The document provides an overview of the new drug development process, outlining the key steps from discovery and preclinical testing to clinical trials and regulatory approval. It begins with identifying a target and potential drug candidates, then progresses through preclinical screening and safety testing, IND submission, and formal clinical trials in three phases with increasing numbers of participants. The goal is to demonstrate a drug's safety, efficacy, and appropriate dosage before seeking final regulatory review and approval to market the new drug. The entire process from discovery to approval typically takes 10-12 years and costs over $250 million.

1. New Drug Development
DR G A WAGHMARE
21/8/11 1

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Contents
1. Introduction
2. Definition of NEW DRUG.
3. Regulatory Guidelines.
4. Steps in the drug development
5. Timelines of Patent

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1.Introduction
• Development of new drug is very arduous, time
consuming & very expensive process.
• During last 50 years, hundreds of new drugs have
been introduced, & many older drugs have been
deleted (withdrawn).
• < 1% of compounds that go into test eventually
become licensed medicines.

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• To bring a new drug to market requires a good
understanding of drug development process &
integral role preclinical testing plays in that process.
• 5000– 10,000 compounds yield 1 new drug to
market.
• Overall time required for successful results is 10-
12 years.

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A Pyramid of Uncertainty
• Time:- It takes 12 years on average for an
experimental drug to travel from lab to medicine
chest.
• Success:- Only five in 5,000 compounds that
enter preclinical testing make it to human
testing.
• One of these five tested in humans is approved.
5

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Steps Number of compounds
• Discovery 5,000-10,000
• Preclinical testing 250
• Phase I 5
• Phase II 1
• Phase III 1
• FDA review & approval 1

7. Attrition rate of overall drug development
&
Average cost of drug development
Chemical
Labs
Decision
Filter
10,000
compounds
Pharmacology
Toxicology
Decision
Filter
1000
compounds
Clinical
Trials
Decision
Filter
10
compoundsNDA submission
Decision
Filter
1
compound
NDA Approval
> $ 250million
> $ 250
million
IND submission
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2.New drug
• New drug: definition under Schedule Y
– New substance, which except during local clinical
trials, has not been used ever before in the
country.
– Drug already approved for certain claims but which
is now proposed to be marketed with modified or
new claims (indications, dosage, dosage form,
route of administration).
– FDC of two or more drugs, proposed to be
combined for first time in a fixed ratio.

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3.Regulatory Guidelines.
• Authority to grant permission for New Drug to test &
market new drug in India rests with “Drugs Controller
General of India (DCGI)”, and is given as per Drugs &
Cosmetic rules.
• Schedule Y of Drugs & Cosmetic Rules, regarding
investigation of new drug (NDA) gives details of
preclinical (animal) data required as also issues
guidelines on clinical trials which are required to be
carried out for import & /or manufacture of new drug
in India.

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Regulatory Authorities.
US – FDA
Europe – EMEA
UK – MHRA
Japan – MHLW

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4.Steps in new drug development
A. Idea or Basic Research
B. New drug discovery
C. Screening
D. Preclinical studies
E. Formulation development
F. IND application
G. Clinical studies
H. Official license / Regulations/Marketing

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A. Basic research
1. Start by studying normal & abnormal body
functions.
2. Investigation of each component of the
disease (pathophysiology).
3. Look up information obtained in previous
research and publication.
4. Find out at which stage we can stop
disease progression or development (OUR
TARGET!).
5. Search for targeted drug.
6. Isolate the index compound.
7. Perform animal testing to obtain safety
data.
8. Approval to test in humans.

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Investigate Disease
Investigate each
component of a disease:-
• What is/are the
symptom(s) ?
• What is the cause?
• Which is the target
organ?
• What is/are Biochemical
pathway(s)?
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B. New Drug discovery
1. Target Identification
2. Target validation
3. Lead Identification
4. Lead Optimization

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Target Identification and Validation :
– Often begins with target identification - choosing a biochemical
mechanism involved in a disease condition.
– Drugs usually act on either cellular or genetic chemicals within
our body, known as targets believed to be associated with the
disease.
– Drug candidates are tested for their interaction with drug target.
– Up to 5000-10000 molecules for each potential drug candidate
are subject to rigorous screening process.
– Once scientists confirm interaction with drug target, they
typically validate that target by checking activity against the
disease condition for which the drug is being developed.

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Lead identification :
– Lead compound or substance is one that is believed to
have potential to treat disease. Laboratory scientists
compare known substances with new compounds to
determine their likelihood of success.
– Leads are sometimes developed as collections, or
libraries, of individual molecules that possess properties
needed in new drug. Testing is then done on each of
these molecules to confirm its effect on drug target.

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Lead optimization:
– Compares properties of various lead compounds and
provides information to help pharmaceutical and
biotechnology companies select compound/s with
greatest potential to be developed into safe and effective
medicines.
– Often during this same stage of development, lead
prioritization studies are conducted in living organisms
(in vivo) and in cells in a test tube (in vitro) to compare
various lead compounds, their metabolism, etc.

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Characteristics of Ideal Drug
Candidate• High Potency
• High Selectivity
• Good oral
Bioavailability
• Low or no
interaction with
CYP450
• Less or minimal
adverse effects
• Good therapeutic
index

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C. Screening
– NCEs are subject to battery of screening tests
designed to determine different types of biological
activity.
– Such tests include studies on animal behavior,
isolated tissues, intact animals, animal models of the
disease.
– 1 in every 4000-5000 NCEs screened is marketed.

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Pharmacological screening of candidate
molecules
• Pharmacological observations are made,
depending on expected pharmacological
properties. e.g.
– fall in BP, fall in blood glucose, etc.

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Pharmacological screening of
candidate molecules
• At the cellular level, it is possible to understand the
mechanism of action of a drug, whether is acts as:
– Receptor agonist / antagonist; if so, its
affinity and selectivity.
– Inhibitor of key enzyme, etc.

22. Through this process one can rapidly identify active
compounds, antibodies or genes which modulate
a particular biomolecular pathway.
The results of these experiments provide starting
points for drug design and for understanding the
interaction or role of a particular biochemical
process in biology.
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Pharmacological screening of candidate molecules is
done in isolated organ system and in whole animal
experiment (in vivo), effects of potential drug candidate
on different systems (CVS, CNS, RS etc.) can be studied.
D. Pre-clinical Studies

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• Pharmacologic studies :
– Carried out in experimental animals using in vivo or in vitro
techniques.
– These studies bring out specific biological activities,
mechanism of action, PK, effective dose range of the test
compounds.
• Toxicity studies :
– Detailed toxicity studies are conducted on compounds
tested positive pharmacologically.

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Preclinical safety and toxicity testing
• Evaluated for toxicity-potential risk.
Goals:
• Identifying safe drug
• Identifying potential human toxicity
• Predicting specific and relevant toxicities to be
monitored in clinical trials

26. E. Formulation development
• DRUG +
Additive: filler, lubricant, coating, stabiliser, colour,
binder, disintegrator
Dosage form: capsule, tablet, injection, other?
Manipulate duration/profile: e.g. sustained release
Bioequivalence
Bioavailability
Ease of use
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F. IND application
• IND application is a result of successful preclinical
development program.
• IND is a vehicle through which the sponsor advances to the
next stage of drug development - clinical trials.
• IND not an application for marketing approval.
• Contents :
– Animal pharmacological & toxicology studies.
– Manufacturing information.
– Clinical protocols and investigator information.

28. Sponsor/FDA Meetings ( Pre-IND)
• Prior to clinical studies, the sponsor needs
evidence that the compound is biologically
active, and both sponsor and the FDA needs
data showing that the drug is reasonably safe
for initial administration to humans.
• Meeting at such an early stage in the process
are useful opportunities for open discussion
about testing phases, data, requirements, and
any scientific issues that may need to be
resolved prior to IND submission
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IND
Review
Process

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G. Clinical studies
A new drug, which is expected to have some
advantage over existing ones, after pre-clinical
testing in vitro, short-term and long-term animal
testing for safety, efficacy and toxicity, after due
regulatory and ethics committee permissions, is
subjected to studies in humans as per the
regulatory requirements.

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• Clinical pharmacology (human studies)
– Phase I
– Phase II
– Phase III
– Phase IV

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Phase I trials
– Human / Clinical Pharmacology Trials
– This is a open study conducted in healthy human
volunteers (20-80).
– In special populations (e.g. for anti-cancer drugs).

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Objectives
• Safety & tolerability
Maximum tolerated dose
• Pharmacokinetics
• Pharmacodynamics
• Measurement of drug activity

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Players In Phase I Trials
Participants (20-80)
• Healthy volunteer subjects
• Patients
Place
• Special testing facilities
• Monitored closely
Physician
• Trained investigator

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Phase II trials
• Therapeutic exploratory trials
• First trial in patients with the disease to be
treated.
• 50-300 patients are used for this study.

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Objectives
• Effectiveness of the drug
• Common short term side effects and risks
with I.N.D.
• Determine doses and regimens for phase III
trials
• PK, PD, safety
Additional objectives
• Therapeutic regimens
• Target populations for further studies in phase III

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Players In Phase II Trials
Participants (50-300)
• Patients
Place
• Specialized hospital units
• Closely monitored
Physician
• Trained investigators

38. Sponsor/FDA Meeting (End of Phase
2)
• One month prior to the “end of the Phase 2”, the sponsor
should submit the background information and protocols
for phase 3 studies.
• This information should include data supporting the claim
of the new drug product, chemistry data, animal data and
proposed additional animal data, results of Phase 1 and 2
studies, statistical methods being used, specific protocols
for phase 3 studies, as well as a copy of the proposed
labeling for a drug, if available.
• This summary provides the review team with information
needed to prepare for a productive meeting.
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Phase III trials
• They are initiated when the data generated
shows evidence of efficacy.
• Patients (300-3,000)
• Phase III includes multiple sites , hence most
expensive and most time consuming
• These studies should be intended to provide
an adequate basis for marketing approval.

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Objectives of Phase –III Trials
• Efficacy and safety profile on a larger number of
population (1000+)
• Comparison with current Gold Standard
treatment
• Identification of the disease sub types for which
drug is effective
• To provide data for the product package insert.

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Players in Phase III Trials
• Patients-250-1000+
• SITE
Multi-speciality hospital with adequate
patient attendance and laboratory facilities
• Principal investigator assisted by a clinical
research co-ordinator .

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Clinical Trial Design
• PROSPECTIVE RANDOMISED MULTICENTRIC
• CONTROLLED OR UNCONTROLLED TRIALS
IIIa Trials carried out on a large number of
patients – Regulatory requirement for NDA
IIIb Extended trials of IIIa after applying for
approval but before launch

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H .Official license /Marketing
NDA /MAA
• New drug application (NDA) is a vehicle through which
sponsors formally propose that FDA approve it - new
pharmaceutical - for sale in United States.
• These are examples of applications to market a new drug.
• Such applications document safety and efficacy of the
investigational drug and contain all the information collected
during the DDP.
• Obtaining approval to market a new drug frequently takes
between six months and two years.

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NDA Review Process

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Phase IV
• This constitutes a vigilant post-marketing
surveillance to monitor safety of new drug.
• PMS is a systemic method for surveillance of
adverse reactions, patterns of drug utilization,
additional indication discovered, and is carried
out in patients given marketed drug for therapy.

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Objectives
• Conform the efficacy and safety profile in large
populations during practice
• Detect the unknown adverse drug reaction/s
• Evaluation of over-dosage and concomitant treatments
• Identifications of new indications
• Pharmacoeconomics

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Conduct of Phase IV trial
• Post authorization studies, post marketing
studies, post licensing studies.
• Site Clinics and hospitals
• Players
Principal investigators-General practitioners and
Specialists
Participants patients-2000-10000+

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From Laboratory to Clinics
A Phased Journey
Preclinical IND SUBMISSION
Phase I
Phase II a,b
Phase III b
III a
Phase IV, PMS
Observational
studies
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5. Timelines of Patent
• Lifetime of patent-20 yrs
• Pharma company has exclusive rights for
limited time
• After expiration of patent- any company may
produce and market the drug as a generic
product

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50
The New Drug Development Process:
Steps from Test Tube to New Drug Application Review

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• Drug discovery:
Ideas Drug candidates & biochemical tools
• Drug development:
Drug candidates Drugs
Discovery=find new active structure
Development=convert it to a useful drug

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Advances in drug development.
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Phase 0 microdosing
A new approach to obtain human pharmacokinetic information
before the usual expensive phase I safety program is conducted is
the phase 0 microdosing.
It is hypothesized that microdosing will help to reduce or replace the
extensive animal testing of compounds for kinetics, which may
later be rejected in human studies.
Thus, microdose studies use minute quantities of drug and are not
intended to produce any pharmacologic effect, when administered
to humans, and, therefore, may not cause any adverse events also,
but may produce useful pharmacokinetic information and help in
further development of the compound.21/8/11

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• 1/100th of dose anticipated to produce a pharmacological
effect
• A small dose of your own medicine…..
• Provides sufficiently useful PK information to decide on
confirmatory development (human & animal toxicology)
• Helps in early de-selection: Cost saving related to
manufacturing, scaling up & CTs
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Microdosi
ng
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