NCDD presented by Mahesh Kesalkar

1. “NON CLINICAL DRUG DEVELOPMENT”
Presented by
MAHESH A. KESALKAR
{Pharmaceutics}
Institute of Pharmaceutical Education And
Research, Borgaon (Meghe), Wardha
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Introduction
IND
NDA
ANDA
Investigation of medicinal products dossier
Investigator Brochure
CONTENT

3. INTRODUCTION
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• The discovery and development of a novel therapeutic agent,
whether a small organic molecule or a macromolecule such as a
protein and oligonucleotide, require scientific expertise from a
number of different disciplines and an enormous amount of
time and money.
• While humans may be the ultimate test species to ascertain the
safety and efficacy of a potential new therapeutic agent,
research studies in animal models are necessary to determine
whether a drug candidate has a pharmacological property that
might mediate a human disease process and that the test article
does not have a toxicity profile that could cause adverse
experiences in humans at pharmacological doses.

4. • Present estimates suggest that about 10 to 12 years and more
than $800 million (with this cost including the amount
expended on drug candidates that “died” during development)
are needed to discover and develop a novel therapeutic agent.
• Historically, for every 100 compounds screened for biological
activity in animal models, only one has the necessary
pharmacology and safety profiles for evaluation in humans. Of
those compounds tested in humans, only about 1 in 10 is
successfully brought to the marketplace. This poor rate of
success
INTRODUCTION
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5. • Investigational New Drug is defined under 21 CFR312.3(b) as
‘a new drug or biological drug that is used in clinical
investigation’.
• The term also includes a biological product used in vitro for
diagnostic purposes.
• 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.
INVESTIGATIONAL NEW DRUG (IND)
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6. • The sponsor submits the application for conduct of human
clinical trials called Investigational New Drug (IND)
application to FDA or DCGI.
• Once IND application is submitted , the sponsor must wait for
30 days before initiating any clinical trial.
• 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.
INVESTIGATIONAL NEW DRUG (IND)
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7. • 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.
• 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.
INVESTIGATIONAL NEW DRUG (IND)
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8. TYPES OF IND
A.COMMERCIAL INDs
These are applications that are submitted primarily by the
companies to obtain marketing approval for a new product.
B.NONCOMMERCIAL (Research)INDs
These INDs are filed for noncommercial research.
1. Investigator’s IND- It is submitted by a physician who both
initiates and conducts an investigation and who also
administers and dispenses the IP. A physician might submit a
research IND to propose studying an unapproved drug or an
approved drug for new indications or in new patient
population.
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9. TYPES OF IND
2. Emergency Use IND-This IND allows FDA to allow the use
of an experimental drug in an emergency situation that does
not allow submission of an IND in accordance with 21 CFR
Sec312.23 or Sec 312.34. It can also be used for patients who
do not meet the criteria of an existing study protocol or if an
approved study protocol does not exist.
3. Treatment IND- Also called Expanded Access IND this
IND may be submitted for experimental drugs showing
promise in clinical testing of serious and immediately life
threatening conditions while the final clinical work is
conducted and the FDA review takes place (21 CFR 312.34). 9

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Ind chart

11. IND PROCESS IN INDIA
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 IND has been defined under Rule 122-DA (3) of Drugs and
Cosmetics Rules 1945 as a chemical entity having therapeutic
indication but which have never been earlier tested on
humans.
 No clinical trial for new drug for any purpose be conducted
without permission ,in writing, of theLicensing Authority
(DCGI).
 Application for conducting clinical trials in India require
submission by the sponsor on Form 44 along with requisite
fee (Rs 50k) and documents as providedunder Schedule Y to
Drugs and Cosmetics Act 1940.

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 Data to be submitted along with the application onForm44 to
conduct clinical trials (2 hard copies and 2 soft copies i.e., CDs in
PDF format)
1. Application on Form 44
2. Introduction of the drug
3. Fee Rs 50K through challan form
4. Chemical and Pharmaceutical information as per
Appendix I of Schedule Y
5. Animal Pharmacology as per Appendix IV
6. Animal Toxicology as per Appendix III
7. Human/Clinical Pharmacology data as per Appendix I
8. Regulatory status in other countries as per Appendix I.

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• It takes 4-6 months for the approval but it is not
documented. The Ethical Committee also requires 1-3
months time. Thus , it almost takes 7-9 months for approval
of INDA from DCGI.
• For international applicants, import license to import IP
samples and permission from Director General Foreign
Trade to export blood samples is also needed.

14. NEW DRUG APPLICATION (NDA)
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• The New Drug Application is the vehicle through which
the drug sponsors formally propose FDA or DCGI to
approve a new investigational drug for sale and
marketing after Phase IIIA Pivot trials.
• The official definition of New Drug is in Sec 201(p) of
Federal Drug, Food and Cosmetics Act as;
• Any new drug , the composition of which is such that it
is not recognized among experts qualified by scientific
training as safe and effective for use under prescribed,
recommended or suggested conditions

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NEW DRUG APPLICATION (NDA)
The following letter codes describe the review priority
of the drug;
• S-Standard review: For drugs similar to currently
available drugs
• P-Priority review: For drugs that represent significant
advances over existing treatments.

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Classification of drugs in NDA
Center of 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 previous approved
NDA)

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NDA Chart

18. NDA PROCESS IN INDIA
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In India, New Drug is defined under Rule 122-E of Drugs
and Cosmetics Act as:
a) A drug which has not been used in the country
to any significant extent under various conditions
b) A drug already approved by DCGI for certain claims
which is now proposed to be marketed with new claims
like indications, dosage, dosage form etc.
c) A fixed dose combination of two individually approved
drug being combined for the first time in a fixed ratio or
new ratio in already marketed combination

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d) All vaccines are considered as new drugs.
e) A new drug continues to be considered as new
drug for a period of 4 years from its approval
or its inclusion in Indian Pharmacopoeia.
• After successful finishing of clinical trials, the applicant
seeking for approval to manufacture a new drug requires to
submit application on Form 44 along with data as given in
Appendix I to Schedule Y of Rules 1945 to DCGI who
grants its approval in Form 46 or 46-A.
• Further, the applicant is required to submit evidence that the
drug for manufacturing approval has already been approved
by DCGI

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• In his name while applying to manufacture a new drug
to State Licensing Authority. Thus the applicant is
required to obtain necessary approval from DCGI as
well as SLA for manufacturing a new drug for sale
purposes in India.
• The approval issued is ‘manufacture for sale’ rather
than ‘marketing approval’ as per the practice world
over.

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ABBREVIATED NEW DRUG APPLICATION ( ANDA)
• Generic drug applications are referred to Abbreviated New
Drug Application.
• Pharmaceutical companies must admit ANDAs and receive
FDA’s approval before marketing new generic drugs according
to 21CFR 314.105(d).
• Once ANDA is approved, an applicant can manufacture and
market generic drug to provide safe, effective and low cost
alternative of innovator drug product to the public.
• Generic drugs are termed ‘abbreviated’ as they are not required
to include preclinical and clinical data to establish safety and
efficacy. They must scientifically demonstrate Bioequivalence
to Innovator (brand name) drug

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• A generic drug is comparable to Innovator drug I dosage
form, strength, route of administration, quality, performance
and intended use.
• One of the ways to demonstrate bioequivalence is to
measure the time taken by generic drug to reach bloodstream
in 24-36 healthy volunteers. The time and amount of active
ingredients in the bloodstream should be comparable to those
of Innovator drug.
• Use of bioequivalence as base for approving generic drug
products was established in 1984, also known as HATCH-
WAXMAN ACT. It is because of this act that generic drugs
are cheaper without conducting costly and duplicative
clinical trials.

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ANDA Chart

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Difference between submission of NDA and ANDA
 NDA requires submission of :
1. Well-controlled clinical studies to demonstrate effectiveness.
2. Preclinical and clinical data to show safety.
3. Details of Manufacturing and Packaging.
4. Proposed annotated Labelling
 In contrast ANDA requires submission of :
1. Detailed description of components.
2. Manufacturing, Controls, Packaging, data to assure
bioequivalence and bioavailability and Labeling.
Labeling should be prepared in accordance with DESI
(Drug efficacy study implementation).

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INVESTIGATIONAL MEDICINAL PRODUCT DOSSIER (IMPD)
• The IMPD is the basis for approval of clinical trials by the
competent authorities in the EU.
• The clinical trials directive came into force in April 2001,
harmonizing the laws, regulations and administrative provisions
of the member states relating to the implementation of Good
Clinical Practice (GCP) in the conduct of clinical trials 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.
• In addition, it defines the documentation to be submitted to the
Ethics Committee as well as the Investigational Medicinal
Product Dossier (IMPD) to be submitted to the competent
authority for approval.

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INTRODUCTION
• DOSSIER:-
Dossier is a collection of documents about a particular person,
event or subject.
E.g. Patient medical record.
• IMP DOSSIER
The Investigational Medicinal Product Dossier (IMPD) is
one of several pieces of Investigational Medicinal Product (IMP)
related data required whenever the performance of a clinical trial
is intended in one or more European Union Member States.
The IMPD includes summaries of information related to the
quality, manufacture and control of any IMP (including placebo),
and data from non-clinical and clinical studies.

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GUIDANCE AND LEGAL BASIS
• The following guideline is to be seen in connection with Regulation
(EU) No.536/2014 on clinical trials on medicinal products for
human use, which came into force on June 20, 2014.
• Since clinical trials will often be designed as multi-centre studies,
potentially involving different Member States, it is the aim of this
guideline to define harmonised requirements for the documentation
to be submitted throughout the European Union.
• It should be clearly differentiated between the requirements for a
dossier for a clinical trial and a marketing authorisation dossier.
• Information to be provided for investigational medicinal products
(IMPs) should focus on the risk aspects and should consider the
nature of the product, the state of development/clinical phase,
patient population, nature and severity of the illness as well as type
and duration of the clinical trial itself.

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SCOPE OF THE GUIDELINE
• This guideline addresses the documentation on the chemical
and pharmaceutical quality of IMPs and Auxiliary Medicinal
Products containing chemically defined drug substances to be
submitted to the competent authority for approval prior to
beginning a clinical trial in humans.
• IMPs based on innovative and complex technologies may
need more detailed data to be submitted.
• For certain situations, e.g. where the drug substance from the
specific source to be used for an IMP is already included in a
medicinal product authorized within the EU, not all the
documentation need to be submitted in the IMPD, but a
simplified IMPD will sufficient.

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FULL IMPD AND SIMPLIFIED IMPD
 When applying for a clinical trial authorisation, a full IMPD
is required when little or no information about an IMP has
been previously submitted to competent authorities and/or
when there is no MA in the Community.
 However, there are situations where a simplified IMPD will
be sufficient. A simplified IMPD may be submitted if
information has been assessed previously as part of a
Marketing Authorisation in any clinical trial to that competent
authority.
 There are also situations where the SmPC of a Marketed
Product will sufficient as the IMPD. A SmPC may be
submitted if the IMP has a Marketing Authorisation in any EU
Member state

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PROCEDURE

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CHANGES AND AMENDMENT TO THE IMPD
Although the following list is not exhaustive, substantial
changes to the IMPD are likely to be caused by changes
concerning one or more of the following:
• Importation of the medicinal product.
• Change of name of IMP.
• Packaging material.
• Manufacturer(s) of drug substance.
• Manufacturing process of the drug substance.
• Specifications of active substance.
• Specification (release or shelf-life) of the medicinal product.
• Specification of excipients where these may affect product
performance.
• Major change to the formulation.
• Storage conditions.
• Test procedures of active substance.
• Test procedures of the medicinal product.

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INVESTIGATOR BROCHURE (IB)
• The Investigator's Brochure (IB) is a
compilation of the clinical and nonclinical data
on the investigational product(s) that are
relevant to the study of the product(s) in human
subjects.

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PURPOSE OF I.B.
• Its purpose is to provide Information to the Investigators
and others involved in the trial such as the dose, dose
frequency/interval, methods of administration: and
safety monitoring procedures. The IB also provides
insight to support the clinical management of the study
subjects during the course of the clinical trial. The
information should be presented in a concise and simple
manner
• I.B. enables a clinician, or potential investigator, to
understand it and make his/her own unbiased risk
benefit assessment of the appropriateness of the
proposed trial. For this reason, a medically qualified
person should generally participate in the editing of an
IB

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CONTENT OF IB
The Investigator Brochure should include:
1) Title Page
A. Sponsor name
B. The identity of each investigational product (i.e.,
research number, chemical or approved generic name,
and trade name(s) where legally permissible and desired
by the sponsor),
C. The Release Date.
D. Confidentiality Statement

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1. Table of contents
2. Summary – not exceeding 2 pages. highlighting the
significant physical, chemical, pharmaceutical,
pharmacological, toxicological, pharmacokinetic,
metabolic, and clinical information available of IP
3. Introduction:
chemical name, active ingredients, pharmacological class,
anticipated – therapeutic/ diagnostic indication(s).
General approach to be fallowed in evaluating the IP

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4. Description of I.P. Physical, Chemical and
pharmaceutical properties of I.P. Storage and
handling of I.P.
Any structural similarity with the other known
compound given

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5. Non clinical studies
 The results of all relevant nonclinical pharmacology,
toxicology, pharmacokinetic, and investigational
product metabolism studies should be provided in
summary form.
 The information provided may include:
• Species tested,
• Number of sex in each group
• Unit dose (e.g., milligram/kilogram (mg/kg),
• Dose interval,
• Route of administration and
• Duration of dosing

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6. EFFECTS IN HUMANS
A thorough discussion of the known effects of the
investigational product(s) in humans should be provided,
including information on pharmacokinetics, metabolism,
Pharmacodynamics, dose response, safety, efficacy, and other
pharmacological activities.
(a) Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the
investigational product(s) should be presented.
(b) Safety and Efficacy: A summary of information should be
provided about the investigational product's safety, efficacy,
pharmacodynamics
(c) Marketing Experience: The IB should identify countries
where the investigational product has been marketed or
approved.

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7. Summary of Data and Guidance for the Investigator
This section should contain nonclinical and clinical
data of IP.
 IB – provide the investigator a clear understanding of
• The possible risks
• Adverse reactions
• Observations & precautions needed for the clinical trial.

41. Reference
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o New Drug Approval Process, by Richard A. Guarino, 4th
edition , Vol 139.
o Guidebook for Drug Regulatory Submissions, by Sandy
Weinberg.

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