2. CONTENTS
INTRODUCTION
TARGETS FOR DRUG DEVELOPMENT
CATEGORIES OF DRUGS
PROCEDURES FOR DRUG DISCOVERY
STAGES OF DRUG DISCOVERY
TOXICITY STUDIES
CLINICAL TRIALS AND ITS PHASES
CONCLUSION
REFERENCES
3. INTRODUCTION
Drug discovery is a process which aims at identifying a compound which is
therapeutically useful in curing and treating disease. This process involves the
identification of candidates, synthesis, characterization, validation, optimization,
screening and assays for therapeutic efficacy.
Once a compound has shown its significance in these investigations, it will
initiate the process of drug development earlier to clinical trials. New drug
development process must continue through several stages in order to make a
medicine that is safe, effective, and has approved all regulatory requirements
On an average, a million molecules screened but only a single is explored in late
stage clinical trials and is finally made obtainable for patient
4. PHARMACOKINETICS - What does the body do to the drug . Relates to the
fate of a drug in the body, i.e. its absorption into the body, its distribution
within the body, its metabolism by the body, and its excretion from the body.
PHARMACODYNAMICS - What does the drug do to the body . Studies deal
more specifically with how the drug brings about its characteristic effects.
Physiological effects.
Drug action.
Relationship between drug concentration and effect
5. Targets for Drug Development
Oncology: Angiogenesis, cell signalling receptors and molecules in
tumour growth.
Cardiovascular and metabolic diseases: Type 2 diabetes, obesity,
atherosclerosis/thrombosis
CNS: Alzheimer’s Disease, Parkinson’s disease
HIV / AIDS: Novel targets in viral life cycle
Infectious diseases: Hepatitis B and C, influenza
Asthma: Chronic Obstructive Pulmonary Disease
Autoimmune and inflammatory diseases: Arthritis, psoriasis,
inflammatory bowel disease, multiple sclerosis
6. CATEGORIES OF DRUGS
Over-The-Counter drugs (OTC) - drugs that are considered relatively
safe and can be sold without physician's prescription e.g. vitamins,
antacids, paracetamol etc
Prescription-only drugs - drugs that are used under medical
supervision because they are considered to be unsafe. So they are
dispensed only by registered physician e.g. antibiotics, antidiabetics,
antidepressant, etc.
7. Controlled substances - drugs that are prescribed only by specialized
physicians and must include their registration number on all
prescriptions forms
Categories of controlled substances
• Schedule I: Drugs that are not approved for medical use and have
high abuse potentials e.g. flunitrazepam , heroin.
8. • Schedule II : Drugs that are used medically and have high abuse
potentials: opioid analgesics (e.g., codeine,morphine), CNS stimulants
(e.g cocaine)
• Schedule III: Drugs with less potential for abuse than those in
Schedules I and II, but abuse may lead to psychological or physical
dependence e.g. benzodiazepines.
9. • Schedule IV : Drugs with some potential for abuse e.g. some appetite
suppressants (e.g., mazindol, phentermine)
• Schedule V: Products containing moderate amounts of controlled
substances e.g. antidiarrheal drugs, such as diphenoxylate and
atropine
10. PROCEDURES FOR DRUG DISCOVERY
1 .Random screening
2. Molecular manipulation
3. Molecular designing
4. Metabolites of drug
5. Serendipity
11. RANDOM SCREENING
In this procedure new chemical entities are subjected to screening test
designed to determine diff. types of biological activity. Such test include
studies on animal behavior, Isolated tissues, intact animal and some
times even an animal models of disease.
Such studies are time consuming, expensive and have a low yield. It is
possible that the new drug thus found may be ultimately turn out to be
similar in extraction to already existing drugs, with no added advantages
12. MOLECULAR MANIPULATION
In this procedure, analogues of existing drugs are synthesized and
tested for their biological activity.
This is more logical approach and may yield new compounds with
certain advantages like better absorption, greater potency, more
selective action, fewer side effects
13. MOLECULAR DESIGNING
This is the most rational form of drug research and development. It
ends at designing of substances to fulfill of specific biological task.
In its simplest form this may involve the synthesis of naturally
occurring substance, a hormone, a vitamin or a precursor of a
neurotransmitter. e.g. dopamine for cardiogenic shock, levodopa for
parkinsonism
14. Some times active metabolites of drug are found to posses therapeutic
advantages over parent compound. e.g. Paracetamol is metabolite of
phenacetin and it is effective as an analgesic but does not cause renal
damage.
SERENDIPITY
Means unplanned fortunate discovery by chance and has led to introduction
of many remedies in the past. e.g. use of organomercurials for cardiac
oedema, penicillin as an antibacterial agent
METABOLITES OF DRUG
15. Stages of drug discovery and development
Target identification
Target validation
Lead identification
Lead optimization
Product characterization
Formulation and development
Preclinical research
Investigational New Drug
Clinical trials
New Drug Application
Approval
16. TARGET IDENTIFICATION
The first step in the discovery of a drug is identification of the
biological origin of a disease, and the potential targets for
intervention.
Target identification starts with isolating the function and its role in
the disease.
An ideal target should be efficacious, safe, meet clinical and
commercial requirements
The techniques used for target identification may be based on
principles of molecular biology, biochemistry, genetics, biophysics, or
other disciplines.
17. TARGET VALIDATION
Target validation is the process of demonstrating the functional role
of the identified target in the disease phenotype.
The validation of a drug‘s efficacy and toxicity in numerous disease-
relevant cell models and animal models is extremely valuable
Target validation can be divided into two steps
18. Reproducibility: Once a drug target is identified, the first step is to
repeat the experiment to confirm that it can be successfully
reproduced.
Introduce variation to the drug target environment : Antibodies
interacting to the target with high affinity and blocking further
interactions
19. IDENTIFICATION OF LEAD
A chemical lead is defined as a synthetically stable, feasible, and drug
like molecule active in primary and secondary assays with acceptable
specificity, affinity and selectivity for the target receptor.
Characteristics of a chemical lead are:
Drug ability
Synthetic feasibility
20. In vitro assessment of drug resistance
Evidence of in vivo efficacy of chemical class
PK/Toxicity of chemical class
In order to decrease the number of compounds that fail in the drug
development process, a drug ability assessment is often conducted.
This assessment is important in transforming a compound from a lead
molecule into a drug. For a compound to be considered druggable i.e, it
should have the potential to bind to a specific target
21. LEAD OPTIMIZATION
Is the process by which a drug candidate is designed after an initial
lead compound is identified. The process involves series of synthesis
and characterization of a potential drug to build up in way chemical
structure and activity are related in terms of interactions with its
targets and its metabolism.
The purpose of lead optimization is to maintain favorable properties
in lead compounds, while improving on deficiencies in lead structure.
22. In order to produce a pre-clinical drug candidate, the chemical structures
of lead compouds need to be altered to improve target specificity and
selectivity
Drug metabolism and pharmacokinetics screens have become an essential
part of lead optimization, facilitating the understanding and prediction of
in vivo pharmacokinetics using in vitro tests
23. PRODUCT CHARACTERIZATION
When any new drug molecule shows a promising therapeutic activity,
then the molecule is characterized by its size, shape, strength,
weakness, use, toxicity, and biological activity. Early stages of
pharmacological studies are helpful to characterize the mechanism of
action of the compound.
24. FORMULATION AND DEVELOPMENT
Formulation is a stage of drug development during which the
physicochemical properties of active pharmaceutical ingredients (APIs)
are characterized to produce a bioavailable, stable and optimal dosage
form for a specific administration route
25. During preformulation studies the following parameters are evaluated:
Solubility in different media and solvents
Dissolution of the active pharmaceutical ingredient (API)
Solid state properties ( particle size, particle shape )
Process development for selected dosage forms
Controlled release and sustained release formulations
Self-emulsifying drug delivery systems
Colloidal drug delivery systems
26. PRECLINICAL TESTING
Pre-clinical research in drug development process involves
evaluation of drug‘s safety and efficacy in animal species
These trials are conducted in safe and ethical way and would give
approval for only those drugs which are confirm to be safe and
effective.
The pre-clinical trials can be conducted in two ways:
General pharmacology
Toxicology
27. Pharmacology deals with the pharmacokinetic and pharmacodynamic
parameters of drug . Pharmacokinetic studies are very important to know the
safety and efficacy parameters in terms of absorption, distribution, metabolism
and excretion. Half-life of the drug clarifies the safety outline of the drug
Toxicological studies of the drug can be performed by invitro and in-vivo test
which evaluate the toxicological effects of the drug. In-vitro studies can be
performed to inspect the direct effects on cell proliferation and phenotype.
In-vivo studies can be performed for qualitative and quantitative determination of
toxicological effects. As many drugs are species specific, it is essential to select
appropriate animal species for toxicity study.
28. TOXICITY TESTING
Toxicity testing is used in the screening of newly developed drugs
before it can be used on humans. The use of toxicity testing is not just
to check how safe a test substance is; but to characterize the possible
toxic effects it can produce.
Toxicity testing is of the following types: acute toxicity studies, sub-
acute toxicity studies and chronic toxicity studies
29. Importance of toxicity studies
To establish a dose response curve.
To ensure safety of new chemicals for use as drugs before they are
registered for general use in industry or in clinics.
To establish the mode of action or mechanism for a toxic effect that
may have been seen in other studies.
To validate new methods of testing or investigation, particularly
those conducted in vitro rather than in animals
30. The two basic principles guiding toxicity test
in animals
• To check the effect of the test substances on laboratory animals and
its direct toxic effect on human.
• Exposure of laboratory animals to high doses in order to evaluate its
possible hazard on human that are exposed to much lower doses
31. Acute toxicity studies
• This is a short term assessment and evaluation of potential hazard
test substance or consequences of single dose of a test substance
Acute toxicity testing may be used in risk assessments of chemicals
for humans
Importance of acute toxicity testing
To identify the target organ of toxicity
To provides information needed for the dose selection in prolonged
toxicity studies.
32. Sub-acute toxicity studies
This study is conducted to determine organs affected by different dose
levels. The duration of subacute toxicity studies depend on intended
duration of the test substance
Three dose levels are normally used
Dose that is high enough to elicit definite signs of toxicity but not to
kill many of the animals.
Low dose that is expected to induce no toxic effect.
Intermediate dose.
33. Chronic toxicity studies
This study is basically to determine the organs affected and to check
whether the drug is potentially carcinogenic or not.
This test extends over a long period of time and it involves large
groups of laboratory animals.
34. INVESTIGATIONAL NEW DRUG PROCESS (IND)
Drug developers must file an Investigational New Drug application to
FDA before commencement clinical research
In the IND application, developers must include:
Preclinical and toxicity study data
Drug manufacturing information
Clinical research protocols for studies to be conducted
Previous clinical research data
Information about the investigator/ developer
35. CLINICAL RESEARCH
Clinical trials are conducted in people and intended to answer specific
questions about the safety and efficacy of drugs, vaccines, other
therapies, or new methods of using current treatments.
Clinical trial is based on
Selection criteria for participants
Number of people take part of the study
Duration of study
Dose and route of administration of dosage form
Assessment of parameters
Data collection and analysis
36. HISTORICAL ASPECTS
1537 - first clinical trial of a therapy by Amboise pare
1747 - James Lind introduced control groups in experiment
1923 - concept of randomisation introduced
1931 - concept of randomisation of patients to treatment in clinical trials
1945 - ethical impact of clinical trial has become important, strict
regulation on medical experiments
1948-1st trial using properly randomised treatment and control groups
by medical research council
37. DIFFERENT TYPES OF CLINICAL TRIALS
Treatment trials - test experimental treatments, new combinatons of
drugs, or new approaches to surgery or radiation therapy.
Prevention trials - look for better ways to prevent disease in people
who have never had the disease or to prevent a disease from
returning. These approaches may include medicines, vaccines,
vitamins, minerals, or lifestyle changes.
38. Diagnostic trials - are conducted to find better tests or procedures
for diagnosing a particular disease or condition.
Screening trials - test the best way to detect certain diseases or
health conditions
Quality of Life trials (Supportive Care trials) - explore ways to
improve comfort and the quality of life for individuals with a chronic
illness
39. RANDOMIZED CLINICAL TRIALS
Subjects have equal chance to be assigned to one of two or more
groups just like tossing of coin.
One group gets the most widely accepted treatment
The other gets the new treatment being tested
All groups are as a like as possible and removes the probability of
bias.
Provides the best way to prove the effectiveness of a new agent or
intervention
40. Open label trial Blinded clinical trial
Doctor and patient know which
drug is given
Single Blind: the patient doesn’t
know which treatment he/she is
getting
Double Blind: neither doctor nor
patient knows
41. Prospective Retrospective
Patients are enrolled for the study
before any treatment begins
Progress of patients is monitored
during course of treatment
Past case records & other
statistical data are used for
analysis. Investigator has to rely
on methods employed & data
available
42. Placebo study - It seems to be a real medical treatment but it gives a
fake kind of treatment to account for placebo effect and is most
commonly used in blinded trails . It resembles the active drug in
physical properties but does not have any pharmacological activity.
The new treatment is tested against a placebo.
Pilot Study - A small study that helps to develop a bigger study.
Advantage : to find out possible difficulties , to evaluate feasibility ,
duration , cost , and improve upon study design
43. CROSS-OVER STUDY
a crossover study or crossover trial is a longitudinal study in
which subjects receive a sequence of different treatments (or
exposures).
Crossover designs are common for experiments in pharmaceutical
science, and medicine
A crossover trial has a repeated measures design in which
each patient is assigned to a sequence of two or more treatments, of
which one may be a standard treatment or a placebo In most
crossover trials each subject receives all treatments, in a random
order.
44. PHASE 0 CLINICAL TRIAL
Phase 0 implicates investigative, first-in-human trials that are
conducted according to FDA guidelines.
Phase 0 trials named as human micro dose studies, because of single
sub-therapeutic doses given to 10 to 15 volunteers and give
pharmacokinetic data
Pharmaceutical industries perform Phase 0 studies to pick which of
their drug applicants has pharmacokinetic parameters in humans
45. Phase 1: Safety and dosage
Phase I trials are the first tests of a drug with a lesser number of
healthy human volunteers.
In most cases, 20 to 80 healthy volunteers with the
disease/condition participate in Phase 1
However, if a new drug is proposed for use in diabetes patients,
researchers conduct Phase 1 trials in patients with that type of
diabetes
46. Phase 1 studies are closely monitored and collect information about
Pharmacodynamics in the human body.
Researchers adjust dosage regimen based on animal study data to
find out what dose of a drug can tolerate the body and what are its
acute side effects.
As a Phase 1 trial continues, researchers find out mechanism of
action, the side effects accompanying with increase in dosage, and
information about effectiveness. Almost 70% of drugs travel to the
next phase
47. Single ascending dose studies Multiple ascending dose
studies
Small group of subjects given single
dose of drug and observed for a
period of time
If Pk data is in line with predicted safe
values the dose is increased in a new
group of subjects
Continued till maximum tolerated
dose attained
A group of subjects receives multiple
low doses of the drug
Samples collected at various time
points and analyzed
Gives better understanding of
pharmacokinetics and
pharmacodynamics of the drug
48. PHASE 2: EFFICACY AND SIDE EFFECTS
Phase II trials are conducted on larger groups of patients (few
hundreds) and are aimed to evaluate the efficacy of the drug and to
ensure the Phase I safety assessments.
These trials are not sufficient to confirm whether the drug will be
therapeutic. Phase 2 studies provide with additional safety data to
the researchers.
Around 33% of drugs travel to the next phase. Most prominently,
Phase II clinical studies aid to found therapeutic doses for the large-
scale Phase III studies
49. PHASE 3: EFFICACY AND ADVERSE DRUG
REACTIONS MONITORING
Phase 3 studies deals an action benefit to a specific people or not
These studies comprise 300 to 3,000 volunteers.
Phase 3 studies deliver most of the safety data. Phase 3 studies are
conducted on large no. of volunteers and longer in duration, the
results are more probable to detect long-term or uncommon side
effects.
Around 25-30% of drugs travel to the next phase of clinical research
50. Cell or animal
studies test to
see if the new
treatment will
be safe and
will work on
people
Studies
the safety
of
medicatio
n and
treatment
or people
Studies
the
safety
and
effective
ness on
people
Studies
the
safety
effectiv
eness
and
dosing
on
people
Studies the long
term
effectiveness
and compares
new treatment
to standard
treatment on
people
51. New Drug Application
• A New Drug Application (NDA) expresses the full story of a drug molecule. Its
purpose is to verify that a drug is safe and effective for its proposed use in the
people studied.
• A drug developer must include all about a drug starting from preclinical data to
Phase 3 trial data in the NDA.
NDA also includes
Proposed labeling
Safety updates
Drug abuse information
Patent information
Institutional review board compliance information
Directions for use
52. FDA Review
• Once FDA obtains a complete NDA then FDA may require about 6 to
10 months whether to approve the NDA or not
• If FDA governs that a drug has been revealed to be safe and effective
for its proposed use, it is then essential to define the basis for
approval and direction of how to use the drug.
53. Phase 4: Post-Market Drug Safety Monitoring
Phase 4 trials are conducted when the drug has been approved by
FDA. These trials are also recognized as postmarketing surveillance to
evaluate the efficacy, cost effectiveness, and safety .
Therefore, the drug‘s safety essentially requires over the months
and even years.
FDA reviews reports of complications with prescription , to add
precautions to the dosage for more serious adverse drug reactions
55. CONCLUSION
The drug discovery and development process is a long and complicated
process. Before any newly discovered drug is placed on the market, it
must undergo extensive testing. Each success is built on many, prior
failures. Advances in understanding human biology and disease are
opening up exciting new possibilities for breakthrough in medicines
56. REFERENCES
• Deore AB, Dhumane JR, Wagh R, Sonawane R. The stages of drug discovery and
development process. Asian Journal of Pharmaceutical Research and Development. 2019
Dec 15;7(6):62-7.
• Akhondzadeh S. The importance of clinical trials in drug development. Avicenna journal
of medical biotechnology. 2016 Sep 26;8(4):151-.
• Drug discovery and development process by abhay pandey
• Importance of toxicity testing – Arome david
