Drug Development method by responsees .ppt

Drug Development method by responsees .ppt

1. DRUG DEVELOPMENT
Concerted Action

2. Drug Development:-
Drug development may be defined as series of
specialized events performed to satisfy criteria,
internal (i.e. competitive industry benchmarks)
and external (i.e. regulatory compliance), to
produce a novel drug.
Novel Drug:-
The drug that does something valuable that
presently not have been possible or that does
safely what could previously have been achieved
only with substantial risk.

3. At present, drug development consists of four
distinct stages:
1-Drug discovery
2-Preclinical development
3-Clinical development
4-Manufacturing
Cost and Time for the Drug Development:-
Discovering and bringing one new molecule
(drug) to the public typically costs a
pharmaceutical or biotechnology company from $
800 million to more than $ one billion and takes
on average 10-15 years.

4. 1-2 years
1.2
Regulatory
Approval
Submission
of full data
and review
by
regulatory
agencies
DRUG
DISCOVERY
Target
selection
Lead-finding
Lead
optimisation
Pharmacolo-
gical
Profiling
2-5 year
100 Projects
Drug
Candidate
PRECLINICAL
DEVELOPMENT
Pharmacoki
-netics
Short-term
toxicity
Formulation
Synthesis
Scale-up
1.5 year
20
compounds
CLINICAL DEVELOPMENT
Phase I
Pharmaco-
kinetics,
Tolerability
side-effects
in
healthy
volunteers
Phase II
Small-scale
Trials in
patients
To assess
efficacy
& dosage
Long-term
Toxicology
studies
Phase III
Large-scale
Controlled
clinical trials
10 5 2
Phase IV
Post
marketing
surve-
illance
1
Development
Compound
Regulatory
Submission
Drug
approved for
marketing
5-7 years
The stages of development of a “typical” new drug, a synthetic compound
being developed for systemic use.

5. Drug Discovery
1-Target Selection:-
In the past, drug discovery programs were often
based, successfully, on measuring a complex
response in vivo, like, lowering of blood glucose
level, lowering blood pressure or prevention of
experimentally induced seizures without the prior
identification of drug target.
Now-a-days, the drug discovery process is often
initiated with a decision to begin research on a
new biological target. Studies are performed to
characterize and define the target to establish the
biological rationale. So target identification is the
first step in drug development.

6. In the past, four main kinds of regulatory proteins
were commonly involved as primary drug targets,
namely:
Receptors
Enzymes
Carrier molecules (Transporters)
Ion channels
Currently available therapeutic agents are believed
to address about 120 distinct targets, but many
proteins are thought to play a role in disease for
which still no cognate drug.
In the past thirty years, the evolution of molecular

7. medicine (including recombinant DNA technology)
has led to a new pathway of drug discovery;
Pharmacogenomics.
This term encompasses all genes in the genome that
may determine drug response, desired and
undesired. Completion of Human Genome Project
in 2001 yielded a minimum of 30,000 potential
drug targets, although the functions of many of
these genes remains unknown. It is expected that
in future drug may be designed according to
individual genotype, thereby enhancing safety as
well as efficacy.

8. Now new drug could target at selected groups of
patients based on their genetic make up (basis of
pharmacogenetics). There are high expectations
that pharmacogenetics/pharmacogenomics/
pharmacoproteomics will help in identification of
subgroups of patients with a disease or syndrome
based on their genotype and in targeting of
specific drugs for patients with specific gene
variants.
Definition
Proteomics is the systematic study
of all of the proteins in a cell, tissue,
or organism.

9. Proteomics:-
A broad working definition of proteomics may be
that proteomics is a high-throughput, data-rich,
comprehensive, systematic, large-scale, and
quantitative analysis of the expression of proteins
and their associated peptides in biological/clinical
samples obtained under specific (patho)
physiological settings. Thus, proteomics provides a
unique means to gain insights into the relative
abundance of protein components present in
complex biological samples, a capability that is
important for the discovery of biomarkers and
novel drug targets.

10. Pharmacoproteomics:-
A term that is a synthesis of “pharmacology” and
“proteomics”, refers to the comprehensive
proteomics analysis that is relevant to novel drug
target discovery, drug metabolism, as well as drug
efficacy and toxicity.
BIOMARKER:-In medicine, a biomarkeris a term
often used to refer to a protein measured in blood
whose concentration reflects the severity or presence
of some disease state. More generally a biomarkeris
anything that can be used as an indicator of a
particular disease state or some other physiological
stateof an organism.

11. Drug Discovery:-
Drug discovery comes in several ways.
1-Old Approaches:-
i-Natural Products:-
a) plants:-Many plants and herbs contain
substances that have useful pharmacological
actions and new examples are continually being
discovered.
Examples: Morphine from Papaversomniferum.
Atropine (Atropabelladonna), digoxin
Antimalarialdrugs from Artemisiaspecies

12. b)Animals:-
Several drugs have been discovered from the study
of endogenous substances of animals.
Examples are insulin (originally from dog
pancreas).
Anticoagulant from medicinal leech etc.
Multinational companies now scour the world to
find leads from microorganisms (in soil or sewage
or even insects entombed) fungi, plants and
animals. Developing countries in the tropics have
luxuriant natural resources and are prominent
targets in this search.

13. ii-Chemical Modification of a Known Molecules:-
This approach obviously produces more agents
with similar basic properties having little
improvement in therapeutic value. It is in this area
that “me too” and “me again” drugs are
developed.
iii-Serendipity:-
Discoveries made by accidents and sagacity fall in
this category.
Examples penicillin by AlexenderFleming
Sildenafiloriginally developed for antianginal
property is being used in erectile dysfunction.

14. The first noted use of "serendipity" in the English
language was by Horace Walpole(1717–1792). In
a letter to Horace Mann(dated January 28th 1754)
he said he formed it from the Persian fairy tale
The Three Princes of Serendip, whose heroes
"were always making discoveries, by accidents
and sagacity, of things they were not in quest of".
The name stems from Serendip, an old name for
Ceylon (modern Sri Lanka), from Arabic
Sarandib, from SanskritSimhaladvipawhich
literally translates to "Dwelling-Place-of-Lions
Island"[3]

15. Hypoglycemic effect of sulfonamides in patients
treating typhoid fever led to the development of
structurally related sulfonylureas hypoglycemics.
IV Metabolite of Existing Drug:-
Some active metabolites of drugs have therapeutic
value and advantage over the original parent
compound e.g. Paracetamol is metabolite of
phenacetin and it is not renotoxic. Sulfasalazine is
metabolized to sulfapyridine (active antibacterial)
and 5-aminosalicylic acid.
VRandom Screening:-Random screening of
synthesized and natural product might result into
finding of lead compound.

16. VI-Combination of Drugs:-
Combination of known drugs may be exploited
to obtain the additive, synergistic or
repositioning of a known drug for a new
therapeutic use, e.g. co-trimoxazole
(combination of sulfamethoxazole and
trimethoprim).

17. 2-New or Future Techniques of Drug Discovery:-
I-Molecular Modeling:-
The technique of molecular modeling by three-dimensional
computer graphics allows the design of structures based on
known and new molecules to improve their desired, and to
eliminate undesired properties. This helps to create highly
target selective compounds.
II-Combinatorial Chemistry:-
This branch of chemistry involves the random mixing and
matching of large numbers of chemical building units
(amino acids, nucleotides, simple chemicals) to create
‘libraries’of all possible combinations. This technology
can generate billions of new compounds that are initially

18. evaluated by automated robotic High-throughput
screening devices. These devices can evaluate
thousands of compound in a day. If any
compound seems to have promising
pharmacological activity, it is then subjected to
traditional investigational laboratory methods, and
the compound is manipulated to increase
selectivity and/or potency.
III-Biotechnology (Proteins as medicines):-
Proteins are the target of most drugs and, in past,
lack of technology was the main obstacle in
exploitation of proteins (and peptides) as
medicines.

19. With the invention of technology, there is great
break through in this field. Biotechnology
involves the use of recombinant DNA
technology/genetic engineering to clone and
express human genes, for example in microbial
(Escherichi coli or yeast) cells, so that they
manufacture proteins that medicinal chemists have
not been able to synthesize. Such techniques can
deliver hormones and autocoids in commercial
amounts (like insulin, growth hormone,
erythropoietins, cell growth factors and
plasminogen activators, interferons, vaccines and
immune bodies). Two approaches are being
employed for this technology:

20. a.Transgenic Animals: Transgenic animals (that
breed true for gene) are also being developed as
models for human disease as well as production
of medicines.
b.Polymerase Chain Reaction:
This is a method of amplification that does not
require living cells; it takes place in-vitro and
can produce (in a cost effective way)
commercial quantities of pure potential
medicines.

21. IV. Genetic Medicines
In this technique synthetic oligonucleotides are
developed to target sites, DNA sequences or genes
(double-stranded DNA: triplex approach) or
messenger RNA (the antisense approach), so that
the production of disease –related proteins is
blocked. These oligonucleotides offer prospects
of treatment for cancers and viruses without
damaging the healthy tissues.

22. Anoligonucleotide(fromGreekprefixoligo-,
"havingfew,havinglittle")isashortnucleicacid
polymer,typicallywithfiftyorfewerbases.

23. V. Gene Therapy:-
Advances in molecular and cellular biology have
described the proteins that mediate numerous
disease processes, whereas the DNA technology
provides direct access to the genes that control
such events. Gene therapy has overcome the
hazards encountered in maneuvering disease
producing proteins. Gene therapy involves
selective introduction of recombinant DNA into
tissues to modify the genetic repertoire for
therapeutic purposes.

24. VI-Immunopharmacology:-
Knowledge of the molecular basis of immune
responses has made easy to define the mechanisms
by which cellular function is altered by the local
hormones or autocoids in cancer, infections,
autoimmune diseases or tissue transplant rejection.
Thus agents that augment the immune response or
selectively modify the balance of various
components of immune system are also becoming
important in the management of diseases like
cancer, AIDS etc.

25. Vii-Positron Emission Tomography (PET):-
This technique allows non-invasive
pharmacokinetic and pharmacodynamic studies in
previously inaccessible sites, e.g. the brain in
living humans and animals.
2-Lead-Finding or Identification:-
Lead Compound:
A lead compound (i.e. the leading compound, not
lead metal, for a successful new drug) in drug
discovery is a chemical substance that possesses
pharmacological or biological activity and has
potential to treat disease. The chemical structure

26. of lead compound is used as a starting point for
chemical modifications in order to improve
potency, selectivity or pharmacokinetic
parameters. Lead compounds are often found
through High-Throughput Screening or secondary
metabolites from natural sources.
After the selection of target, discovery of a new
lead substance represents the most uncertain stage
in drug development program. Until the 1970s,
the discovery of Lead Compound depended
essentially on randomly occurring parameters
such as accidental observation, fortuitous findings
or laborious screening of a large number of
molecules.

27. Since then more rational approaches, based on
knowledge of structures of endogenous
metabolites, the enzymes, the receptors, or nature of the
biochemical disorder implied in the disease, have
become available. Today human genome represents a
great mine of potentially useful targets for which
ligands have to be found.
In 1997, it was estimated that the synthesis and
screening of 100,000 compounds was required for the
discovery of single good quality lead compound and
this process could take up 2-4 years.

28. Secondary metabolitesareorganic
compoundsthat are not directly involved in the
normalgrowth,development, orreproductionof an
organism.
Secondary metabolites often play an important role
inplant defense against herbivoryand other
interspecies defenses. Humans use secondary
metabolites as medicines, flavorings, and
recreational drugs.

29. In the past, compounds were either isolated from
natural source or synthesized one by one and it
used to take weeks or even months for each
compound, but presently, the use of combinatorial
chemistry allows formation of families of several
thousands of related compounds simultaneously.
The combined application of such High Speed
Chemistryand High-Throughput Assaysystems
has reduced the lead finding period from years to
few months.
High-Throughput screening:-
This is a method for scientific experimentation
used in drug discovery and relevant to the

30. fields of biology and chemistry. Using robotics,
data processing and control software, liquid
handling devices and sensitive detectors, High
Throughput Screening (HTS) allows a researcher
to quickly conduct millions of biochemical,
genetic or pharmacological tests. Through this
process, the researcher can rapidly identify active
compounds, antibodies or genes that modulate a
particular pathway. The testing vessel of HTS is
the microtitre plate. HTS robots can test up to
100,000 compounds per day. The Ultra High-
Throughput Screening(uHTS) refers to screening
in excess of 100,000 compounds per day.

31. A patent application would be filed for a novel
compound (a composition of matter patent) that is
efficacious, or for a new and non-obvious
therapeutic use (a use patent) for a previously
known chemical entity.
Lead Optimization:-
Lead optimization aims at increasing the potency
of lead compound(s) at target site and to optimize
it with respect to selectivity and metabolic
stability.

32. In this phase broader range of assays on
different test systems are employed to compare the
potencies of various lead compounds to select the
one or more with greatest potential to be
developed into safe and effective medicine(s).
The intuitive approaches such as synthesis of
analogues and isomers and the modification of
ring systems are used for optimization. These
methods may rest on computer-assisted design,
such as identifying pharmacophores by molecular
modeling or optimizing activity by means of
SARs.
Pharmacophore[fahr´mah-ko-for″] the group of
atoms in the molecule of a drug responsible for the
drug's action.

33. Lead optimizing studies are conducted in animal
models (in vivo) and in cells in the test tube (in
vitro) to explore pharmacokinetics and
pharmacodynamics in different clinical conditions
similar to humans. Occurrence of untoward
effects and evidence of genotoxicity is also
studied in animals. It can take up to 5 years for
the completion of this phase. Infact very few
molecules, after the completion of lead
optimization, proceed to next stage of preclinical
development.

34. Preclinical Development (Studies in
animals):-
In the preclinical stage of drug development, an
investigational drug (optimized Lead Compound)
must be tested extensively in the laboratory models
to ensure that it will be safe to administer to
humans for first time. This testing may be
completed in 1-5 years, however shorter periods are
predicted. The work of this stage falls into
following categories.
i-Pharmacodynamics:-
The preclinical laboratory tests document the

35. effect of investigational drug (optimized lead
compound) in living organisms (in-vivo) in cells
in the test tube (in-vitro) or even in silico. The
objective is to investigate the actions relating to
the proposed therapeutic use and to find potential
undesirable effects on physiological functions.
These tests are performed to check that the drug
does not produce any hazardous acute effects,
such as bronchoconstriction, cardiac
dysarrhythmias, blood pressure changes and ataxia
(this is termed safe pharmacology).

36. ii-Pharmacokinetics:-
The pharmacokinetics testing includes studies on
absorption, distribution, metabolism
(biotransformation) and elimination in animals.
The program is designed to allow comparison and
extrapolation between animals and humans.
iii-Toxicology:-
Acute (single dose), chronic and sub-chronic
(repeat dose) toxicity studies are carried out to
characterize toxicological profile of the drug and
to reveal physiological and/or histopathological
changes induced by drug.

37. Generally, test be performed in two relevant
species, based on pharmacokinetic profile, one a
rodent and one non-rodent/ the duration depends
on the clinical use and is defined by Regulatory
Agencies (standard charts). The studies are used
to determine maximum non-toxic dose, effect on
weight, histological and biochemical evidence of
tissue damage (post-mortem) and other gross
changes.
iv-Genotoxicity:-
A standard battery of investigational tests is used
to study changes that a drug causes in genetic
material of individuals or cells.

38. v-Carcinogenicity:-
If a medicinal product is expected to be used for
prolonged (about six months) either continuously
or repeatedly, studies are recommended to
determine the carcinogenic potential of new drug.
vi-Reproductive & Developmental Toxicity:-
These tests study effects on adult male or female
reproductive functions, toxic and teratogenic
effects at all stages of development from
conception to sexual maturity and latent effects
when investigation drugs are given to the

39. female during pregnancy. Embryo/fetal toxicity
studies are normally conducted on two mammalian
species.
vii-Chemical & Pharmaceutical Development:-
During preclinical development, the structure,
physical and chemical characteristics and
stereochemical identity of the new drug are fully
characterized. Appropriate bioanalytical methods
are developed to assay the drug and its metabolites
in body fluids. Stability study data of compound
are collected.

40. All the results of preclinical tests are used by
experts to assess the feasibility of large scale
synthesis and purification, to assess the stability of
the compound under different conditions and to
develop a suitable formation (at least stable for six
months) to start clinical studies.
How are Investigational Drugs Tested in Human?
Testing of an investigational drug begins with
submission of information about the drugs and
application for permission to begin administration
to healthy volunteers.

41. Investigational New Drug (IND)/Clinical Trials
Exception (CTX)/Clinical Trials
Authorization (CTA) Application:-
INDs (in the U.S.A.) CTXs (in the U.K.) and
CTAs (in Australia) are examples of requests
submitted to appropriate regulatory authorities for
permission to conduct investigational research in
humans. This research can be testing of a new
dosage form or new use of a drug already
approved to be marketed.
In addition to obtaining permission from
appropriate regulatory authorities, an institutional
or Independent Review Board (IRB)or ethical
advisory boardmust approve the

42. protocol for testing as well as the informed
consent documents that volunteers sign prior to
participating in a clinical study. An IRB is
independent committee of physicians, community
advocates and others that ensures that a clinical
trial is ethical and the rights of study participants
are protected.
“ The regulatory authority may refuse permission or
require further work to be done before granting
permission|”.

43. Clinical Trial
Synonyms:-
Clinical study, interventional trial, medical
research, clinical investigation, research study.
Definition:-
Although there are many definitions of clinical
trials, they are generally considered to be
biomedical or health-related research studies in
humans that follow a pre-defined protocol.
A clinical trial may be defined as a prospective
carefully designed biomedical or behavioral
research performed in human subjects to
investigate safety, efficacy & effectiveness

44. of new drugs or combination of drugs, cells and
other biological products, surgical procedures,
radiological procedures, devices, behavioral
treatments, process-of-care changes and
preventive care to improve the diagnosis of
disease and quality of the life of the patient.
Types of Clinical Trials
1-Treatment Trials:-
In treatment trials experimental treatments, new
drugs, combination of drugs, new approaches to
surgery or radio-therapy etc are tested.

45. 2-Prevention Trials:-
This type of trials look for better ways to prevent
disease in persons who never had the disease or to
prevent the reoccurrence of the disease.. These
approaches include vaccines, medicines, minerals,
vitamins or changes in life-style.
3-Diagnostic Trials:-
These trials are performed to search for better tests
or procedures for diagnosis of a particular disease
or condition.
4-Screening Trials:-
These are conducted to find ways and tests to
detect certain diseases or health conditions.

46. 5-Supportive Care Trials (Quality of life trials):-
These trials are conducted to find ways to improve
comfort and quality of life of individuals with
chronic illness.

47. Control Study:-
A study in which the investigational drug is
compared with a treatment that has known effects.
The control group may receive either no drug,
placebo or standard treatment.
Consent:-
In any study on human beings, each subject must
be fully informed of the aims, methods, sources of
funding any possible conflicts of interest,
institutional affiliations of researcher, the
anticipated benefits and potential risks of the study
and the discomfort it may entail.

48. The subject should be informed of the right to
abstain from participation in the study or to
withdraw consent to participate at any time
without reprisal. After ensuring that the subject
has completely understood the information, the
physician then should obtain the subject’s freely
given informed consent, preferably in writing. If
the consent cannot be obtained in writing, the non-
written consent must be formally documented and
Witnessed -Article 22, Declaration of Helsinki.