non clinical drug development

1. “NON CLINICAL DRUG
DEVELOPMENT”
1
Presented by
Dhanasekar J
Mpharm 1st semester
Department of pharmaceutics
Nandha College of pharmacy

2. 2
Introduction
IND
NDA
ANDA
Investigation of medicinal products
dossier
Investigator Brochure
CONTENT

3. INTRODUCTION
3
• 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
4

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)
5

6. • The sponsor submits the application for conduct of
human clinical trials called Investigational New Drug (IND)
application to FDAor 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 FDAand 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)
6

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)
7

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.
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 anapproved drug
for new indications or in new patient population.

9. TYPES OF IND
9
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.
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
FDAreview takes place (21 CFR 312.34).

10. IND CHART
10

11. IND PROCESS IN INDIA
11
 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 theLicensingAuthority
(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 CosmeticsAct 1940.

12.  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 perAppendix IV
6. Animal Toxicology as perAppendix III
7. Human/Clinical Pharmacology data as perAppendix I
8. Regulatory status in other countries as perAppendix I.
12

13. 13
•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 INDAfrom 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)
14
• The New DrugApplication 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 IIIAPivot trials.
• The official definition of New Drug is in Sec 201(p) of
Federal Drug, Food and CosmeticsAct 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

15. NEW DRUG APPLICATION
(NDA)
15
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.

16. 16
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)

17. NDA CHART
17

18. IN INDIANDA PROCESS
18
In India, New Drug is defined under Rule 122-E of Drugs
and CosmeticsAct as:
a) Adrug 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)Afixed dose combination of two individually approved
drug being combined for the first time in a fixed ratio or
new ratio in already marketed combination

19. d) All vaccines are considered as new drugs.
e)Anew 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
19

20. • In his name while applying to manufacture a new drug
to State LicensingAuthority. 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.
20

21. ABBREVIATED NEW DRUG APPLICATION
( ANDA)
21
• Generic drug applications are referred toAbbreviated New
DrugApplication.
• Pharmaceutical companies must admit ANDAs and receive
FDA’s approval before marketing new generic drugs
according to 21CFR 314.105(d).
• OnceANDA 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

22. • 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.
22

23. ANDA CHART
23

24. DIFFERENCE BETWEEN SUBMISSION OF
NDA AND ANDA
24
 NDArequires 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 contrastANDA 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).

25. 25

26. 26
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.
.

27. INTRODUCTION
• DOSSIER
Dossier is a collection of documents about a particular person,
event or subject.
E.g. Patient medical record.
• IMPDOSSIER
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.
27

28. GUIDANCE AND LEGAL BASIS
28
• 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.

29. SCOPE OF THE GUIDELINE
29
• 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.

30. 30
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 MAin 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
MarketingAuthorisation 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 MarketingAuthorisation in any EU
Member state

31. 31
PROCEDURE

32. 32
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

33. INVESTIGATOR BROCHURE
(IB)
33
• 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.

34. PURPOSE OF I.B.
34
• 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

35. CONTENT OF IB
35
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

36. 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
36

37. 4. Description of I.P. Physical, Chemical and
pharmaceutical properties of I.P. Storage and
handling of I.P.
37
Any structural similarity with the other known
compound given

38. 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
38

39. 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:Asummary 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.
39

40. 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.
40

41. REFERENCE
41
Pritchard JF, Jurima-Romet M, Reimer ML,
Mortimer E, Rolfe B, Cayen MN. Making better
drugs: decision gates in non-clinical drug
development. Nature reviews Drug discovery. 2003
Jul 1;2(7):542-53.
Stergiopoulos S, Getz KA. Mapping and
Characterizing the Development Pathway from Non-
Clinical through Early Clinical Drug Development.
Pharmaceutical Medicine. 2012 Oct;26:297-307.

42. THANK YOU.