
been previously submitted to competent authorities.
Simplified IMPD: A simplified IMPD may be submitted if
information has been assessed previously as part of marketing
authorization to competent authority.
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51. • Covering letter
• Application form
• List of all CAs where application has been submitted
• Copy of IEC approval or comments
• Any letter of concern received from any MS
• Copy of any scientific advice
• Aletter of authorization for use when applicant is not the sponsor
• Confirmation that CA will accept application in English
• Informed consent form
• Subject information ( if any)
• Arrangement for recruitment of subjects
• Protocol with any amendments
• Summary of protocol in the national language
• Peer review of trial if available
• Ethical assessment by principal investigator
• IB
• Report of any trial with same IMP
• Example of label in the national language
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52. ➢Swapna G, Bindu M, Anusha P, Rupa T, Mohini D,Venkkana ,B
“comparitive study of dossier submission process for drug
product in USA, EU, & “Indian regulatory”W.J. of Pharma RES.
Volume 3, issue 6, 406-411.
➢RichardA,Guarino M.D. ,New DrugApproval Process fifth
edition.
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